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  • 51.
    Dahlgren, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Eriksson, Niklas
    Lundmark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Berne, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Variants in the HHEX gene are associated with biochemical markers for beta-cell function in the ULSAM cohort2012Article in journal (Refereed)
  • 52.
    de Miranda, Joachim R.
    et al.
    Swedish Univ Agr Sci, Dept Ecol, S-75007 Uppsala, Sweden..
    Hedman, Harald
    Swedish Univ Agr Sci, Dept Ecol, S-75007 Uppsala, Sweden..
    Onorati, Piero
    Swedish Univ Agr Sci, Dept Ecol, S-75007 Uppsala, Sweden..
    Stephan, Jorg
    Swedish Univ Agr Sci, Dept Ecol, S-75007 Uppsala, Sweden..
    Karlberg, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Vanadis Diagnost, Vetenskapsvagen 10, S-19138 Sollentuna, Sweden..
    Bylund, Helena
    Swedish Univ Agr Sci, Dept Ecol, S-75007 Uppsala, Sweden..
    Terenius, Olle
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology. Swedish Univ Agr Sci, Dept Ecol, S-75007 Uppsala, Sweden..
    Characterization of a Novel RNA Virus Discovered in the Autumnal Moth Epirrita autumnata in Sweden2017In: Viruses, E-ISSN 1999-4915, Vol. 9, no 8, article id 214Article in journal (Refereed)
    Abstract [en]

    A novel, 10 kb RNA virus-tentatively named 'Abisko virus'-was discovered in the transcriptome data of a diseased autumnal moth (Epirrita autumnata) larva, as part of a search for the possible causes of the cyclical nature and mortality associated with geometrid moth dynamics and outbreaks in northern Fennoscandia. Abisko virus has a genome organization similar to that of the insect-infecting negeviruses, but phylogenetic and compositional bias analyses also reveal strong affiliations with plant-infecting viruses, such that both the primary host origin and taxonomic identity of the virus remain in doubt. In an extensive set of larval, pupal, and adult autumnal moth and winter moth (Operophtera brumata) outbreak samples, the virus was only detected in a few adult E. autumnata moths as well as the single larval transcriptome. The Abisko virus is therefore unlikely to be a factor in the Fennoscandia geometrid population dynamics.

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  • 53. Deloukas, Panos
    et al.
    Kanoni, Stavroula
    Willenborg, Christina
    Farrall, Martin
    Assimes, Themistocles L
    Thompson, John R
    Ingelsson, Erik
    Saleheen, Danish
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Erdmann, Jeanette
    Goldstein, Benjamin A
    Stirrups, Kathleen
    König, Inke R
    Cazier, Jean-Baptiste
    Johansson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Hall, Alistair S
    Lee, Jong-Young
    Willer, Cristen J
    Chambers, John C
    Esko, Tõnu
    Folkersen, Lasse
    Goel, Anuj
    Grundberg, Elin
    Havulinna, Aki S
    Ho, Weang K
    Hopewell, Jemma C
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Kleber, Marcus E
    Kristiansson, Kati
    Lundmark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Lyytikäinen, Leo-Pekka
    Rafelt, Suzanne
    Shungin, Dmitry
    Strawbridge, Rona J
    Thorleifsson, Gudmar
    Tikkanen, Emmi
    van Zuydam, Natalie
    Voight, Benjamin F
    Waite, Lindsay L
    Zhang, Weihua
    Ziegler, Andreas
    Absher, Devin
    Altshuler, David
    Balmforth, Anthony J
    Barroso, Inês
    Braund, Peter S
    Burgdorf, Christof
    Claudi-Boehm, Simone
    Cox, David
    Dimitriou, Maria
    Do, Ron
    Doney, Alex S F
    Mokhtari, Noureddine El
    Eriksson, Per
    Fischer, Krista
    Fontanillas, Pierre
    Franco-Cereceda, Anders
    Gigante, Bruna
    Groop, Leif
    Gustafsson, Stefan
    Hager, Jörg
    Hallmans, Göran
    Han, Bok-Ghee
    Hunt, Sarah E
    Kang, Hyun M
    Illig, Thomas
    Kessler, Thorsten
    Knowles, Joshua W
    Kolovou, Genovefa
    Kuusisto, Johanna
    Langenberg, Claudia
    Langford, Cordelia
    Leander, Karin
    Lokki, Marja-Liisa
    Lundmark, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    McCarthy, Mark I
    Meisinger, Christa
    Melander, Olle
    Mihailov, Evelin
    Maouche, Seraya
    Morris, Andrew D
    Müller-Nurasyid, Martina
    Nikus, Kjell
    Peden, John F
    Rayner, N William
    Rasheed, Asif
    Rosinger, Silke
    Rubin, Diana
    Rumpf, Moritz P
    Schäfer, Arne
    Sivananthan, Mohan
    Song, Ci
    Stewart, Alexandre F R
    Tan, Sian-Tsung
    Thorgeirsson, Gudmundur
    Schoot, C Ellen van der
    Wagner, Peter J
    Wells, George A
    Wild, Philipp S
    Yang, Tsun-Po
    Amouyel, Philippe
    Arveiler, Dominique
    Basart, Hanneke
    Boehnke, Michael
    Boerwinkle, Eric
    Brambilla, Paolo
    Cambien, Francois
    Cupples, Adrienne L
    de Faire, Ulf
    Dehghan, Abbas
    Diemert, Patrick
    Epstein, Stephen E
    Evans, Alun
    Ferrario, Marco M
    Ferrières, Jean
    Gauguier, Dominique
    Go, Alan S
    Goodall, Alison H
    Gudnason, Villi
    Hazen, Stanley L
    Holm, Hilma
    Iribarren, Carlos
    Jang, Yangsoo
    Kähönen, Mika
    Kee, Frank
    Kim, Hyo-Soo
    Klopp, Norman
    Koenig, Wolfgang
    Kratzer, Wolfgang
    Kuulasmaa, Kari
    Laakso, Markku
    Laaksonen, Reijo
    Lee, Ji-Young
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ouwehand, Willem H
    Parish, Sarah
    Park, Jeong E
    Pedersen, Nancy L
    Peters, Annette
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Quertermous, Thomas
    Rader, Daniel J
    Salomaa, Veikko
    Schadt, Eric
    Shah, Svati H
    Sinisalo, Juha
    Stark, Klaus
    Stefansson, Kari
    Trégouët, David-Alexandre
    Virtamo, Jarmo
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wareham, Nicholas
    Zimmermann, Martina E
    Nieminen, Markku S
    Hengstenberg, Christian
    Sandhu, Manjinder S
    Pastinen, Tomi
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Hovingh, G Kees
    Dedoussis, George
    Franks, Paul W
    Lehtimäki, Terho
    Metspalu, Andres
    Zalloua, Pierre A
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Schreiber, Stefan
    Ripatti, Samuli
    Blankenberg, Stefan S
    Perola, Markus
    Clarke, Robert
    Boehm, Bernhard O
    O'Donnell, Christopher
    Reilly, Muredach P
    März, Winfried
    Collins, Rory
    Kathiresan, Sekar
    Hamsten, Anders
    Kooner, Jaspal S
    Thorsteinsdottir, Unnur
    Danesh, John
    Palmer, Colin N A
    Roberts, Robert
    Watkins, Hugh
    Schunkert, Heribert
    Samani, Nilesh J
    Large-scale association analysis identifies new risk loci for coronary artery disease2013In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 45, no 1, p. 25-33Article in journal (Refereed)
    Abstract [en]

    Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r2 < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.

  • 54.
    den Hoed, Marcel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Strawbridge, Rona J
    Almgren, Peter
    Gustafsson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Engström, Gunnar
    de Faire, Ulf
    Hedblad, Bo
    Humphries, Steve E
    Lindgren, Cecilia M
    Morris, Andrew P
    Östling, Gerd
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Tremoli, Elena
    Hamsten, Anders
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Melander, Olle
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    GWAS-identified loci for coronary heart disease are associated with intima-media thickness and plaque presence at the carotid artery bulb2015In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 239, no 2, p. 304-310Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Large-scale genome-wide association studies (GWAS) have so far identified 45 loci that are robustly associated with coronary heart disease (CHD) in data from adult men and women of European descent.

    OBJECTIVES: To examine whether the CHD-associated loci are associated with measures of atherosclerosis in data from up to 9582 individuals of European ancestry.

    METHODS: Forty-five SNPs representing the CHD-associated loci were genotyped in middle-aged to elderly individuals of European descent from four independent population-based studies (IMPROVE, MDC-CC, ULSAM and PIVUS). Intima-media thickness (IMT) was measured by external B-mode ultrasonography at the far wall of the bulb (sinus) and common carotid artery. Plaque presence was defined as a maximal IMT of the bulb >1.5 mm. We meta-analysed single-SNP associations across the four studies, and combined them in a genetic predisposition score. We subsequently examined the association of the genetic predisposition score with prevalent CHD and the three indices of atherosclerosis, adjusting for sex, age and Framingham risk factors.

    RESULTS: As anticipated, the genetic predisposition score was associated with prevalent CHD, with each additional risk allele increasing the odds of disease by 5.5% (p = 4.1 × 10(-6)). Moreover, each additional CHD-risk allele across the 45 loci was associated with a 0.24% increase in IMT (p = 4.0 × 10(-3)), and with a 2.8% increased odds of plaque presence (p = 7.4 × 10(-6)) at the far wall of the bulb. The genetic predisposition score was not associated with IMT of the common carotid artery (p = 0.47).

    CONCLUSIONS: Our results suggest that the association between the 45 previously identified loci and CHD at least partly acts through atherosclerosis.

  • 55.
    Diamanti, Klev
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Inda Díaz, Juan Salvador
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Raine, Amanda
    Chalmers Univ Technol & Univ Gothenburg, Dept Math Sci, Gothenburg, Sweden..
    Pan, Gang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wadelius, Claes
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Cavalli, Marco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Single nucleus transcriptomics data integration recapitulates the major cell types in human liver2021In: Hepatology Research, ISSN 1386-6346, E-ISSN 1872-034X, Vol. 51, no 2, p. 233-238Article in journal (Refereed)
    Abstract [en]

    Aim: The aim of this study was to explore the benefits of data integration from different platforms for single nucleus transcriptomics profiling to characterize cell populations in human liver.

    Methods: We generated single-nucleus RNA sequencing data from Chromium 10X Genomics and Drop-seq for a human liver sample. We utilized state of the art bioinformatics tools to undertake a rigorous quality control and to integrate the data into a common space summarizing the gene expression variation from the respective platforms, while accounting for known and unknown confounding factors.

    Results: Analysis of single nuclei transcriptomes from both 10X and Drop-seq allowed identification of the major liver cell types, while the integrated set obtained enough statistical power to separate a small population of inactive hepatic stellate cells that was not characterized in either of the platforms.

    Conclusions: Integration of droplet-based single nucleus transcriptomics data enabled identification of a small cluster of inactive hepatic stellate cells that highlights the potential of our approach. We suggest single-nucleus RNA sequencing integrative approaches could be utilized to design larger and cost-effective studies.

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  • 56.
    Diamanti, Klev
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Visvanathar, Robin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Pereira, Maria J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Cavalli, Marco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pan, Gang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Kumar, Chanchal
    Translational Science & Experimental Medicine, Early Cardiovascular, Renal and Metabolism, R&D BioPharmaceuticals, AstraZeneca; Karolinska Institute/AstraZeneca Integrated CardioMetabolic Centre (KI/AZ ICMC), Department of Medicine.
    Stanko, Stanko
    Pharmaceutical Technology & Development, AstraZeneca AB; Department of Medicine, Sahlgrenska University Hospital, Gothenburg.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Fall, Tove
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Lind, Lars
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wadelius, Claes
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Komorowski, Jan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Integration of whole-body PET/MRI with non-targeted metabolomics provides new insights into insulin sensitivity of various tissuesManuscript (preprint) (Other academic)
    Abstract [en]

    Background: Alteration of various metabolites has been linked to type 2 diabetes (T2D) and insulin resistance. However, identifying significant associations between metabolites and tissue-specific alterations is challenging and requires a multi-omics approach. In this study, we aimed at discovering associations of metabolites from subcutaneous adipose tissue (SAT) and plasma with the volume, the fat fraction (FF) and the insulin sensitivity (Ki) of specific tissues using [18F]FDG PET/MRI.

    Materials and Methods: In a cohort of 42 subjects with different levels of glucose tolerance (normal, prediabetes and T2D) matched for age and body-mass-index (BMI) we calculated associations between parameters of whole-body FDG PET/MRI during clamp and non-targeted metabolomics profiling for SAT and blood plasma. We also used a rule-based classifier to identify a large collection of prevalent patterns of co-dependent metabolites that characterize non-diabetes (ND) and T2D.

    Results: The plasma metabolomics profiling revealed that hepatic fat content was positively associated with tyrosine, and negatively associated with lysoPC(P-16:0). Ki in visceral adipose tissue (VAT) and SAT, was positively associated with several species of lysophospholipids while the opposite applied to branched-chain amino acids (BCAA) and their intermediates. The adipose tissue metabolomics revealed a positive association between non-esterified fatty acids and, VAT and liver Ki. On the contrary, bile acids and carnitines in adipose tissue were inversely associated with VAT Ki. Finally, we presented a transparent machine-learning model that predicted ND or T2D in “unseen” data with an accuracy of 78%.

    Conclusions: Novel associations of several metabolites from SAT and plasma with the FF, volume and insulin senstivity of various tissues throughout the body were discovered using PET/MRI and a new integrative multi-omics approach. A promising computational model that predicted ND and T2D with high certainty, suggested novel non-linear interdependencies of metabolites.

  • 57. Dick, Katherine J.
    et al.
    Nelson, Christopher P.
    Tsaprouni, Loukia
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Aissi, Dylan
    Wahl, Simone
    Meduri, Eshwar
    Morange, Pierre-Emmanuel
    Gagnon, France
    Grallert, Harald
    Waldenberger, Melanie
    Peters, Annette
    Erdmann, Jeanette
    Hengstenberg, Christian
    Cambien, Francois
    Goodall, Alison H.
    Ouwehand, Willem H.
    Schunkert, Heribert
    Thompson, John R.
    Spector, Tim D.
    Gieger, Christian
    Tregout, David-Alexandre
    Deloukas, Panos
    Samani, Nilesh J.
    DNA methylation and body-mass index: a genome-wide analysis2014In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 383, no 9933, p. 1990-1998Article in journal (Refereed)
    Abstract [en]

    Background Obesity is a major health problem that is determined by interactions between lifestyle and environmental and genetic factors. Although associations between several genetic variants and body-mass index (BMI) have been identified, little is known about epigenetic changes related to BMI. We undertook a genome-wide analysis of methylation at CpG sites in relation to BMI. Methods 479 individuals of European origin recruited by the Cardiogenics Consortium formed our discovery cohort. We typed their whole-blood DNA with the Infinium HumanMethylation450 array. After quality control, methylation levels were tested for association with BMI. Methylation sites showing an association with BMI at a false discovery rate q value of 0.05 or less were taken forward for replication in a cohort of 339 unrelated white patients of northern European origin from the MARTHA cohort. Sites that remained significant in this primary replication cohort were tested in a second replication cohort of 1789 white patients of European origin from the KORA cohort. We examined whether methylation levels at identified sites also showed an association with BMI in DNA from adipose tissue (n=635) and skin (n=395) obtained from white female individuals participating in the MuTHER study. Finally, we examined the association of methylation at BMI-associated sites with genetic variants and with gene expression. Findings 20 individuals from the discovery cohort were excluded from analyses after quality-control checks, leaving 459 participants. After adjustment for covariates, we identified an association (q value <= 0.05) between methylation at five probes across three different genes and BMI. The associations with three of these probes-cg22891070, cg27146050, and cg16672562, all of which are in intron 1 of HIF3A-were confirmed in both the primary and second replication cohorts. For every 0.1 increase in methylation beta value at cg22891070, BMI was 3.6% (95% CI 2.4-4.9) higher in the discovery cohort, 2.7% (1.2-4.2) higher in the primary replication cohort, and 0.8% (0.2-1.4) higher in the second replication cohort. For the MuTHER cohort, methylation at cg22891070 was associated with BMI in adipose tissue (p=1.72 x 10(-5)) but not in skin (p=0.882). We observed a significant inverse correlation (p=0.005) between methylation at cg22891070 and expression of one HIF3A gene-expression probe in adipose tissue. Two single nucleotide polymorphisms-rs8102595 and rs3826795-had independent associations with methylation at cg22891070 in all cohorts. However, these single nucleotide polymorphisms were not significantly associated with BMI. Interpretation Increased BMI in adults of European origin is associated with increased methylation at the HIF3A locus in blood cells and in adipose tissue. Our findings suggest that perturbation of hypoxia inducible transcription factor pathways could have an important role in the response to increased weight in people.

  • 58.
    Dideberg, Vinciane
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Kristjansdottir, Gudlaug
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Milani, Lili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Libioulle, C.
    Sigurdsson, Snaevar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Louis, E.
    Wiman, Ann-Christin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Vermeire, S.
    Rutgeerts, P.
    Belaiche, J.
    Franchimont, D.
    Van Gossum, A.
    Bours, V.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    An insertion-deletion polymorphism in the Interferon Regulatory Factor 5 (IRF5) gene confers risk of inflammatory bowel diseases2007In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 16, no 24, p. 3008-3016Article in journal (Refereed)
    Abstract [en]

    The interferon regulatory factor 5 (IRF5) gene encodes a transcriptionfactor that plays an important role in the innate as well asin the cell-mediated immune responses. The IRF5 gene has beenshown to be associated with systemic lupus erythematosus andrheumatoid arthritis. We studied whether the IRF5 gene is alsoassociated with inflammatory bowel diseases (IBD), Crohn disease(CD) and ulcerative colitis (UC). Twelve polymorphisms in theIRF5 gene were genotyped in a cohort of 1007 IBD patients (748CD and 241 UC) and 241 controls from Wallonia, Belgium. Thesame polymorphisms were genotyped in a confirmatory cohort of311 controls and 687 IBD patients (488 CD and 192 UC) from Leuven,Belgium. A strong signal of association (p = 1.9 x 10–5,OR: 1.81 (1.37-2.39)) with IBD was observed for a 5bp indel(CGGGG) polymorphism in the promoter region of the IRF5 gene.The association was detectable (p = 6.8 x 10–4) also inCD patients, and was particularly strong among the UC patients(p = 5.3 x 10–8, OR 2.42 (1.76 -3.34)). The associationof the CGGGG indel was confirmed in the second cohort (p = 3.2x 10–5, OR 1.59 (1.28 - 1.98)). The insertion of one CGGGGunit is predicted to create an additional binding site for thetranscription factor SP1. Using an electrophoretic mobilityshift assay we show allele-specific differences in protein bindingto this repetitive DNA-stretch, which suggest a potential functionrole for the CGGGG indel.

  • 59.
    Dumanski, Jan P.
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Medical University of Gdańsk.
    Halvardson, Jonatan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Davies, Hanna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Rychlicka-Buniowska, Edyta
    Mattisson, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Torabi Moghadam, Behrooz
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Nagy, Noemi
    Węglarczyk, Kazimierz
    Bukowska-Strakova, Karolina
    Danielsson, Marcus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Olszewski, Paweł
    Piotrowski, Arkadiusz
    Oerton, Erin
    Ambicka, Aleksandra
    Przewoźnik, Marcin
    Bełch, Łukasz
    Grodzicki, Tomasz
    Chłosta, Piotr L.
    Imreh, Stefan
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Nordlund, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gyllensten, Ulf
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Johansson, Åsa
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Józkowicz, Alicja
    Siedlar, Maciej
    Klich-Rączka, Alicja
    Jaszczyński, Janusz
    Enroth, Stefan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Baran, Jarosław
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Perry, John R. B.
    Ryś, Janusz
    Forsberg, Lars A.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Immune cells lacking Y chromosome show dysregulation of autosomal gene expression2021In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 78, no 8, p. 4019-4033Article in journal (Refereed)
    Abstract [en]

    Epidemiological investigations show that mosaic loss of chromosome Y (LOY) in leukocytes is associated with earlier mortality and morbidity from many diseases in men. LOY is the most common acquired mutation and is associated with aberrant clonal expansion of cells, yet it remains unclear whether this mosaicism exerts a direct physiological effect. We studied DNA and RNA from leukocytes in sorted- and single-cells in vivo and in vitro. DNA analyses of sorted cells showed that men diagnosed with Alzheimer’s disease was primarily affected with LOY in NK cells whereas prostate cancer patients more frequently displayed LOY in CD4 + T cells and granulocytes. Moreover, bulk and single-cell RNA sequencing in leukocytes allowed scoring of LOY from mRNA data and confirmed considerable variation in the rate of LOY across individuals and cell types. LOY-associated transcriptional effect (LATE) was observed in ~ 500 autosomal genes showing dysregulation in leukocytes with LOY. The fraction of LATE genes within specific cell types was substantially larger than the fraction of LATE genes shared between different subsets of leukocytes, suggesting that LOY might have pleiotropic effects. LATE genes are involved in immune functions but also encode proteins with roles in other diverse biological processes. Our findings highlight a surprisingly broad role for chromosome Y, challenging the view of it as a “genetic wasteland”, and support the hypothesis that altered immune function in leukocytes could be a mechanism linking LOY to increased risk for disease.

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  • 60.
    Duran-Ferrer, Marti
    et al.
    Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain.;CIBERONC, Ctr Invest Biomed Red Canc, Madrid, Spain..
    Clot, Guillem
    Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain.;CIBERONC, Ctr Invest Biomed Red Canc, Madrid, Spain..
    Nadeu, Ferran
    Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain.;CIBERONC, Ctr Invest Biomed Red Canc, Madrid, Spain..
    Beekman, Renee
    Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain.;CIBERONC, Ctr Invest Biomed Red Canc, Madrid, Spain..
    Baumann, Tycho
    CIBERONC, Ctr Invest Biomed Red Canc, Madrid, Spain.;IDIBAPS, Hosp Clin, Serv Hematol, Barcelona, Spain..
    Nordlund, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Marincevic-Zuniga, Yanara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lönnerholm, Gudmar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Neuropediatrics/Paediatric oncology.
    Rivas-Delgado, Alfredo
    Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain.;IDIBAPS, Hosp Clin, Serv Hematol, Barcelona, Spain..
    Martin, Silvia
    Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain.;CIBERONC, Ctr Invest Biomed Red Canc, Madrid, Spain..
    Ordonez, Raquel
    CIBERONC, Ctr Invest Biomed Red Canc, Madrid, Spain.;IDISNA, Ctr Invest Med Aplicada CIMA, Pamplona, Spain..
    Castellano, Giancarlo
    Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain..
    Kulis, Marta
    Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain..
    Queiros, Ana C.
    Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain..
    Lee, Seung-Tae
    Yonsei Univ, Coll Med, Dept Lab Med, Seoul, South Korea..
    Wiemels, Joseph
    Univ Southern Calif, Ctr Genet Epidemiol, Los Angeles, CA 90007 USA..
    Royo, Romina
    Univ Barcelona, Spanish Natl Bioinformat Inst, Inst Recerca Biomed IRB, Programa Conjunto Biol Computac,Barcelona Superco, Barcelona, Spain..
    Puiggros, Montserrat
    Univ Barcelona, Spanish Natl Bioinformat Inst, Inst Recerca Biomed IRB, Programa Conjunto Biol Computac,Barcelona Superco, Barcelona, Spain..
    Lu, Junyan
    European Mol Biol Lab EMBL, Heidelberg, Germany..
    Gine, Eva
    Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain.;CIBERONC, Ctr Invest Biomed Red Canc, Madrid, Spain.;IDIBAPS, Hosp Clin, Serv Hematol, Barcelona, Spain..
    Bea, Silvia
    Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain.;CIBERONC, Ctr Invest Biomed Red Canc, Madrid, Spain.;Ohio State Univ, Dept Internal Med, Div Hematol, Columbus, OH 43210 USA..
    Jares, Pedro
    Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain.;CIBERONC, Ctr Invest Biomed Red Canc, Madrid, Spain.;Ohio State Univ, Dept Internal Med, Div Hematol, Columbus, OH 43210 USA..
    Agirre, Xabier
    CIBERONC, Ctr Invest Biomed Red Canc, Madrid, Spain.;IDISNA, Ctr Invest Med Aplicada CIMA, Pamplona, Spain..
    Prosper, Felipe
    CIBERONC, Ctr Invest Biomed Red Canc, Madrid, Spain.;IDISNA, Ctr Invest Med Aplicada CIMA, Pamplona, Spain.;Univ Navarra, Clin Univ Navarra, Hematol & Cell Therapy Dept, Pamplona, Spain..
    Lopez-Otin, Carlos
    CIBERONC, Ctr Invest Biomed Red Canc, Madrid, Spain.;Univ Oviedo, Inst Univ Oncol IUOPA, Dept Bioquim & Biol Mol, Oviedo, Spain..
    Puente, Xose S.
    CIBERONC, Ctr Invest Biomed Red Canc, Madrid, Spain.;Univ Oviedo, Inst Univ Oncol IUOPA, Dept Bioquim & Biol Mol, Oviedo, Spain..
    Oakes, Christopher C.
    Ohio State Univ, Dept Internal Med, Div Hematol, Columbus, OH 43210 USA..
    Zenz, Thorsten
    Ohio State Univ, Dept Internal Med, Div Hematol, Columbus, OH 43210 USA.;Univ Hosp Zurich, Dept Med Oncol & Hematol, Zurich, Switzerland.;Univ Zurich, Zurich, Switzerland..
    Delgado, Julio
    Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain.;CIBERONC, Ctr Invest Biomed Red Canc, Madrid, Spain.;IDIBAPS, Hosp Clin, Serv Hematol, Barcelona, Spain..
    Lopez-Guillermo, Armando
    Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain.;CIBERONC, Ctr Invest Biomed Red Canc, Madrid, Spain.;IDIBAPS, Hosp Clin, Serv Hematol, Barcelona, Spain..
    Campo, Elias
    Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain.;CIBERONC, Ctr Invest Biomed Red Canc, Madrid, Spain.;Univ Barcelona, Fac Med, Dept Fonaments Clin, Barcelona, Spain..
    Ignacio Martin-Subero, Jose
    Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain.;CIBERONC, Ctr Invest Biomed Red Canc, Madrid, Spain.;Univ Barcelona, Fac Med, Dept Fonaments Clin, Barcelona, Spain.;Inst Catalana Recerca & Estudis Avancats ICREA, Barcelona, Spain..
    The proliferative history shapes the DNA methylome of B-cell tumors and predicts clinical outcome2020In: NATURE CANCER, ISSN 2662-1347, Vol. 1, no 11, p. 1066-1081Article in journal (Refereed)
    Abstract [en]

    We report a systematic analysis of the DNA methylation variability in 1,595 samples of normal cell subpopulations and 14 tumor subtypes spanning the entire human B-cell lineage. Differential methylation among tumor entities relates to differences in cellular origin and to de novo epigenetic alterations, which allowed us to build an accurate machine learning-based diagnostic algorithm. We identify extensive individual-specific methylation variability in silenced chromatin associated with the proliferative history of normal and neoplastic B cells. Mitotic activity generally leaves both hyper- and hypomethylation imprints, but some B-cell neoplasms preferentially gain or lose DNA methylation. We construct a DNA-methylation-based mitotic clock, called epiCMIT, whose lapse magnitude represents a strong independent prognostic variable in B-cell tumors and is associated with particular driver genetic alterations. Our findings reveal DNA methylation as a holistic tracer of B-cell tumor developmental history, with implications in differential diagnosis and the prediction of clinical outcome. Martin-Subero and colleagues analyze DNA methylation patterns in B-cell tumors and their normal cells of origin, and develop epiCMIT, a methylation-based mitotic clock with prognostic relevance.

  • 61. Edvardsen, H.
    et al.
    Brunsvig, P F.
    Solvang, H.
    Tsalenko, A.
    Andersen, A.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Yakhini, Z.
    Børresen-Dale, A-L.
    Olsen, H.
    Aamdal, S.
    Kristensen, V. N.
    SNPs in genes coding for ROS metabolism and signalling in association with docetaxel clearance2010In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 10, no 6, p. 513-523Article in journal (Refereed)
    Abstract [en]

    The dose of docetaxel is currently calculated based on body surface area and does not reflect the pharmacokinetic, metabolic potential or genetic background of the patients. The influence of genetic variation on the clearance of docetaxel was analysed in a two-stage analysis. In step one, 583 single-nucleotide polymorphisms (SNPs) in 203 genes were genotyped on samples from 24 patients with locally advanced non-small cell lung cancer. We found that many of the genes harbour several SNPs associated with clearance of docetaxel. Most notably these were four SNPs in EGF, three SNPs in PRDX4 and XPC, and two SNPs in GSTA4, TGFBR2, TNFAIP2, BCL2, DPYD and EGFR. The multiple SNPs per gene suggested the existence of common haplotypes associated with clearance. These were confirmed with detailed haplotype analysis. On the basis of analysis of variance (ANOVA), quantitative mutual information score (QMIS) and Kruskal-Wallis (KW) analysis SNPs significantly associated with clearance of docetaxel were confirmed for GSTA4, PRDX4, TGFBR2 and XPC and additional putative markers were found in CYP2C8, EPHX1, IGF2, IL1R2, MAPK7, NDUFB4, TGFBR3, TPMT (2 SNPs), (P<0.05 or borderline significant for all three methods, 14 SNPs in total). In step two, these 14 SNPs were genotyped in additional 9 samples and the results combined with the genotyping results from the first step. For 7 of the 14 SNPs, the results are still significant/borderline significant by all three methods: ANOVA, QMIS and KW analysis strengthening our hypothesis that they are associated with the clearance of docetaxel..

  • 62. Edvardsen, Hege
    et al.
    Alaes, Grethe Irene Grenaker
    Tsalenko, Anya
    Mulcahy, Tanya
    Yuryev, Anton
    Lindersson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Lien, Sigbjörn
    Omholt, Stig
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Borresen-Dale, Anne-Lise
    Kristensen, Vessela N.
    Experimental validation of data mined single nucleotide polymorphisms from several databases and consecutive dbSNP builds2006In: Pharmacogenetics & Genomics, ISSN 1744-6872, E-ISSN 1744-6880, Vol. 16, no 3, p. 207-217Article in journal (Refereed)
    Abstract [en]

    Rapid development in the annotation of human genetic variation has increased the numbers of single nucleotide polymorphisms (SNPs) in candidate genes by several orders of magnitude. The selection of both useful target SNPs; for disease-gene association studies and SNPs associated with the treatment response is therefore an increasingly challenging task. We describe a workflow for selecting SNPs based on their putative function and frequency in candidate genes extracted from PubMed resources. The annotation of each SNP and its frequency in a Caucasian population was assessed in several databases. Approximately 4000 SNPs were identified from an initial 233 candidate genes. In a case study, we performed actual genotyping of 1030 of these SNPs in 213 genes and obtained 710 successfully genotyped SNPs. Using the flow-chart outlined here, only 87 SNPs were monomorphic (approximately 12%). This study reports the frequency of SNPs in a Caucasian population, selected in silico, using a candidate gene approach and validated by actually genotyping 193 individuals. The selected genotypes represent a valuable set of verified candidate SNPs for pharmacogenetic studies in Caucasian populations.

  • 63. Edvardsen, Hege
    et al.
    Landmark-Høyvik, Hege
    Reinertsen, Kristin V
    Zhao, Xi
    Grenaker-Alnæs, Grethe Irene
    Nebdal, Daniel
    Syvänen, Ann-Christine
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Rødningen, Olaug
    Alsner, Jan
    Overgaard, Jens
    Borresen-Dale, Anne-Lise
    Fosså, Sophie D
    Kristensen, Vessela N
    SNP in TXNRD2 Associated With Radiation-Induced Fibrosis: A Study of Genetic Variation in Reactive Oxygen Species Metabolism and Signaling.2013In: International journal of radiation oncology, biology, physics, ISSN 1879-355x, Vol. 86, no 4, p. 791-9Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The aim of the study was to identify noninvasive markers of treatment-induced side effects. Reactive oxygen species (ROS) are generated after irradiation, and genetic variation in genes related to ROS metabolism might influence the level of radiation-induced adverse effects (AEs).

    METHODS AND MATERIALS: 92 breast cancer (BC) survivors previously treated with hypofractionated radiation therapy were assessed for the AEs subcutaneous atrophy and fibrosis, costal fractures, lung fibrosis, pleural thickening, and telangiectasias (median follow-up time 17.1 years). Single-nucleotide polymorphisms (SNPs) in 203 genes were analyzed for association to AE grade. SNPs associated with subcutaneous fibrosis were validated in an independent BC survivor material (n=283). The influence of the studied genetic variation on messenger ribonucleic acid (mRNA) expression level of 18 genes previously associated with fibrosis was assessed in fibroblast cell lines from BC patients.

    RESULTS: Subcutaneous fibrosis and atrophy had the highest correlation (r=0.76) of all assessed AEs. The nonsynonymous SNP rs1139793 in TXNRD2 was associated with grade of subcutaneous fibrosis, the reference T-allele being more prevalent in the group experiencing severe levels of fibrosis. This was confirmed in another sample cohort of 283 BC survivors, and rs1139793 was found significantly associated with mRNA expression level of TXNRD2 in blood. Genetic variation in 24 ROS-related genes, including EGFR, CENPE, APEX1, and GSTP1, was associated with mRNA expression of 14 genes previously linked to fibrosis (P≤.005).

    CONCLUSION: Development of subcutaneous fibrosis can be associated with genetic variation in the mitochondrial enzyme TXNRD2, critically involved in removal of ROS, and maintenance of the intracellular redox balance.

  • 64.
    Ehret, Georg B.
    et al.
    Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Baltimore, MD USA; Univ Hosp Geneva, Dept Med, Cardiol, Geneva, Switzerland.
    Ferreira, Teresa
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.
    Chasman, Daniel I.
    Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA; Harvard Med Sch, Boston, MA USA.
    Jackson, Anne U.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Schmidt, Ellen M.
    Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA..
    Johnson, Toby
    Queen Mary Univ London, William Harvey Res Inst, Clin Pharmacol, London, England.;GlaxoSmithKline, Stevenage, Herts, England..
    Thorleifsson, Gudmar
    deCODE Genet Amgen Inc, Reykjavik, Iceland..
    Luan, Jian'an
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge Biomed Campus, Cambridge, England..
    Donnelly, Louise A.
    Univ Dundee, Ninewells Hosp & Med Sch, Med Res Inst, Dundee, Scotland..
    Kanoni, Stavroula
    Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England..
    Petersen, Ann -Kristin
    Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany..
    Pihurl, Vasyl
    Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Baltimore, MD USA..
    Strawbridge, Rona J.
    Karolinska Inst, Dept Med, Cardiovasc Res Unit, Ctr Mol Med, Stockholm, Sweden.;Karolinska Univ Hosp Solna, Ctr Mol Med, Stockholm, Sweden..
    Shungin, Dmitry
    Umeå Univ, Dept Publ Hlth & Clin Med, Umeå, Sweden.;Lund Univ, Genet & Mol Epidemiol Unit, Dept Clin Sci, Malmö, Sweden.;Umeå Univ, Dept Odontol, Umeå, Sweden..
    Hughes, Maria F.
    Queens Univ Belfast, Ctr Excellence Publ Hlth, Belfast, Antrim, North Ireland..
    Meirelles, Osorio
    NIA, Genet Lab, Intramural Res Program, US Natl Inst Hlth, Baltimore, MD 21224 USA..
    Kaakinen, Marika
    Imperial Coll London, Sch Publ Hlth, Hammersmith Hosp, Dept Genom Common Dis, London, England..
    Bouatia-Naji, Nabila
    INSERM UMR 970, Paris Cardiovasc Res Ctr PARCC, Paris, France.;Univ Paris 05, Sorbonne Paris Cite, Paris, France..
    Kristiansson, Kati
    Natl Inst Hlth & Welf, Helsinki, Finland.;Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland..
    Shah, Sonia
    UCL, Dept Epidemiol & Publ Hlth, Genet Epidemiol Grp, London, England..
    Kleber, Marcus E.
    Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany..
    Guo, Xiuqing
    Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA.;Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA..
    Lyytikainen, Leo-Pekka
    Fimlab Labs, Dept Clin Chem, Tampere, Finland.;Univ Tampere, Dept Clin Chem, Sch Med, Tampere, Finland..
    Fava, Cristiano
    Lund Univ, Dept Internal Med, Malmö, Sweden.;Univ Verona, Dept Med, Verona, Italy..
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Nolte, Ilja M.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Magnusson, Patrik K.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Salfati, Elias L.
    Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA..
    Rallidis, Loukianos S.
    Univ Athens, Sch Med, Attikon Hosp, Dept Cardiol 2, Athens, Greece..
    Theusch, Elizabeth
    Childrens Hosp Oakland Res Inst, Oakland, CA USA..
    Smith, Andrew J. P.
    UCL, Inst Cardiovasc Sci, Ctr Cardiovasc Genet, London, England..
    Folkersen, Lasse
    Karolinska Inst, Dept Med, Cardiovasc Res Unit, Ctr Mol Med, Stockholm, Sweden..
    Witkowska, Kate
    Queen Mary Univ London, William Harvey Res Inst, Clin Pharmacol, London, England.;Queen Mary Univ London, NIHR Barts Cardiovasc Biomed Res Unit, London, England..
    Pers, Tune H.
    Boston Childrens Hosp, Div Endocrinol, Boston, MA USA.;Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA USA.;Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, Metab Sect, Genet,Fac Hlth & Med Sci, Copenhagen, Denmark.;Statens Serum Inst, Dept Epidemiol Res, Copenhagen, Denmark..
    Joehanes, Roby
    NHLBI, Framingham Heart Study, Framingham, MA USA..
    Kim, Stuart K.
    Stanford Univ, Med Ctr, Dept Dev Biol & Genet, Stanford, CA 94305 USA..
    Lataniotis, Lazaros
    Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England..
    Jansen, Rick
    Vrije Univ Amsterdam, Dept Psychiat, Med Ctr, Amsterdam, Netherlands..
    Johnson, Andrew D.
    NHLBI, Framingham Heart Study, Framingham, MA USA.;NHLBI, Cardiovasc Epidemiol & Human Genom Branch, Bldg 10, Bethesda, MD 20892 USA..
    Warren, Helen
    Queen Mary Univ London, William Harvey Res Inst, Clin Pharmacol, London, England.;Queen Mary Univ London, NIHR Barts Cardiovasc Biomed Res Unit, London, England..
    Kim, Young Jin
    Natl Inst Hlth, Ctr Genome Sci, Osong Hlth Technol Adm Complex, Chungcheongbuk Do, South Korea..
    Zhao, Wei
    Univ Penn, Dept Med, Div Translat Med & Human Genet, Philadelphia, PA 19104 USA..
    Wu, Ying
    Univ N Carolina, Dept Genet, Chapel Hill, NC USA..
    Tayo, Bamidele O.
    Loyola Univ, Chicago Stritch Sch Med, Dept Publ Hlth Sci, Maywood, IL 60153 USA..
    Bochud, Murielle
    CHU Vaudois, Inst Social & Prevent Med IUMSP, Lausanne, Switzerland.;Univ Lausanne, Lausanne, Switzerland..
    Absher, Devin
    HudsonAlpha Inst Biotechnol, Huntsville, AL USA..
    Adair, Linda S.
    Univ N Carolina, Dept Nutr, Chapel Hill, NC USA..
    Amin, Najaf
    Erasmus MC, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands..
    Arkingl, Dan E.
    Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Baltimore, MD USA..
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Baldassarre, Damian
    Univ Milan, Dipartimento Sci Farmacol & Biomol, Milan, Italy.;IRCCS, Ctr Cardiol Monzino, Milan, Italy..
    Balkau, Beverley
    Univ Paris 11, Ctr Res Epidemiol & Populat Hlth, INSERM U1018, URMS 1018, Villejuif, France..
    Bandinelli, Stefania
    ASF, Geriatr Unit, Florence, Italy..
    Barnes, Michael R.
    Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England.;Queen Mary Univ London, NIHR Barts Cardiovasc Biomed Res Unit, London, England..
    Barroso, Ines
    Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton, England.;Univ Cambridge, Inst Metab Sci, Addenbrookes Hosp, Metab Res Labs, Cambridge, England.;Addenbrookes Hosp, NIHR Cambridge Biomed Res Ctr, Inst Metab Sci, Cambridge, England..
    Bevan, Stephen
    Lincoln Univ, Joseph Banks Labs, Sch Life Sci, Lincoln, England..
    Bis, Joshua C.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA..
    Bjornsdottir, Gyda
    deCODE Genet Amgen Inc, Reykjavik, Iceland..
    Boehnke, Michael
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Boerwinkle, Eric
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Human Genet Ctr, Houston, TX 77030 USA..
    Bonnycastle, Lori L.
    NHGRI, Med Genom & Metab Genet Branch, US Natl Inst Hlth, Bethesda, MD 20892 USA..
    Boomsma, Dorret I.
    Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands..
    Bornstein, Stefan R.
    Univ Dresden, Med Fac Carl Gustav Carus, Dept Med 3, Dresden, Germany..
    Brown, Morris J.
    Queen Mary Univ London, Barts Heart Ctr, William Harvey Res Inst, London, England..
    Burnier, Michel
    CHU Vaudois, Nephrol, Lausanne, Switzerland.;Univ Lausanne, Lausanne, Switzerland..
    Cabrera, Claudia P.
    Queen Mary Univ London, William Harvey Res Inst, Clin Pharmacol, London, England.;Queen Mary Univ London, NIHR Barts Cardiovasc Biomed Res Unit, London, England..
    Chambers, John C.
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.;Imperial Coll Healthcare NHS Trust, London, England..
    Chang, I-Shou
    Natl Inst Canc Res, Natl Hlth Res Inst, Zhunan Town, Taiwan..
    Cheng, Ching-Yu
    Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Duke NUS Grad Med Sch Singapore, Singapore, Singapore.;Natl Univ Singapore, Dept Ophthalmol, Singapore, Singapore.;Natl Univ Hlth Syst, Singapore, Singapore..
    Chines, Peter S.
    NHGRI, Med Genom & Metab Genet Branch, US Natl Inst Hlth, Bethesda, MD 20892 USA..
    Chung, Ren-Hua
    Natl Hlth Res Inst, Div Biostat & Bioinformat, Inst Populat Hlth Sci, Zhunan Town, Taiwan..
    Collins, Francis S.
    NHGRI, Med Genom & Metab Genet Branch, US Natl Inst Hlth, Bethesda, MD 20892 USA..
    Connell, John M.
    Univ Dundee, Ninewells Hosp & Med Sch, Dundee, Scotland..
    Doring, Angela
    Helmholtz Zentrum Munchen, Inst Epidemiol 1, Neuherberg, Germany.;Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany..
    Dallongeville, Jean
    Univ Lille 2, INSERM UMR 1167, Inst Pasteur Lille, Lille, France..
    Danesh, John
    Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton, England.;Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England.;Univ Cambridge, Dept Publ Hlth & Primary Care, NIHR Blood & Transplant Res Unit Donor Hlth & Gen, Cambridge, England..
    de Faire, Ulf
    Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, Stockholm, Sweden..
    Delgado, Graciela
    Heidelberg Univ, Med Fac Mannheim, Dept Med 5, Mannheim, Germany..
    Dominiczak, Anna F.
    Univ Glasgow, Inst Cardiovasc & Med Sci, BHF Glasgow Cardiovasc Res Ctr, Glasgow, Lanark, Scotland..
    Doney, Alex S. F.
    Univ Dundee, Ninewells Hosp & Med Sch, Med Res Inst, Dundee, Scotland..
    Drenos, Fotios
    UCL, Inst Cardiovasc Sci, Ctr Cardiovasc Genet, London, England.;Univ Bristol, Sch Social & Community Med, Med Res Council Integrat Epidemiol Unit, Oakfield House, Bristol, Avon, England..
    Edkins, Sarah
    Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton, England..
    Eicher, John D.
    NHLBI, Framingham Heart Study, Framingham, MA USA.;NHLBI, Cardiovasc Epidemiol & Human Genom Branch, Bldg 10, Bethesda, MD 20892 USA..
    Elosua, Roberto
    Inst Hosp Mar Invest Med IMIM, Cardiovasc Epidemiol & Genet, Barcelona, Spain..
    Enroth, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Erdmann, Jeanette
    Univ Lubeck, Inst Integrat & Expt Genom, Lubeck, Germany.;Deutsch Zentrum Herz Kreislauf Forsch DZHK, Partner Site Hamburg, Kiel, Germany..
    Eriksson, Per
    Karolinska Inst, Dept Med, Cardiovasc Res Unit, Ctr Mol Med, Stockholm, Sweden..
    Esko, Tonu
    Boston Childrens Hosp, Div Endocrinol, Boston, MA USA.;Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.;Broad Inst MIT & Harvard, Cambridge, MA USA..
    Evangelou, Evangelos
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.;Univ Ioannina, Dept Hyg & Epidemiol, Sch Med, Ioannina, Greece..
    Evans, Alun
    Queens Univ Belfast, Ctr Excellence Publ Hlth, Belfast, Antrim, North Ireland..
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Farra, Martin
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford, England..
    Felixl, Janine F.
    Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, Rotterdam, Netherlands..
    Ferrieres, Jean
    Toulouse Univ, Sch Med, Rangueil Univ Hosp, INSERM UMR 1027, Toulouse, France..
    Ferrucci, Luigi
    NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA..
    Fornage, Myriam
    Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA..
    Forrester, Terrence
    Univ West Indies, Trop Metab Res Unit, Res Inst Trop Med, Kingston, Jamaica..
    Franceschinil, Nora
    Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA..
    Franco, Oscar H.
    Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, Rotterdam, Netherlands..
    Franco-Cereceda, Anders
    Karolinska Inst, Dept Mol Med & Surg, Cardiothorac Surg Unit, Stockholm, Sweden..
    Fraser, Ross M.
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland.;Synpromics Ltd, Edinburgh, Midlothian, Scotland..
    Ganesh, Santhi K.
    Univ Michigan, Sch Med, Dept Cardiol, Ann Arbor, MI 48109 USA..
    Gao, He
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England..
    Gertow, Karl
    Karolinska Inst, Dept Med, Cardiovasc Res Unit, Ctr Mol Med, Stockholm, Sweden.;Karolinska Univ Hosp Solna, Ctr Mol Med, Stockholm, Sweden..
    Gianfagna, Francesco
    Univ Insubria, Dept Clin & Expt Med, Epidemiol & Prevent Med EPIMED Res Ctr, Varese, Italy.;IRCCS, Ist Neurol Mediterraneo NEUROMED, Dept Epidemiol & Prevent, Pozzilli, Italy..
    Gigante, Bruna
    Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, Stockholm, Sweden..
    Giulianini, Franco
    Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA..
    Goe, Anuj
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford, England..
    Goodall, Alison H.
    Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester, Leics, England.;Glenfield Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England..
    Goodarzi, Mark
    Cedars Sinai Med Ctr, Div Endocrinol Diabet & Metab, Los Angeles, CA 90048 USA..
    Gorski, Mathias
    Univ Regensburg, Inst Epidemiol & Prevent Med, Dept Genet Epidemiol, Regensburg, Germany.;Univ Hosp Regensburg, Dept Nephrol, Regensburg, Germany..
    Grassler, Jurgen
    Tech Univ Dresden, Dept Med 2, Div Pathobiochem, Dresden, Germany..
    Groves, Christopher J.
    Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Gudnason, Vilmundur
    Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hallmans, Göran
    Umeå Univ, Dept Publ Hlth & Clin Med, Umeå, Sweden..
    Hartikainen, Anna-Liisa
    Univ Oulu, Inst Clin Med Obstet & Gynaecol, Oulu, Finland.;Oulu Univ Hosp, Med Res Ctr, Oulu, Finland..
    Hassinen, Maija
    Kuopio Res Inst Exercise Med, Kuopio, Finland..
    Havulinna, Aki S.
    Natl Inst Hlth & Welf, Helsinki, Finland..
    Hayward, Caroline
    Western Gen Hosp, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland..
    Hercberg, Serge
    Univ Paris 13, UREN, INSERM U557, INRA U1125,Sorbonne Paris Cite, Bobigny, France..
    Herzig, Karl-Heinz
    Univ Oulu, Inst Biomed, Med Res Ctr Oulu, Oulu, Finland.;Oulu Univ Hosp, Oulu, Finland.;Univ Oulu, Bioctr Oulu, Oulu, Finland.;Poznan Univ Med Sci, Dept Gastroenterol & Metab, Poznan, Poland..
    Hicks, Andrew A.
    European Acad Bozen Bolzano EURAC, Ctr Biomed, Bolzano, Italy.;Univ Lubeck, Inst, Lubeck, Germany..
    Hingorani, Aroon D.
    UCL, Dept Epidemiol & Publ Hlth, Genet Epidemiol Grp, London, England..
    Hirschhorn, Joel N.
    Boston Childrens Hosp, Div Endocrinol, Boston, MA USA.;Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA USA.;Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA.;Harvard Med Sch, Dept Genet, Boston, MA USA..
    Hofmanl, Albert
    Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, Rotterdam, Netherlands.;Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA..
    Holmen, Jostein
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, Levanger, Norway..
    Holmen, Oddgeir Lingaas
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, Levanger, Norway.;Univ Trondheim Hosp, St Olav Hosp, Trondheim, Norway..
    Hottenga, Jouke-Jan
    Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands..
    Howard, Phil
    UCL, Inst Cardiovasc Sci, Ctr Cardiovasc Genet, London, England..
    Hsiung, Chao A.
    Natl Hlth Res Inst, Div Biostat & Bioinformat, Inst Populat Hlth Sci, Zhunan Town, Taiwan..
    Hunt, Steven C.
    Univ Utah, Sch Med, Cardiovasc Genet Div, Salt Lake City, UT USA.;Weill Cornell Med Coll Qatar, Dept Genet Med, Doha, Qatar..
    Ikram, M. Arfan
    Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, Rotterdam, Netherlands.;Erasmus MC, Dept Radiol, Rotterdam, Netherlands.;Erasmus MC, Univ Med Ctr Rotterdam, Dept Neurol, Rotterdam, Netherlands..
    Illig, Thomas
    Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany.;Hannover Med Sch, Inst Human Genet, Hannover, Germany..
    Iribarren, Carlos
    Kaiser Permanente, Div Res, Oakland, CA USA..
    Jensen, Richard A.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA.;Univ Tampere, Sch Med, Dept Clin Physiol, Tampere, Finland..
    Kahonen, Mika
    Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA USA.;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA..
    Kang, Hyun Min
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Kathiresan, Sekar
    Harvard Med Sch, Dept Med, Boston, MA USA.;Univ Penn, Dept Surg, Div Transplantat, Philadelphia, PA 19104 USA.;Univ Penn, Dept Pediat, Philadelphia, PA 19104 USA..
    Keating, Brendan J.
    Univ Cambridge, Inst Publ Hlth, Dept Publ Hlth & Primary Care, Cambridge, England.;Onassis Cardiac Surg Ctr, Dept Cardiol 1, Athens, Greece..
    Khaw, Kay-Tee
    Imperial Coll London, Hammersmith Hosp Campus, Natl Heart & Lung Inst, London, England..
    Kim, Yun Kyoung
    Natl Inst Hlth, Ctr Genome Sci, Osong Hlth Technol Adm Complex, Chungcheongbuk Do, South Korea..
    Kim, Eric
    Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA.;Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA..
    Kivimaki, Mika
    UCL, Dept Epidemiol & Publ Hlth, Genet Epidemiol Grp, London, England..
    Klopp, Norman
    Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany.;Hannover Med Sch, Hannover Unified Biobank, Hannover, Germany..
    Kolovou, Genovefa
    Childrens Hosp Oakland, Res Inst, Dept Med, Oakland, CA 94609 USA..
    Komulainen, Pirjo
    Kuopio Res Inst Exercise Med, Kuopio, Finland..
    Kooner, Jaspal S.
    Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England.;Imperial Coll Healthcare NHS Trust, London, England.;MRC Unit Lifelong Hlth & Ageing UCL, London, England..
    Kosova, Gulum
    Broad Inst MIT & Harvard, Cambridge, MA USA.;Harvard Med Sch, Dept Med, Boston, MA USA.;Massachusetts Gen Hosp, Div Cardiol, Dept Med, Boston, MA 02114 USA..
    Krauss, Ronald M.
    Univ Lausanne, Dept Med Genet, Lausanne, Switzerland..
    Kuh, Diana
    Swiss Inst Bioinformat, Lausanne, Switzerland..
    Kutalik, Zoltan
    Univ Eastern Finland, Dept Med, Kuopio, Finland.;Kuopio Univ Hosp, Kuopio, Finland.;Univ Eastern Finland, Inst Biomed Physiol, Kuopio, Finland..
    Kuusisto, Johanna
    Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, Kuopio, Finland..
    Kvaloy, Kirsti
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, Levanger, Norway..
    Lakka, Timo A.
    Kuopio Res Inst Exercise Med, Kuopio, Finland.;Off Populat Studies Fdn Inc, Cebu, Philippines.;Univ San Carlos, Dept Anthropol Sociol & Hist, Cebu, Philippines..
    Lee, Nanette R.
    Taichung Vet Gen Hosp, Dept Internal Med, Div Endocrine & Metab, Taichung, Taiwan.;Natl Yang Ming Univ, Sch Med, Taipei, Taiwan..
    Lee, I-Te
    Taichung Vet Gen Hosp, Dept Med Res, Taichung, Taiwan.;NHLBI, Populat Sci Branch, US Natl Inst Hlth, Bldg 10, Bethesda, MD 20892 USA..
    Lee, Wen-Jane
    Taichung Vet Gen Hosp, Cardiovasc Ctr, Taichung, Taiwan..
    Levy, Daniel
    NHLBI, Framingham Heart Study, Framingham, MA USA.;Natl Yang Ming Univ, Inst Clin Med, Sch Med, Taipei, Taiwan..
    Li, Xiaohui
    Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA.;Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA..
    Liang, Kae-Woei
    Boston Univ, Sch Med, Sect Computat Biomed, Dept Med, Boston, MA 02215 USA.;EGID, Lille, France..
    Lin, Honghuang
    NHLBI, Framingham Heart Study, Framingham, MA USA.;Lille Pasteur Inst, CNRS UMR 8199, Lille, France..
    Lin, Li
    Univ Hosp Geneva, Dept Med, Cardiol, Geneva, Switzerland..
    Lindstrom, Jaana
    Natl Inst Hlth & Welf, Helsinki, Finland..
    Lobbens, Stephane
    Univ Lille 2, Lille, France.;Univ Dresden, Med Fac Carl Gustav Carus, Ctr Evidence Based Healthcare, Dresden, Germany.;Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany..
    Mannisto, Satu
    Natl Inst Hlth & Welf, Helsinki, Finland..
    Muller, Gabriele
    Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany..
    Muller-Nurasyid, Martina
    Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany.;Univ Cambridge, Neurol Unit, Biomed Campus, Cambridge, England.;Harokopio Univ, Dept Dietet Nutr, Athens, Greece..
    Mach, Francois
    Univ Hosp Geneva, Dept Med, Cardiol, Geneva, Switzerland..
    Markus, Hugh S.
    Univ Paris 13, Univ Paris 06, Sorbonne Univ, INSERM U1142,LIMICS,UMRS 1142, Paris, France..
    Marouli, Eirini
    Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England.;Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    McCarthy, Mark I.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    McKenzie, Colin A.
    Univ West Indies, Trop Metab Res Unit, Res Inst Trop Med, Kingston, Jamaica..
    Meneton, Pierre
    Univ Verona, Dept Life & Reprod Sci, Verona, Italy..
    Menni, Cristina
    Kuopio Univ Hosp, Dept Med, Kuopio, Finland..
    Metspalu, Andres
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Mijatovic, Vladan
    Oulu Univ Hosp, Unit Gen Practice, Oulu, Finland..
    Moilanen, Leena
    Univ Maryland, Sch Med, Dept Med, Program Personalized & Genom Med, Baltimore, MD 21201 USA.;Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Dept Epidemiol Human Genet & Environm Sci, Houston, TX 77030 USA..
    Montasser, May E.
    Cittadella Univ Monseratto, IRGB, CNR, Cagliari, Italy..
    Morris, Andrew D.
    Univ Dundee, Ninewells Hosp & Med Sch, Med Res Inst, Dundee, Scotland..
    Morrison, Alanna C.
    Tampere Univ Hosp, Ctr Heart, Dept Cardiol, Tampere, Finland..
    Mulas, Antonella
    Univ Tampere, Sch Med, Dept Cardiol, Tampere, Finland..
    Nagaraja, Ramaiah
    NIA, Genet Lab, Intramural Res Program, US Natl Inst Hlth, Baltimore, MD 21224 USA..
    Narisu, Narisu
    NHGRI, Med Genom & Metab Genet Branch, US Natl Inst Hlth, Bethesda, MD 20892 USA..
    Nikus, Kjell
    NHLBI, Div Cardiovasc Sci, Bldg 10, Bethesda, MD 20892 USA.;Kings Coll London, Inst Psychiat Psychol & Neurosci, London, England..
    O'Donnell, Christopher J.
    NHLBI, Framingham Heart Study, Framingham, MA USA.;Univ Penn, Dept Pediat, Philadelphia, PA 19104 USA.;Childrens Hosp Boston, Genet & Program Genom, Boston, MA USA..
    O'Reilly, Paul F.
    Vrije Univ Amsterdam, Dept Psychiat, EMGO Inst, Med Ctr, Neurosci Campus, Amsterdam, Netherlands..
    Ong, Ken K.
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge Biomed Campus, Cambridge, England..
    Paccaud, Fred
    Childrens Hosp Oakland, Res Inst, Dept Med, Oakland, CA 94609 USA..
    Palmer, Cameron D.
    Boston Childrens Hosp, Div Endocrinol, Boston, MA USA.;Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA.;Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands..
    Parsa, Afshin
    Cittadella Univ Monseratto, IRGB, CNR, Cagliari, Italy..
    Pedersen, Nancy L.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Penninx, Brenda W.
    Leiden Univ, Med Ctr, Dept Psychiat, Leiden, Netherlands.;Imperial Coll London, Int Ctr Circulatory Hlth, London, England.;Gen Cent Hosp, Dept Neurol, Bolzano, Italy..
    Perola, Markus
    Natl Inst Hlth & Welf, Helsinki, Finland.;Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland.;Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Peters, Annette
    Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany..
    Poulter, Neil
    Univ Lubeck, Dept Neurol, Lubeck, Germany..
    Pramstaller, Peter P.
    European Acad Bozen Bolzano EURAC, Ctr Biomed, Bolzano, Italy.;Univ Lubeck, Inst, Lubeck, Germany.;Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA.;Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA..
    Psaty, Bruce M.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA.;Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA USA.;Washington Univ, Sch Med, Div Biostat, St Louis, DC USA.;Ctr Noncommunicable Dis, Karachi, Pakistan..
    Quertermous, Thomas
    Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA..
    Rao, Dabeeru C.
    Umeå Univ, Dept Biobank Res, Umeå, Sweden..
    Rasheed, Asif
    Univ Med Greifswald, Inst Physiol, Greifswald, Germany..
    Rayner, N. William
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton, England.;Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Renstrom, Frida
    Umeå Univ, Dept Publ Hlth & Clin Med, Umeå, Sweden.;Lund Univ, Genet & Mol Epidemiol Unit, Dept Clin Sci, Malmö, Sweden.;Univ Washington, Dept Biostat, Seattle, WA 98195 USA..
    Rettig, Rainer
    Univ Ottawa, Inst Heart, Cardiovasc Res Methods Ctr Ontario, Ottawa, ON, Canada..
    Rice, Kenneth M.
    Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada..
    Roberts, Robert
    South Karelia Cent Hosp, Lappeenranta, Finland.;Deutsch Herzzentrum Munich, Munich, Germany..
    Rose, Lynda M.
    Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA..
    Rossouw, Jacques
    Childrens Hosp Boston, Genet & Program Genom, Boston, MA USA..
    Samani, Nilesh J.
    Univ Leicester, Glenfield Hosp, Dept Cardiovasc Sci, Leicester, Leics, England.;Glenfield Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England..
    Sanna, Serena
    Univ Tampere, Sch Med, Dept Cardiol, Tampere, Finland..
    Saramies, Jouko
    Tech Univ Munich, Munich, Germany..
    Schunkert, Heribert
    Deutsch Zentrum Herz Kreislauf Forsch DZHK, Munich, Germany.;Munich Heart Alliance, Munich, Germany.;Univ Oulu, Ctr Lifecourse Hlth Res, Oulu, Finland..
    Sebert, Sylvain
    Univ Oulu, Bioctr Oulu, Oulu, Finland.;Univ San Carlos, Dept Anthropol Sociol & Hist, Cebu, Philippines.;Natl Def Med Ctr, Coll Med, Taipei, Taiwan. Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore. Natl Univ Hlth Syst, Singapore, Singapore..
    Sheu, Wayne H-H
    Karolinska Univ Hosp Solna, Ctr Mol Med, Stockholm, Sweden.;Taichung Vet Gen Hosp, Dept Med Res, Taichung, Taiwan.;NHLBI, Populat Sci Branch, US Natl Inst Hlth, Bldg 10, Bethesda, MD 20892 USA.;Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA USA..
    Shin, Young-Ah
    Natl Inst Hlth, Ctr Genome Sci, Osong Hlth Technol Adm Complex, Chungcheongbuk Do, South Korea..
    Sim, Xueling
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA.;Univ Eastern Finland, Kuopio, Finland.;Kuopio Univ Hosp, Kuopio, Finland..
    Smit, Johannes H.
    Leiden Univ, Med Ctr, Dept Psychiat, Leiden, Netherlands..
    Smith, Albert V.
    Iceland Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Sosa, Maria X.
    Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Baltimore, MD USA..
    Spector, Tim D.
    Kuopio Univ Hosp, Dept Med, Kuopio, Finland..
    Stancakova, Alena
    Royal Coll Surgeons Ireland, Mol & Cellular Therapeut, Dublin, Ireland..
    Stanton, Alice V.
    Univ Cambridge, Dept Haematol, Cambridge, England..
    Stirrups, Kathleen E.
    Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England.;Natl Univ Singapore, Dept Med, Singapore, Singapore.;Natl Univ Hlth Syst, Singapore, Singapore..
    Stringham, Heather M.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI 48109 USA..
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Swift, Amy J.
    NHGRI, Med Genom & Metab Genet Branch, US Natl Inst Hlth, Bethesda, MD 20892 USA..
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Tai, E-Shyong
    Duke NUS Grad Med Sch Singapore, Singapore, Singapore.;Univ Eastern Finland, Kuopio, Finland.;Kuopio Univ Hosp, Kuopio, Finland.;NIA, Intramural Res Program, Lab Cardiovasc Sci, US Natl Inst Hlth, Baltimore, MD 21224 USA..
    Tanaka, Toshiko
    NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA..
    Tarasov, Kirill V.
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany..
    Teumer, Alexander
    Univ Leicester, Dept Hlth Sci, Leicester, Leics, England..
    Thorsteinsdottir, Unnur
    deCODE Genet Amgen Inc, Reykjavik, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Tobin, Martin D.
    Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    Tremoli, Elena
    Univ Milan, Dipartimento Sci Farmacol & Biomol, Milan, Italy.;IRCCS, Ctr Cardiol Monzino, Milan, Italy..
    Uitterlinden, Andre G.
    Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, Rotterdam, Netherlands.;Univ Eastern Finland, Dept Publ Hlth & Clin Nutr, Kuopio, Finland..
    Uusitupa, Matti
    Kuopio Univ Hosp, Res Unit, Kuopio, Finland.;Isfahan Univ Med Sci, Res Inst Primordial Prevent Noncommunicable Dis, Esfahan, Iran..
    Vaez, Ahmad
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands.;Johns Hopkins Med Inst, Baltimore, MD 21205 USA..
    Vaidya, Dhananjay
    NGI Erasmus Med Ctr, Ctr Med Syst Biol CMSB 12, Rotterdam, Netherlands..
    van Duijn, Cornelia M.
    Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, Rotterdam, Netherlands.;Acad Med Ctr, Dept Clin Epidemiol Biostat & Bioinformat, Amsterdam, Netherlands..
    van Iperen, Erik P. A.
    ICIN Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, Utrecht, Netherlands.;Boston Univ, Dept Med, Sect Prevent Med, Sch Med, Boston, MA USA..
    Vasan, Ramachandran S.
    NHLBI, Framingham Heart Study, Framingham, MA USA.;Boston Univ, Sch Med, Dept Med, Cardiol, Boston, MA 02215 USA.;Univ Penn, Perelman Sch Med, Dept Genet, Dept Syst Pharmacol & Translat Therapeut, Philadelphia, PA 19104 USA..
    Verwoert, Germaine C.
    Erasmus MC, Univ Med Ctr Rotterdam, Dept Epidemiol, Rotterdam, Netherlands..
    Virtamo, Jarmo
    Natl Inst Hlth & Welf, Helsinki, Finland..
    Vitart, Veronique
    Western Gen Hosp, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland..
    Voight, Benjamin F.
    Univ Lausanne Hosp, Dept Internal Med, Lausanne, Switzerland..
    Vollenweider, Peter
    Univ Strasbourg, EA3430, Dept Epidemiol & Publ Hlth, Strasbourg, France..
    Wagner, Aline
    Univ Michigan, Sch Med, Div Cardiovasc Med, Dept Internal Med, Ann Arbor, MI 48109 USA..
    Wain, Louise V.
    Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    Wareham, Nicholas J.
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge Biomed Campus, Cambridge, England..
    Watldns, Hugh
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford, England..
    Weder, Alan B.
    Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands..
    Westra, Harm Jan
    Univ West Indies, Res Inst Trop Med, Epidemiol Res Unit, Kingston, Jamaica..
    Wilks, Rainford
    Univ Tromso, Dept Community Med, Fac Hlth Sci, Tromso, Norway..
    Wilsgaard, Tom
    Univ Tromso, Fac Hlth Sci, Dept Clin Med, Tromso, Norway.;Univ Cambridge, MRC Canc Unit, Cambridge, England..
    Wilson, James F.
    Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland.;Western Gen Hosp, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland..
    Wong, Tien Y.
    Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Duke NUS Grad Med Sch Singapore, Singapore, Singapore.;Natl Univ Singapore, Dept Ophthalmol, Singapore, Singapore.;Natl Univ Hlth Syst, Singapore, Singapore..
    Yang, Tsun-Po
    Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England.;Case Western Reserve Univ, Dept Epidemiol & Biostat, Sch Med, Cleveland, OH 44106 USA..
    Yao, Jie
    Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA.;Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA..
    Yengo, Loic
    Univ Lille 2, Lille, France.;Univ Dresden, Med Fac Carl Gustav Carus, Ctr Evidence Based Healthcare, Dresden, Germany.;Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany..
    Zhang, Weihua
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.;Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England..
    Zhao, Jing Hua
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge Biomed Campus, Cambridge, England..
    Zhu, Xiaofeng
    Minist Hlth, Victoria, Seychelles..
    Bovet, Pascal
    CHU Vaudois, Inst Social & Prevent Med IUMSP, Lausanne, Switzerland.;Univ Lausanne, Lausanne, Switzerland.;Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA..
    Cooper, Richard S.
    Loyola Univ, Chicago Stritch Sch Med, Dept Publ Hlth Sci, Maywood, IL 60153 USA..
    Mohlke, Karen L.
    Univ N Carolina, Dept Genet, Chapel Hill, NC USA..
    Saleheen, Danish
    Univ Med Greifswald, Inst Physiol, Greifswald, Germany.;Imperial Coll London, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, London, England..
    Lee, Jong-Young
    Natl Inst Hlth, Ctr Genome Sci, Osong Hlth Technol Adm Complex, Chungcheongbuk Do, South Korea..
    Elliott, Paul
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.;Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands..
    Gierman, Hinco J.
    Stanford Univ, Med Ctr, Dept Dev Biol & Genet, Stanford, CA 94305 USA.;Acad Med Ctr, Dept Vasc Med, Amsterdam, Netherlands..
    Willer, Cristen J.
    Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA.;Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands..
    Franke, Lude
    Hovingh, G. Kees
    Taylor, Kent D.
    Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA.;Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA..
    Dedoussis, George
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Sever, Peter
    Univ Lubeck, Dept Neurol, Lubeck, Germany..
    Wong, Andrew
    Swiss Inst Bioinformat, Lausanne, Switzerland..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Assimes, Themistocles L.
    Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA..
    Njolstad, Inger
    Univ Tromso, Fac Hlth Sci, Dept Clin Med, Tromso, Norway.;Univ Cambridge, MRC Canc Unit, Cambridge, England..
    Schwarz, Peter E. H.
    Univ Dresden, Med Fac Carl Gustav Carus, Dept Med 3, Dresden, Germany.;Univ Hosp, Paul Langerhans Inst Dresden, Helmholtz Ctr Munich, Dresden, Germany.;Tech Univ Dresden, Fac Med, Dresden, Germany.;German Ctr Diabet Res DZD, Neuherberg, Germany..
    Langenberg, Claudia
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge Biomed Campus, Cambridge, England..
    Snieder, Harold
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Caulfield, Mark J.
    Queen Mary Univ London, William Harvey Res Inst, Clin Pharmacol, London, England.;Queen Mary Univ London, NIHR Barts Cardiovasc Biomed Res Unit, London, England..
    Melander, E.
    Lund Univ, Dept Internal Med, Malmö, Sweden..
    Laakso, Markku
    Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, Kuopio, Finland..
    Saltevo, Juha
    Cent Finland Hlth Care Dist, Dept Med, Jyvaskyla, Finland..
    Rauramaa, Rainer
    Kuopio Res Inst Exercise Med, Kuopio, Finland.;Univ San Carlos, Dept Anthropol Sociol & Hist, Cebu, Philippines..
    Tuomilehto, Jaakko
    Natl Inst Hlth & Welf, Helsinki, Finland.;Dasman Diabet Inst, Dasman, Kuwait.;King Abdulaziz Univ, Saudi Diabet Res Grp, Jeddah, Saudi Arabia.;Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria..
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA.
    Lehtimaki, Terho
    Fimlab Labs, Dept Clin Chem, Tampere, Finland.;Univ Tampere, Dept Clin Chem, Sch Med, Tampere, Finland..
    Hveem, Kristian
    Norwegian Univ Sci & Technol, Dept Publ Hlth & Gen Practice, HUNT Res Ctr, Levanger, Norway..
    Palmas, Walter
    Columbia Univ, Dept Med, New York, NY USA..
    Marz, Winfried
    Synlab Acad, Synlab Serv, Mannheim, Germany.;Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria..
    Kumar, Meena
    UCL, Dept Epidemiol & Publ Hlth, Genet Epidemiol Grp, London, England..
    Salomaa, Veikko
    Natl Inst Hlth & Welf, Helsinki, Finland..
    Chen, Yii-Der I.
    Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA.;Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA..
    Rotter, Jerome I.
    Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA.;Harbor UCLA Med Ctr, Dept Pediat, Torrance, CA 90509 USA..
    Froguel, Philippe
    Iceland Heart Assoc, Kopavogur, Iceland.;Univ Lille 2, Lille, France.;Univ Dresden, Med Fac Carl Gustav Carus, Ctr Evidence Based Healthcare, Dresden, Germany.;Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany..
    Jarvelin, Marjo-Riitta
    Univ Oulu, Bioctr Oulu, Oulu, Finland.;Natl Def Med Ctr, Coll Med, Taipei, Taiwan. Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore. Natl Univ Hlth Syst, Singapore, Singapore.;Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands.;Oulu Univ Hosp, Unit Primary Care, Oulu, Finland..
    Lakatta, Edward G.
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany..
    Kuulasmaa, Kari
    Natl Inst Hlth & Welf, Helsinki, Finland..
    Franks, Paul W.
    Umeå Univ, Dept Publ Hlth & Clin Med, Umeå, Sweden.;Lund Univ, Genet & Mol Epidemiol Unit, Dept Clin Sci, Malmö, Sweden.;Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA..
    Hamsten, Anders
    Karolinska Inst, Dept Med, Cardiovasc Res Unit, Ctr Mol Med, Stockholm, Sweden.;Karolinska Univ Hosp Solna, Ctr Mol Med, Stockholm, Sweden..
    Wichmann, H-Erich
    Helmholtz Zentrum Munchen, Inst Epidemiol 1, Neuherberg, Germany.;Harokopio Univ, Dept Dietet Nutr, Athens, Greece.;Tech Univ Munich, Inst Med Stat & Epidemiol, Munich, Germany..
    Palmer, Colin N. A.
    Univ Dundee, Ninewells Hosp & Med Sch, Med Res Inst, Dundee, Scotland..
    Stefansson, Kari
    deCODE Genet Amgen Inc, Reykjavik, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Ridker, Paul M.
    Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA..
    Loos, Ruth J. F.
    Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC Epidemiol Unit, Cambridge Biomed Campus, Cambridge, England.;Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Mindich Child Hlth Dev Inst, New York, NY 10029 USA..
    Chalcravarti, Aravinda
    Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Baltimore, MD USA..
    Deloukas, Panos
    Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England.;King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah, Saudi Arabia..
    Morris, Andrew P.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England..
    Newton-Cheh, Christopher
    Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA.;Broad Inst MIT & Harvard, Cambridge, MA USA.;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Div Cardiol, Dept Med, Boston, MA 02114 USA..
    Munroe, Patricia B.
    Queen Mary Univ London, William Harvey Res Inst, Clin Pharmacol, London, England.;Queen Mary Univ London, NIHR Barts Cardiovasc Biomed Res Unit, London, England..
    The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals2016In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 48, no 10, p. 1171-1184Article in journal (Refereed)
    Abstract [en]

    To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.

  • 65. Eriksson, Anna L.
    et al.
    Lorentzon, Mattias
    Vandenput, Liesbeth
    Labrie, Fernand
    Lindersson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Orwoll, Eric S.
    Cummings, Steven R.
    Zmuda, Joseph M.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Karlsson, Magnus K.
    Mellström, Dan
    Ohlsson, Claes
    Genetic variations in sex steroid-related genes as predictors of serum estrogen levels in men2009In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 94, no 3, p. 1033-1041Article in journal (Refereed)
    Abstract [en]

    Context:

    The risk of many conditions, including prostate cancer, breast cancer, and osteoporosis, is associated with serum levels of sex steroids.

    Objective:

    The aim of the study was to identify genetic variations in sex steroid-related genes that are associated with serum levels of estradiol (E2) and/or testosterone in men.

    Design:

    Genotyping of 604 single nucleotide polymorphisms in 50 sex steroid-related candidate genes was performed in the Gothenburg Osteoporosis and Obesity Determinants (GOOD) study (n = 1041 men; age, 18.9 ± 0.6 yr). Replications of significant associations were performed in the Osteoporotic Fractures in Men (MrOS) Sweden study (n = 2568 men; age, 75.5 ± 3.2 yr) and in the MrOS US study (n = 1922 men; age, 73.5 ± 5.8 yr). Serum E2, testosterone, and estrone (E1) levels were analyzed using gas chromatography/mass spectrometry.

    Results:

    The screening in the GOOD cohort identified the single nucleotide polymorphism rs2470152 in intron 1 of the CYP19 gene, which codes for aromatase, responsible for the final step of the biosynthesis of E2 and E1, to be most significantly associated with serum E2 levels (P = 2 × 10−6). This association was confirmed both in the MrOS Sweden study (P = 9 × 10−7) and in the MrOS US study (P = 1 × 10−4). When analyzed in all subjects (n = 5531), rs2470152 was clearly associated with both E2 (P = 2 × 10−14) and E1 (P = 8 × 10−19) levels. In addition, this polymorphism was modestly associated with lumbar spine BMD (P < 0.01) and prevalent self-reported fractures (P < 0.05).

    Conclusions:

    rs2470152 of the CYP19 gene is clearly associated with serum E2 and E1 levels in men.

  • 66.
    Eriksson, Karin G.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Zickert, Agneta
    Sandling, Johanna K.
    Jonsen, Andreas
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Behrens, Timothy W.
    Graham, Robert R.
    Ortmann, Ward
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Gunnarsson, Iva
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Association of STAT4, IRF5 and BLK polymorphisms with severity and outcome in lupus nephritis2012In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 71, p. A55-A55Article in journal (Other academic)
  • 67.
    Eriksson, Niclas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Berglund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Axelsson, Tomas
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Connolly, Stuart
    Hamilton Hlth Sci, Populat Hlth Res Inst, Hamilton, ON, Canada.;McMaster Univ, Hamilton, ON, Canada..
    Eikelboom, John
    Hamilton Hlth Sci, Populat Hlth Res Inst, Hamilton, ON, Canada.;McMaster Univ, Hamilton, ON, Canada..
    Ezekowitz, Michael
    Thomas Jefferson Univ, Sidney Kimmel Med Collage, Philadelphia, PA 19107 USA..
    Oldgren, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Pare, Guillaume
    Hamilton Hlth Sci, Populat Hlth Res Inst, Hamilton, ON, Canada.;McMaster Univ, Hamilton, ON, Canada..
    Reilly, Paul
    Boehringer Ingelheim Pharma Inc, Ridgefield, CT USA..
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Syvänen, Ann-Christine
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Wadelius, Claes
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Yusuf, Salim
    Hamilton Hlth Sci, Populat Hlth Res Inst, Hamilton, ON, Canada.;McMaster Univ, Hamilton, ON, Canada..
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genetic determinants of warfarin maintenance dose and time in therapeutic treatment range: a RE-LY genomics substudy2016In: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 17, no 13, p. 1425-1439Article in journal (Refereed)
    Abstract [en]

    Aims: We investigated associations between genetic variation in candidate genes and on a genome-wide scale with warfarin maintenance dose, time in therapeutic range (TTR), and risk of major bleeding. Materials & methods: In total, 982 warfarin-treated patients from the RE-LY trial were studied. Results: After adjusting for SNPs in VKORC1 and CYP2C9, SNPs in DDHD1 (rs17126068) and NEDD4 (rs2288344) were associated with dose. Adding these SNPs and CYP4F2 (rs2108622) to a base model increased R-2 by 2.9%. An SNP in ASPH (rs4379440) was associated with TTR (-6.8% per minor allele). VKORC1 was associated with time less than INR 2.0. VKORC1 and CYP2C9 were associated with time more than INR 3.0, but not with major bleeding. Conclusions: We identified two novel genes associated with warfarin maintenance dose and one gene associated with TTR. These genes need to be replicated in an independent cohort.

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  • 68.
    Fall, Tove
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hägg, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Maegi, Reedik
    Ploner, Alexander
    Fischer, Krista
    Horikoshi, Momoko
    Sarin, Antti-Pekka
    Thorleifsson, Gudmar
    Ladenvall, Claes
    Kals, Mart
    Kuningas, Maris
    Draisma, Harmen H. M.
    Ried, Janina S.
    van Zuydam, Natalie R.
    Huikari, Ville
    Mangino, Massimo
    Sonestedt, Emily
    Benyamin, Beben
    Nelson, Christopher P.
    Rivera, Natalia V.
    Kristiansson, Kati
    Shen, Huei-yi
    Havulinna, Aki S.
    Dehghan, Abbas
    Donnelly, Louise A.
    Kaakinen, Marika
    Nuotio, Marja-Liisa
    Robertson, Neil
    de Bruijn, Renee F. A. G.
    Ikram, M. Arfan
    Amin, Najaf
    Balmforth, Anthony J.
    Braund, Peter S.
    Doney, Alexander S. F.
    Doering, Angela
    Elliott, Paul
    Esko, Tonu
    Franco, Oscar H.
    Gretarsdottir, Solveig
    Hartikainen, Anna-Liisa
    Heikkila, Kauko
    Herzig, Karl-Heinz
    Holm, Hilma
    Hottenga, Jouke Jan
    Hypponen, Elina
    Illig, Thomas
    Isaacs, Aaron
    Isomaa, Bo
    Karssen, Lennart C.
    Kettunen, Johannes
    Koenig, Wolfgang
    Kuulasmaa, Kari
    Laatikainen, Tiina
    Laitinen, Jaana
    Lindgren, Cecilia
    Lyssenko, Valeriya
    Laara, Esa
    Rayner, Nigel W.
    Mannisto, Satu
    Pouta, Anneli
    Rathmann, Wolfgang
    Rivadeneira, Fernando
    Ruokonen, Aimo
    Savolainen, Markku J.
    Sijbrands, Eric J. G.
    Small, Kerrin S.
    Smit, Jan H.
    Steinthorsdottir, Valgerdur
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Taanila, Anja
    Tobin, Martin D.
    Uitterlinden, Andre G.
    Willems, Sara M.
    Willemsen, Gonneke
    Witteman, Jacqueline
    Perola, Markus
    Evans, Alun
    Ferrieres, Jean
    Virtamo, Jarmo
    Kee, Frank
    Tregouet, David-Alexandre
    Arveiler, Dominique
    Amouyel, Philippe
    Ferrario, Marco M.
    Brambilla, Paolo
    Hall, Alistair S.
    Heath, AndrewC.
    Madden, Pamela A. F.
    Martin, Nicholas G.
    Montgomery, Grant W.
    Whitfield, John B.
    Jula, Antti
    Knekt, Paul
    Oostra, Ben
    van Duijn, Cornelia M.
    Penninx, Brenda W. J. H.
    Smith, George Davey
    Kaprio, Jaakko
    Samani, Nilesh J.
    Gieger, Christian
    Peters, Annette
    Wichmann, H. -Erich
    Boomsma, Dorret I.
    de Geus, Eco J. C.
    Tuomi, TiinaMaija
    Power, Chris
    Hammond, Christopher J.
    Spector, Tim D.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Orho-Melander, Marju
    Palmer, Colin Neil Alexander
    Morris, Andrew D.
    Groop, Leif
    Jarvelin, Marjo-Riitta
    Salomaa, Veikko
    Vartiainen, Erkki
    Hofman, Albert
    Ripatti, Samuli
    Metspalu, Andres
    Thorsteinsdottir, Unnur
    Stefansson, Kari
    Pedersen, Nancy L.
    McCarthy, Mark I.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Prokopenko, Inga
    The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis2013In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 10, no 6, p. e1001474-Article in journal (Refereed)
    Abstract [en]

    Background: The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach. Methods and Findings: We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses. Age-and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n = 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI-trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03-1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1-1.4; all p<0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p<0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p = 0.001). Conclusions: We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.

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  • 69.
    Fall, Tove
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hägg, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ploner, Alexander
    Mägi, Reedik
    Fischer, Krista
    Draisma, Harmen H M
    Sarin, Antti-Pekka
    Benyamin, Beben
    Ladenvall, Claes
    Åkerlund, Mikael
    Kals, Mart
    Esko, Tõnu
    Nelson, Christopher P
    Kaakinen, Marika
    Huikari, Ville
    Mangino, Massimo
    Meirhaeghe, Aline
    Kristiansson, Kati
    Nuotio, Marja-Liisa
    Kobl, Michael
    Grallert, Harald
    Dehghan, Abbas
    Kuningas, Maris
    de Vries, Paul S
    de Bruijn, Renée F A G
    Willems, Sara M
    Heikkilä, Kauko
    Silventoinen, Karri
    Pietiläinen, Kirsi H
    Legry, Vanessa
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Goumidi, Louisa
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Strauch, Konstantin
    Koenig, Wolfgang
    Lichtner, Peter
    Herder, Christian
    Palotie, Aarno
    Menni, Cristina
    Uitterlinden, André G
    Kuulasmaa, Kari
    Havulinna, Aki S
    Moreno, Luis A
    Gonzalez-Gross, Marcela
    Evans, Alun
    Tregouet, David-Alexandre
    Yarnell, John W G
    Virtamo, Jarmo
    Ferrières, Jean
    Veronesi, Giovanni
    Perola, Markus
    Arveiler, Dominique
    Brambilla, Paolo
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Kaprio, Jaakko
    Hofman, Albert
    Stricker, Bruno H
    van Duijn, Cornelia M
    Ikram, M Arfan
    Franco, Oscar H
    Cottel, Dominique
    Dallongeville, Jean
    Hall, Alistair S
    Jula, Antti
    Tobin, Martin D
    Penninx, Brenda W
    Peters, Annette
    Gieger, Christian
    Samani, Nilesh J
    Montgomery, Grant W
    Whitfield, John B
    Martin, Nicholas G
    Groop, Leif
    Spector, Tim D
    Magnusson, Patrik K
    Amouyel, Philippe
    Boomsma, Dorret I
    Nilsson, Peter M
    Järvelin, Marjo-Riitta
    Lyssenko, Valeriya
    Metspalu, Andres
    Strachan, David P
    Salomaa, Veikko
    Ripatti, Samuli
    Pedersen, Nancy L
    Prokopenko, Inga
    McCarthy, Mark I
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Age- and sex-specific causal effects of adiposity on cardiovascular risk factors2015In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, no 5, p. 1841-1852Article in journal (Refereed)
    Abstract [en]

    Observational studies have reported different effects of adiposity on cardiovascular risk factors across age and sex. Since cardiovascular risk factors are enriched in obese individuals, it has not been easy to dissect the effects of adiposity from those of other risk factors. We used a Mendelian randomization approach, applying a set of 32 genetic markers to estimate the causal effect of adiposity on blood pressure, glycemic indices, circulating lipid levels, and markers of inflammation and liver disease in up to 67,553 individuals. All analyses were stratified by age (cutoff 55 years of age) and sex. The genetic score was associated with BMI in both nonstratified analysis (P = 2.8 × 10(-107)) and stratified analyses (all P < 3.3 × 10(-30)). We found evidence of a causal effect of adiposity on blood pressure, fasting levels of insulin, C-reactive protein, interleukin-6, HDL cholesterol, and triglycerides in a nonstratified analysis and in the <55-year stratum. Further, we found evidence of a smaller causal effect on total cholesterol (P for difference = 0.015) in the ≥55-year stratum than in the <55-year stratum, a finding that could be explained by biology, survival bias, or differential medication. In conclusion, this study extends previous knowledge of the effects of adiposity by providing sex- and age-specific causal estimates on cardiovascular risk factors.

  • 70.
    Fang, Li Tai
    et al.
    Roche Sequencing Solut Inc, Bioinformat Res & Early Dev, Belmont, CA USA..
    Zhu, Bin
    NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA..
    Zhao, Yongmei
    Frederick Natl Lab Canc Res, Adv Biomed & Computat Sci, Biomed Informat & Data Sci Directorate, Frederick, MD USA..
    Chen, Wanqiu
    Loma Linda Univ, Sch Med, Ctr Genom, Loma Linda, CA 92350 USA..
    Yang, Zhaowei
    Loma Linda Univ, Sch Med, Ctr Genom, Loma Linda, CA 92350 USA.;Guangzhou Med Univ, Affiliated Hosp 1, Guangzhou Inst Resp Hlth,Dept Allergy & Clin Immu, Natl Clin Res Ctr Resp Dis,State Key Lab Resp Dis, Guangzhou, Peoples R China..
    Kerrigan, Liz
    ATCC Amer Type Culture Collect, Manassas, VA USA..
    Langenbach, Kurt
    ATCC Amer Type Culture Collect, Manassas, VA USA..
    de Mars, Maryellen
    ATCC Amer Type Culture Collect, Manassas, VA USA..
    Lu, Charles
    AbbVie, Genom Res Ctr GRC, Computat Genom, N Chicago, IL 60064 USA..
    Idler, Kenneth
    AbbVie, Genom Res Ctr GRC, Computat Genom, N Chicago, IL 60064 USA..
    Jacob, Howard
    AbbVie, Genom Res Ctr GRC, Computat Genom, N Chicago, IL 60064 USA..
    Zheng, Yuanting
    Fudan Univ, Sch Life Sci, Human Phenome Inst, State Key Lab Genet Engn, Shanghai, Peoples R China.;Fudan Univ, Shanghai Canc Ctr, Shanghai, Peoples R China..
    Ren, Luyao
    Fudan Univ, Sch Life Sci, Human Phenome Inst, State Key Lab Genet Engn, Shanghai, Peoples R China.;Fudan Univ, Shanghai Canc Ctr, Shanghai, Peoples R China..
    Yu, Ying
    Fudan Univ, Sch Life Sci, Human Phenome Inst, State Key Lab Genet Engn, Shanghai, Peoples R China.;Fudan Univ, Shanghai Canc Ctr, Shanghai, Peoples R China..
    Jaeger, Erich
    Illumina Inc, Foster City, CA USA..
    Schroth, Gary P.
    Illumina Inc, Foster City, CA USA..
    Abaan, Ogan D.
    Illumina Inc, Foster City, CA USA..
    Talsania, Keyur
    Frederick Natl Lab Canc Res, Adv Biomed & Computat Sci, Biomed Informat & Data Sci Directorate, Frederick, MD USA..
    Lack, Justin
    Frederick Natl Lab Canc Res, Adv Biomed & Computat Sci, Biomed Informat & Data Sci Directorate, Frederick, MD USA..
    Shen, Tsai-Wei
    Frederick Natl Lab Canc Res, Adv Biomed & Computat Sci, Biomed Informat & Data Sci Directorate, Frederick, MD USA..
    Chen, Zhong
    Loma Linda Univ, Sch Med, Ctr Genom, Loma Linda, CA 92350 USA..
    Stanbouly, Seta
    Loma Linda Univ, Sch Med, Ctr Genom, Loma Linda, CA 92350 USA..
    Tran, Bao
    Frederick Natl Lab Canc Res, Canc Res Technol Program, Sequencing Facil, Frederick, MD USA..
    Shetty, Jyoti
    Frederick Natl Lab Canc Res, Canc Res Technol Program, Sequencing Facil, Frederick, MD USA..
    Kriga, Yuliya
    Frederick Natl Lab Canc Res, Canc Res Technol Program, Sequencing Facil, Frederick, MD USA..
    Meerzaman, Daoud
    NCI, Computat Genom & Bioinformat Branch, Ctr Biomed Informat & Informat Technol CBIIT, Rockville, MD USA..
    Nguyen, Cu
    NCI, Computat Genom & Bioinformat Branch, Ctr Biomed Informat & Informat Technol CBIIT, Rockville, MD USA..
    Petitjean, Virginie
    Novartis Inst Biomed Res, Biomarker Dev, Basel, Switzerland..
    Sultan, Marc
    Novartis Inst Biomed Res, Biomarker Dev, Basel, Switzerland..
    Cam, Margaret
    Ctr Canc Res, Off Sci & Technol Resources, CCR Collaborat Bioinformat Resource CCBR, Bethesda, MD USA..
    Mehta, Monika
    Frederick Natl Lab Canc Res, Canc Res Technol Program, Sequencing Facil, Frederick, MD USA..
    Hung, Tiffany
    Genentech Inc, San Francisco, CA 94080 USA..
    Peters, Eric
    Genentech Inc, San Francisco, CA 94080 USA..
    Kalamegham, Rasika
    Genentech Inc, San Francisco, CA 94080 USA..
    Sahraeian, Sayed Mohammad Ebrahim
    Roche Sequencing Solut Inc, Bioinformat Res & Early Dev, Belmont, CA USA..
    Mohiyuddin, Marghoob
    Roche Sequencing Solut Inc, Bioinformat Res & Early Dev, Belmont, CA USA..
    Guo, Yunfei
    Roche Sequencing Solut Inc, Bioinformat Res & Early Dev, Belmont, CA USA..
    Yao, Lijing
    Roche Sequencing Solut Inc, Bioinformat Res & Early Dev, Belmont, CA USA..
    Song, Lei
    NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA..
    Lam, Hugo Y. K.
    Roche Sequencing Solut Inc, Bioinformat Res & Early Dev, Belmont, CA USA..
    Drabek, Jiri
    Palacky Univ, Fac Med & Dent, IMTM, Olomouc, Czech Republic.;European Infrastruct Translat Med, Amsterdam, Netherlands..
    Vojta, Petr
    European Infrastruct Translat Med, Amsterdam, Netherlands.;NCI, Ctr Riferimento Oncol Aviano CRO IRCCS, Unit Oncogenet & Funct Oncogen, Aviano, Italy..
    Maestro, Roberta
    European Infrastruct Translat Med, Amsterdam, Netherlands.;NCI, Ctr Riferimento Oncol Aviano CRO IRCCS, Unit Oncogenet & Funct Oncogen, Aviano, Italy..
    Gasparotto, Daniela
    European Infrastruct Translat Med, Amsterdam, Netherlands.;Perron Inst Neurol & Translat Sci, Nedlands, WA, Australia.;Univ Tartu, Estonian Genome Ctr, Inst Genom, Tartu, Estonia..
    Koks, Sulev
    European Infrastruct Translat Med, Amsterdam, Netherlands.;Univ Tartu, Estonian Genome Ctr, Inst Genom, Tartu, Estonia..
    Reimann, Ene
    European Infrastruct Translat Med, Amsterdam, Netherlands.;Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland..
    Scherer, Andreas
    European Infrastruct Translat Med, Amsterdam, Netherlands.;Uppsala Univ, Dept Med Sci, Mol Med & Sci Life Lab, Uppsala, Sweden..
    Nordlund, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab. European Infrastruct Translat Med, Amsterdam, Netherlands; Biomarker Development, Novartis Institutes for Biomedical Research, Basel, Switzerland.
    Liljedahl, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab. European Infrastruct Translat Med, Amsterdam, Netherlands.
    Jensen, Roderick, V
    Virginia Tech, Dept Biol Sci, Blacksburg, VA USA..
    Pirooznia, Mehdi
    NHLBI, Bioinformat & Computat Biol Core, NIH, Bldg 10, Bethesda, MD 20892 USA..
    Li, Zhipan
    Sentieon Inc, Mountain View, CA USA..
    Xiao, Chunlin
    NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA..
    Sherry, Stephen T.
    NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA..
    Kusko, Rebecca
    Immuneering Corp, Boston, MA USA..
    Moos, Malcolm
    US FDA, Ctr Biol Evaluat & Res, Silver Spring, MD USA..
    Donaldson, Eric
    US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA..
    Tezak, Zivana
    US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA..
    Ning, Baitang
    US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA..
    Tong, Weida
    US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA..
    Li, Jing
    Guangzhou Med Univ, Affiliated Hosp 1, Guangzhou Inst Resp Hlth,Dept Allergy & Clin Immu, Natl Clin Res Ctr Resp Dis,State Key Lab Resp Dis, Guangzhou, Peoples R China..
    Duerken-Hughes, Penelope
    Loma Linda Univ, Sch Med, Dept Basic Sci, Loma Linda, CA 92350 USA..
    Catalanotti, Claudia
    10x Genom, Pleasanton, CA USA..
    Maheshwari, Shamoni
    10x Genom, Pleasanton, CA USA..
    Shuga, Joe
    10x Genom, Pleasanton, CA USA..
    Liang, Winnie S.
    Translat Genom Res Inst, Phoenix, AZ USA..
    Keats, Jonathan
    Translat Genom Res Inst, Phoenix, AZ USA..
    Adkins, Jonathan
    Translat Genom Res Inst, Phoenix, AZ USA..
    Tassone, Erica
    Translat Genom Res Inst, Phoenix, AZ USA..
    Zismann, Victoria
    Translat Genom Res Inst, Phoenix, AZ USA..
    McDaniel, Timothy
    Translat Genom Res Inst, Phoenix, AZ USA..
    Trent, Jeffrey
    Translat Genom Res Inst, Phoenix, AZ USA..
    Foox, Jonathan
    Weill Cornell Med, Dept Physiol & Biophys, New York, NY USA..
    Butler, Daniel
    Weill Cornell Med, Dept Physiol & Biophys, New York, NY USA..
    Mason, Christopher E.
    Weill Cornell Med, Dept Physiol & Biophys, New York, NY USA..
    Hong, Huixiao
    US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA..
    Shi, Leming
    Fudan Univ, Sch Life Sci, Human Phenome Inst, State Key Lab Genet Engn, Shanghai, Peoples R China.;Fudan Univ, Shanghai Canc Ctr, Shanghai, Peoples R China..
    Wang, Charles
    Loma Linda Univ, Sch Med, Ctr Genom, Loma Linda, CA 92350 USA.;Loma Linda Univ, Sch Med, Dept Basic Sci, Loma Linda, CA 92350 USA..
    Xiao, Wenming
    US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA..
    Establishing community reference samples, data and call sets for benchmarking cancer mutation detection using whole-genome sequencing2021In: Nature Biotechnology, ISSN 1087-0156, E-ISSN 1546-1696, Vol. 39, no 9, p. 1151-1160Article in journal (Refereed)
    Abstract [en]

    Tumor-normal paired DNA samples from a breast cancer cell line and a matched lymphoblastoid cell line enable calibration of clinical sequencing pipelines and benchmarking 'tumor-only' or 'matched tumor-normal' analyses. The lack of samples for generating standardized DNA datasets for setting up a sequencing pipeline or benchmarking the performance of different algorithms limits the implementation and uptake of cancer genomics. Here, we describe reference call sets obtained from paired tumor-normal genomic DNA (gDNA) samples derived from a breast cancer cell line-which is highly heterogeneous, with an aneuploid genome, and enriched in somatic alterations-and a matched lymphoblastoid cell line. We partially validated both somatic mutations and germline variants in these call sets via whole-exome sequencing (WES) with different sequencing platforms and targeted sequencing with >2,000-fold coverage, spanning 82% of genomic regions with high confidence. Although the gDNA reference samples are not representative of primary cancer cells from a clinical sample, when setting up a sequencing pipeline, they not only minimize potential biases from technologies, assays and informatics but also provide a unique resource for benchmarking 'tumor-only' or 'matched tumor-normal' analyses.

  • 71.
    Farias, Fabiana H. G.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA.
    Dahlqvist, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kozyrev, Sergey V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Leonard, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wilbe, Maria
    Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences (SLU), Box 7023, SE-750 07, Uppsala, Sweden.
    Abramov, Sergei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, 420008, Russia.
    Alexsson, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pielberg, Gerli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hansson-Hamlin, Helene
    Department of Clinical Sciences, Swedish University of Agricultural Sciences (SLU), Box 7054, SE-750 07, Uppsala, Sweden.
    Andersson, Göran
    Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences (SLU), Box 7023, SE-750 07, Uppsala, Sweden.
    Tandre, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bengtsson, Anders A
    Department of Clinical Sciences Lund, Lund University, Skane University Hospital, SE-221 00, Lund, Sweden.
    Sjöwall, Christopher
    Department of Clinical and Experimental Medicine, Rheumatology/Division of Neuro and Inflammation Sciences, Linköping University, SE-581 85, Linköping, Sweden.
    Svenungsson, Elisabet
    Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, SE-171 76, Stockholm, Sweden.
    Gunnarsson, Iva
    Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, SE-171 76, Stockholm, Sweden.
    Rantapää-Dahlqvist, Solbritt
    Department of Public Health and Clinical Medicine/Rheumatology, Umeå University, SE-901 85, Umeå, Sweden.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Broad Institute, Cambridge, 7 Cambridge Center, Cambridge, MA, 02142, USA.
    A rare regulatory variant in the MEF2D gene affects gene regulation and splicing and is associated with a SLE sub-phenotype in Swedish cohorts2019In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, p. 432-441Article in journal (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is an autoimmune disorder with heterogeneous clinical presentation and complex etiology involving the interplay between genetic, epigenetic, environmental and hormonal factors. Many common SNPs identified by genome wide-association studies (GWAS) explain only a small part of the disease heritability suggesting the contribution from rare genetic variants, undetectable in GWAS, and complex epistatic interactions. Using targeted re-sequencing of coding and conserved regulatory regions within and around 215 candidate genes selected on the basis of their known role in autoimmunity and genes associated with canine immune-mediated diseases, we identified a rare regulatory variant rs200395694:G > T located in intron 4 of the MEF2D gene encoding the myocyte-specific enhancer factor 2D transcription factor and associated with SLE in Swedish cohorts (504 SLE patients and 839 healthy controls, p = 0.014, CI = 1.1-10). Fisher's exact test revealed an association between the genetic variant and a triad of disease manifestations including Raynaud, anti-U1-ribonucleoprotein (anti-RNP), and anti-Smith (anti-Sm) antibodies (p = 0.00037) among the patients. The DNA-binding activity of the allele was further studied by EMSA, reporter assays, and minigenes. The region has properties of an active cell-specific enhancer, differentially affected by the alleles of rs200395694:G > T. In addition, the risk allele exerts an inhibitory effect on the splicing of the alternative tissue-specific isoform, and thus may modify the target gene set regulated by this isoform. These findings emphasize the potential of dissecting traits of complex diseases and correlating them with rare risk alleles with strong biological effects.

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  • 72.
    Flannick, Jason
    et al.
    Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA USA.;Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Fuchsberger, Christian
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI USA..
    Mahajan, Anubha
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England..
    Teslovich, Tanya M.
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI USA..
    Agarwala, Vineeta
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.;MIT, Harvard Div Hlth Sci & Technol, Cambridge, MA USA..
    Gaulton, Kyle J.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England..
    Caulkins, Lizz
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Koesterer, Ryan
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Ma, Clement
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI USA..
    Moutsianas, Loukas
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England..
    McCarthy, Davis J.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Dept Stat, Oxford, England..
    Rivas, Manuel A.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England..
    Perry, John R. B.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Exeter, Univ Exeter Med Sch, Genet Complex Traits, Exeter, Devon, England.;Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England.;Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Sim, Xueling
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI USA..
    Blackwell, Thomas W.
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI USA..
    Robertson, Neil R.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Rayner, N. William
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, Cambridgeshire, England..
    Cingolani, Pablo
    McGill Univ, Sch Comp Sci, Montreal, PQ, Canada.;McGill Univ, Genome Quebec Innovat Ctr, Montreal, PQ H3A 2T5, Canada..
    Locke, Adam E.
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI USA..
    Tajes, Juan Fernandez
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England..
    Highland, Heather M.
    Univ Texas Grad Sch Biomed Sci, Ctr Human Genet, Univ Texas Hlth Sci Ctr, Houston, TX USA..
    Dupuis, Josee
    Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA USA.;Boston Univ Sch Publ Hlth, Dept Biostatist, Boston, MA USA.;Nat Heart Lung & Blood Inst Framingham Heart Stud, Framingham, MA USA..
    Chines, Peter S.
    NIH, Natl Human Genome Res Inst, Med Genom & Metab Genet Branch, Bethesda, MD USA..
    Lindgren, Cecilia M.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.;Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England..
    Hartl, Christopher
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Jackson, Anne U.
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI USA..
    Chen, Han
    Boston Univ Sch Publ Hlth, Dept Biostatist, Boston, MA USA.;Harvard Sch Publ Hlth, Dept Biostatist, Boston, MA USA..
    Huyghe, Jeroen R.
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI USA..
    De Bunt, Martijn Van
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Pearson, Richard D.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England..
    Kumar, Ashish
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Basel, Swiss Trop & Publ Hlth Inst, Chron Dis Epidemiol, Basel, Switzerland..
    Muller-Nurasyid, Martina
    German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Univ Hosp Grosshadern, Ludwig Maximilians Univ, Dept Med I, Munich, Germany.;Ludwig Maximilians Univ Munchen, IBE, Chair Genet Epidemiol, Fac Med, Munich, Germany.;DZHK German Ctr Cardiovascular Res, Munich Heart Alliance, Munich, Germany..
    Grarup, Niels
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Stringham, Heather M.
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI USA..
    Gamazon, Eric R.
    Univ Chicago, Med Genet Sect, Dept Med, Chicago, IL USA..
    Lee, Jaehoon
    Seoul Natl Univ, Dept Stat, Seoul, South Korea..
    Chen, Yuhui
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England..
    Scott, Robert A.
    Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England..
    Below, Jennifer E.
    Univ Texas Hlth Sci Ctr, Sch Publ Hlth, Ctr Human Genet, Houston, TX USA..
    Chen, Peng
    Natl Univ Singapore, Natl Univ Hlth Syst, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore..
    Huang, Jinyan
    Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA..
    Go, Min Jin
    Korea Natl Inst Hlth, Ctr Genome Sci, Chungcheongbukdo, South Korea..
    Stitzel, Michael L.
    Jackson Lab Genom Med, Farmington, CT USA..
    Pasko, Dorota
    Univ Exeter, Univ Exeter Med Sch, Genet Complex Traits, Exeter, Devon, England..
    Parker, Stephen C. J.
    Univ Michigan, Dept Computat Med Bioinformat, Ann Arbor, MI USA.;Univ Michigan, Dept Human Genet, Ann Arbor, MI USA..
    Varga, Tibor V.
    Lund Univ, Lund Univ Diabet Ctr, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden..
    Green, Todd
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Beer, Nicola L.
    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Day-Williams, Aaron G.
    Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, Cambridgeshire, England..
    Ferreira, Teresa
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England..
    Fingerlin, Tasha
    Univ Colorado, Colorado Sch Publ Hlth, Dept Epidemiol, Aurora, CO USA..
    Horikoshi, Momoko
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Hu, Cheng
    Shanghai Jiao Tong Univ, Shanghai Diabet Inst, Dept Endocrinol & Metab, Sixth Peoples Hosp, Shanghai, Peoples R China..
    Huh, Iksoo
    Seoul Natl Univ, Dept Stat, Seoul, South Korea..
    Ikram, Mohammad Kamran
    Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Natl Univ Singapore, Natl Univ Hlth Syst, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore.;Eye Acad Clin Programme, Duke NUS Grad Med Sch, Singapore, Singapore..
    Kim, Bong-Jo
    Korea Natl Inst Hlth, Ctr Genome Sci, Chungcheongbukdo, South Korea..
    Kim, Yongkang
    Seoul Natl Univ, Dept Stat, Seoul, South Korea..
    Kim, Young Jin
    Korea Natl Inst Hlth, Ctr Genome Sci, Chungcheongbukdo, South Korea..
    Kwon, Min-Seok
    Seoul Natl Univ, Interdisciplinary Program Bioinformat, Seoul, South Korea..
    Lee, Juyoung
    Korea Natl Inst Hlth, Ctr Genome Sci, Chungcheongbukdo, South Korea..
    Lee, Selyeong
    Seoul Natl Univ, Dept Stat, Seoul, South Korea..
    Lin, Keng-Han
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI USA..
    Maxwell, Taylor J.
    Univ Texas Hlth Sci Ctr, Sch Publ Hlth, Ctr Human Genet, Houston, TX USA..
    Nagai, Yoshihiko
    McGill Univ, Genome Quebec Innovat Ctr, Montreal, PQ H3A 2T5, Canada.;McGill Univ, Dept Human Genet, Montreal, PQ, Canada.;Res Inst McGill Univ Hlth Ctr, Montreal, PQ, Canada..
    Wang, Xu
    Natl Univ Singapore, Natl Univ Hlth Syst, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore..
    Welch, Ryan P.
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI USA..
    Yoon, Joon
    Seoul Natl Univ, Interdisciplinary Program Bioinformat, Seoul, South Korea..
    Zhang, Weihua
    Imperial Coll London, Dept Epidemiol & Biostat, London, England.;Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England..
    Barzilai, Nir
    Albert Einstein Coll Med, Dept Med, New York, NY USA.;Albert Einstein Coll Med, Dept Genet, New York, NY USA..
    Voight, Benjamin F.
    Univ Pennsylvania, Dept Syst Pharmacol & Translat Therapeut, Perelman Sch Med, Philadelphia, PA USA.;Univ Pennsylvania, Dept Genet, Perelman Sch Med, Philadelphia, PA USA..
    Han, Bok-Ghee
    Korea Natl Inst Hlth, Ctr Genome Sci, Chungcheongbukdo, South Korea..
    Jenkinson, Christopher P.
    Univ Texas Hlth Sci Ctr, Dept Med, San Antonio, TX USA.;South Texas Vet Hlth Care Syst, Res, San Antonio, TX USA..
    Kuulasmaa, Teemu
    Univ Eastern Finland, Inst Clin Med, Fac Hlth Sci, Internal Med, Kuopio, Finland..
    Kuusisto, Johanna
    Univ Eastern Finland, Inst Clin Med, Fac Hlth Sci, Internal Med, Kuopio, Finland.;Kuopio Univ Hosp, Kuopio, Finland..
    Manning, Alisa
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Ng, Maggie C. Y.
    Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA..
    Palmer, Nicholette D.
    Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA.;Wake Forest Sch Med, Dept Biochem, Winston Salem, NC USA..
    Balkau, Beverley
    Inserm U1018, Ctr Res Epidemiol & Populat Hlth, Villejuif, France..
    Stancakova, Alena
    Univ Eastern Finland, Inst Clin Med, Fac Hlth Sci, Internal Med, Kuopio, Finland..
    Abboud, Hanna E.
    Univ Texas Hlth Sci Ctr, Dept Med, San Antonio, TX USA..
    Boeing, Heiner
    German Inst Human Nutr Potsdam Rehbrucke, Nuthetal, Germany..
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Prabhakaran, Dorairaj
    Ctr Chron Dis Control, New Delhi, India..
    Gottesman, Omri
    Charles Bronfman Inst Personalized Med, Icahn Sch Med, Mt Sinai, New York, NY USA..
    Scott, James
    Natl Heart & Lung Inst, Cardiovascular Sci, Imperial Coll London, Hammersmith Campus, London, England..
    Carey, Jason
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Kwan, Phoenix
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI USA..
    Grant, George
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Smith, Joshua D.
    Univ Washington Sch Med, Dept Genome Sci, Seattle, WA USA..
    Neale, Benjamin M.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.;Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA USA..
    Purcell, Shaun
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.;Massachusetts Gen Hosp, Dept Med, Ctr Genom Med, Boston, MA USA.;Icahn Inst Genom & Multiscale Biol, Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY USA..
    Butterworth, Adam S.
    Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England..
    Howson, Joanna M. M.
    Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England..
    Lee, Heung Man
    Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Peoples R China..
    Lu, Yingchang
    Charles Bronfman Inst Personalized Med, Icahn Sch Med, Mt Sinai, New York, NY USA..
    Kwak, Soo-Heon
    Seoul Natl Univ Coll Med, Dept Internal Med, Seoul, South Korea..
    Zhao, Wei
    Univ Pennsylvania, Dept Med, Philadelphia, PA USA..
    Danesh, John
    Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, Cambridgeshire, England.;Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England.;Univ Cambridge, Dept Publ Hlth & Primary Care, NIHR Blood & Transplant Res Unit Donor Hlth & Gen, Cambridge, England..
    Lam, Vincent K. L.
    Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Peoples R China..
    Park, Kyong Soo
    Seoul Natl Univ, Dept Mol Med & Biopharmaceut Sci, Grad Sch Convergence Sci & Technol, Seoul, South Korea.;Seoul Natl Univ, Coll Med, Seoul, South Korea..
    Saleheen, Danish
    Univ Pennsylvania, Dept Biostatist & Epidemiol, Philadelphia, PA USA.;Ctr Non Communicable Dis, Karachi, Pakistan..
    So, Wing Yee
    Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Peoples R China..
    Tam, Claudia H. T.
    Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Peoples R China..
    Afzal, Uzma
    Imperial Coll London, Dept Epidemiol & Biostat, London, England..
    Aguilar, David
    Baylor Coll Med, Cardiovascular Div, Houston, TX USA..
    Arya, Rector
    Univ Texas Hlth Sci Ctr, Dept Pediat, San Antonio, TX USA..
    Aung, Tin
    Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Natl Univ Singapore, Natl Univ Hlth Syst, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore.;Eye Acad Clin Programme, Duke NUS Grad Med Sch, Singapore, Singapore..
    Chan, Edmund
    Natl Univ Singapore, Natl Univ Hlth Syst, Yong Loo Lin Sch Med, Dept Med, Singapore, Singapore..
    Navarro, Carmen
    Murcia Reg Hlth Council, Dept Epidemiol, IMIB Arrixaca, Murcia, Spain.;CIBER Epidemiol Salud Publ CIBERESP, Madrid, Spain.;Univ Murcia, Sch Med, Unit Prevent Med & Publ Hlth, Murcia, Spain..
    Cheng, Ching-Yu
    Natl Univ Singapore, Natl Univ Hlth Syst, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Natl Univ Singapore, Natl Univ Hlth Syst, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore.;Eye Acad Clin Programme, Duke NUS Grad Med Sch, Singapore, Singapore..
    Palli, Domenico
    Canc Res & Prevent Inst ISPO, Florence, Italy..
    Correa, Adolfo
    Univ Mississippi Med Ctr, Dept Med, Jackson, MS USA..
    Curran, Joanne E.
    Univ Texas Hlth Sci Ctr, San Antonio Univ Texas Rio Grande Valley, Reg Acad Hlth Ctr, South Texas Diabet & Obes Inst, Brownsville, TX USA..
    Rybin, Dennis
    Boston Univ Sch Publ Hlth, Dept Biostatist, Boston, MA USA..
    Farook, Vidya S.
    Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA..
    Fowler, Sharon P.
    Univ Texas Hlth Sci Ctr, Dept Med, San Antonio, TX USA..
    Freedman, Barry I.
    Wake Forest Sch Med, Nephrol Sect, Dept Internal Med, Winston Salem, NC USA..
    Griswold, Michael
    Univ Mississippi, Med Ctr, Ctr Biostat & Bioinformat, Jackson, MS 39216 USA..
    Hale, Daniel Esten
    Univ Texas Hlth Sci Ctr, Dept Pediat, San Antonio, TX USA..
    Hicks, Pamela J.
    Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA.;Wake Forest Sch Med, Dept Biochem, Winston Salem, NC USA..
    Khor, Chiea-Chuen
    Natl Univ Singapore, Natl Univ Hlth Syst, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Natl Univ Singapore, Natl Univ Hlth Syst, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore.;Natl Univ Singapore, Natl Univ Hlth Syst, Dept Paediat, Yong Loo Lin Sch Med, Singapore, Singapore..
    Kumar, Satish
    Univ Texas Hlth Sci Ctr, San Antonio Univ Texas Rio Grande Valley, Reg Acad Hlth Ctr, South Texas Diabet & Obes Inst, Brownsville, TX USA..
    Lehne, Benjamin
    Imperial Coll London, Dept Epidemiol & Biostat, London, England..
    Thuillier, Dorothee
    Univ Lille, Lille Pasteur Inst, CNRS UMR8199, Lille, France..
    Lim, Wei Yen
    Natl Univ Singapore, Natl Univ Hlth Syst, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore..
    Liu, Jianjun
    Natl Univ Singapore, Natl Univ Hlth Syst, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;ASTAR, Genome Inst Singapore, Divis Human Genet, Singapore, Singapore..
    Loh, Marie
    Imperial Coll London, Dept Epidemiol & Biostat, London, England.;Univ Oulu, Inst Hlth Sci, Oulu, Finland.;ASTAR, Translat Lab Genet Med TLGM, Singapore, Singapore..
    Musani, Solomon K.
    Univ Mississippi, Med Ctr, Jackson Heart Study, Jackson, MS 39216 USA..
    Puppala, Sobha
    Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA..
    Scott, William R.
    Imperial Coll London, Dept Epidemiol & Biostat, London, England..
    Yengo, Loic
    Univ Lille, Lille Pasteur Inst, CNRS UMR8199, Lille, France..
    Tan, Sian-Tsung
    Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England.;Natl Heart & Lung Inst, Cardiovascular Sci, Imperial Coll London, Hammersmith Campus, London, England..
    Taylor, Herman A.
    Univ Mississippi Med Ctr, Dept Med, Jackson, MS USA..
    Thameem, Farook
    Univ Texas Hlth Sci Ctr, Dept Med, San Antonio, TX USA..
    Wilson, Gregory
    Jackson State Univ, Coll Publ Serv, Jackson, MS USA..
    Wong, Tien Yin
    Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Natl Univ Singapore, Natl Univ Hlth Syst, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore.;Eye Acad Clin Programme, Duke NUS Grad Med Sch, Singapore, Singapore..
    Njolstad, Pal Rasmus
    Univ Bergen, Dept Clin Sci, KG Jebsen Ctr Diabet Res, Bergen, Norway.;Haukeland Hosp, Dept Pediat, Bergen, Norway..
    Levy, Jonathan C.
    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Mangino, Massimo
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England.;Guys & St Thomas Fdn Trust, NIHR Biomed Res Ctr, London, England..
    Bonnycastle, Lori L.
    NIH, Natl Human Genome Res Inst, Med Genom & Metab Genet Branch, Bethesda, MD USA..
    Schwarzmayr, Thomas
    Helmholtz Zentrum Munchen, Inst Human Genet, German Res Ctr Environm Hlth, Neuherberg, Germany..
    Fadista, Joao
    Lund Univ, Dept Clin Sci Diabet & Endocrinol, Ctr Diabet, Malmo, Sweden..
    Surdulescu, Gabriela L.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Herder, Christian
    Heinrich Heine Univ, German Diabet Ctr, Leibniz Ctr Diabet Res, Inst Clin Diabetol, Dusseldorf, Germany.;German Ctr Diabet Res DZD, Munich, Germany..
    Groves, Christopher J.
    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Wieland, Thomas
    Helmholtz Zentrum Munchen, Inst Human Genet, German Res Ctr Environm Hlth, Neuherberg, Germany..
    Bork-Jensen, Jette
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Brandslund, Ivan
    Univ Southern Denmark, Inst Reg Hlth Res, Odense, Denmark.;Vejle Hosp, Dept Clin Biochem, Vejle, Denmark..
    Christensen, Cramer
    Vejle Hosp, Dept Internal Med & Endocrinol, Vejle, Denmark..
    Koistinen, Heikki A.
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland.;Univ Helsinki, Abdominal Ctr Endocrinol, Helsinki, Finland.;Helsinki Univ Cent Hosp, Abdominal Ctr Endocrinol, Helsinki, Finland.;Minerva Fdn, Helsinki, Finland.;Univ Helsinki, Dept Med, Helsinki, Finland.;Helsinki Univ Cent Hosp, Dept Med, Helsinki, Finland..
    Doney, Alex S. F.
    Med Res Inst, Ninewells Hosp & Med Sch, Divis Cardiovascular & Diabet Med, Dundee, Scotland..
    Kinnunen, Leena
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland..
    Esko, Tonu
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.;Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.;Harvard Med Sch, Dept Genet, Boston, MA USA.;Boston Childrens Hosp, Divis Endocrinol, Boston, MA USA..
    Farmer, Andrew J.
    Univ Oxford, Nuffield Dept Primary Care Hlth Sci, Oxford, England..
    Hakaste, Liisa
    Univ Helsinki, Abdominal Ctr Endocrinol, Helsinki, Finland.;Helsinki Univ Cent Hosp, Abdominal Ctr Endocrinol, Helsinki, Finland.;Folkhalsan Res Ctr, Helsinki, Finland.;Univ Helsinki, Res Programs Unit, Diabet & Obes, Helsinki, Finland..
    Hodgkiss, Dylan
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Kravic, Jasmina
    Lund Univ, Dept Clin Sci Diabet & Endocrinol, Ctr Diabet, Malmo, Sweden..
    Lyssenko, Valeriya
    Univ Bergen, Dept Clin Sci, KG Jebsen Ctr Diabet Res, Bergen, Norway.;Lund Univ, Dept Clin Sci Diabet & Endocrinol, Ctr Diabet, Malmo, Sweden..
    Hollensted, Mette
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Jorgensen, Marit E.
    Steno Diabet Ctr, Gentofte, Denmark..
    Jorgensen, Torben
    Capital Region Denmark, Res Ctr Prevent & Hlth, Glostrup, Denmark.;Univ Copenhagen, Inst Hlth Sci, Dept Publ Hlth, Copenhagen, Denmark.;Aalborg Univ, Fac Med, Aalborg, Denmark..
    Ladenvall, Claes
    Lund Univ, Dept Clin Sci Diabet & Endocrinol, Ctr Diabet, Malmo, Sweden..
    Justesen, Johanne Marie
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Karajamaki, Annemari
    Vaasa Cent Hosp, Dept Primary Hlth Care, Vaasa, Finland.;Vaasa Hlth Care Ctr, Ctr Diabet, Vaasa, Finland..
    Kriebel, Jennifer
    German Ctr Diabet Res DZD, Munich, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol II, Neuherberg, Germany.;Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Germany..
    Rathmann, Wolfgang
    German Ctr Diabet Res DZD, Munich, Germany.;Heinrich Heine Univ, German Diabet Ctr, Leibniz Ctr Diabet Res, Inst Biometr & Epidemiol, Dusseldorf, Germany..
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lauritzen, Torsten
    Aarhus Univ, Sect Gen Practice, Dept Publ Hlth, Aarhus, Denmark..
    Narisu, Narisu
    NIH, Natl Human Genome Res Inst, Med Genom & Metab Genet Branch, Bethesda, MD USA..
    Linneberg, Allan
    Capital Region Denmark, Res Ctr Prevent & Hlth, Glostrup, Denmark.;Dept Clin Expt Res, Rigshospitalet, Glostrup, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark..
    Melander, Olle
    Lund Univ, Dept Clin Sci, Hypertens & Cardiovascular Dis, Malmo, Sweden..
    Milani, Lili
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Neville, Matt
    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England..
    Orho-Melander, Marju
    Lund Univ, Dept Clin Sci, Diabet & Cardiovascular Dis, Genet Epidemiol, Malmo, Sweden..
    Qi, Lu
    Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Brigham & Womens Hosp & Harvard Med Sch, Channing Div Network Med, Dept Med, Boston, MA USA..
    Qi, Qibin
    Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, New York, NY USA..
    Roden, Michael
    Heinrich Heine Univ, German Diabet Ctr, Leibniz Ctr Diabet Res, Inst Clin Diabetol, Dusseldorf, Germany.;German Ctr Diabet Res DZD, Munich, Germany.;Heinrich Heine Univ, Fac Med, Divis Endocrinol & Diabetol, Dusseldorf, Germany..
    Rolandsson, Olov
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Swift, Amy
    NIH, Natl Human Genome Res Inst, Med Genom & Metab Genet Branch, Bethesda, MD USA..
    Rosengren, Anders H.
    Lund Univ, Dept Clin Sci Diabet & Endocrinol, Ctr Diabet, Malmo, Sweden..
    Stirrups, Kathleen
    Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, Cambridgeshire, England..
    Wood, Andrew R.
    Univ Exeter, Univ Exeter Med Sch, Genet Complex Traits, Exeter, Devon, England..
    Mihailov, Evelin
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Blancher, Christine
    Univ Oxford, Nuffield Dept Med, Oxford Genom Ctr, Wellcome Trust Ctr Human Genet, Oxford, England..
    Carneiro, Mauricio O.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Maguire, Jared
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Poplin, Ryan
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Shakir, Khalid
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Fennell, Timothy
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    DePristo, Mark
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    De Angelis, Martin Hrabe
    German Ctr Diabet Res DZD, Munich, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Expt Genet, Neuherberg, Germany.;Tech Univ Munich, Ctr Life & Food Sci Weihenstephan, Freising Weihenstephan, Germany..
    Deloukas, Panos
    Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, Cambridgeshire, England.;Queen Mary Univ London, William Harvey Res Inst, London, England.;Queen Mary Univ London, London Sch Med & Dent, London, England.;King Abdulaziz Univ, Princess Jawhara Brahim Ctr Excellence Res Heredi, Jeddah, Saudi Arabia..
    Gjesing, Anette P.
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Jun, Goo
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI USA.;Univ Texas Hlth Sci Ctr, Sch Publ Hlth, Ctr Human Genet, Houston, TX USA..
    Nilsson, Peter M.
    Lund Univ, Dept Clin Sci, Malmo, Sweden.;Lund Univ, Dept Med, Malmo, Sweden..
    Murphy, Jacquelyn
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Onofrio, Robert
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Thorand, Barbara
    German Ctr Diabet Res DZD, Munich, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol II, Neuherberg, Germany..
    Hansen, Torben
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark.;Univ Southern Denmark, Fac Hlth Sci, Odense, Denmark..
    Meisinger, Christa
    German Ctr Diabet Res DZD, Munich, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol II, Neuherberg, Germany..
    Hu, Frank B.
    Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA.;Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA..
    Isomaa, Bo
    Folkhalsan Res Ctr, Helsinki, Finland.;Dept Social Serv & Hlth Care, Pietarsaari, Finland..
    Karpe, Fredrik
    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England..
    Liang, Liming
    Harvard Sch Publ Hlth, Dept Biostatist, Boston, MA USA.;Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA..
    Peters, Annette
    DZHK German Ctr Cardiovascular Res, Munich Heart Alliance, Munich, Germany.;German Ctr Diabet Res DZD, Munich, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol II, Neuherberg, Germany..
    Huth, Cornelia
    German Ctr Diabet Res DZD, Munich, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol II, Neuherberg, Germany..
    O'Rahilly, Stephen P.
    Univ Cambridge, Inst Metab Sci, Metabol Res Labs, Cambridge, England..
    Palmer, Colin N. A.
    Ninewells Hosp & Med Sch, Pat Macpherson Ctr Pharmacogenet & Pharmacogenet, Dundee, Scotland.;Ninewells Hosp & Med Sch, Med Res Inst, Dundee, Scotland..
    Pedersen, Oluf
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Rauramaa, Rainer
    Kuopio Res Inst Exercise Med, Foundat Res Hlth Exercise & Nutr, Kuopio, Finland..
    Tuomilehto, Jaakko
    Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria.;King Abdulaziz Univ, Diabetes Res Grp, Jeddah, Saudi Arabia.;Dasman Diabet Inst, Kuwait, Kuwait.;Natl Inst Hlth & Welf, Helsinki, Finland..
    Salomaa, Veikko
    Natl Inst Hlth & Welf, Helsinki, Finland..
    Watanabe, Richard M.
    Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA.;Univ Southern Calif, Keck Sch Med, Dept Physiol Biophys, Los Angeles, CA USA.;Univ Southern Calif, Diabet & Obes Res Inst, Keck Sch Med, Los Angeles, CA USA..
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bergman, Richard N.
    Cedars Sinai Diabet & Obes Res Inst, Los Angeles, CA USA..
    Bharadwaj, Dwaipayan
    CSIR Inst Genom Integrat Biol CSIR IGIB, Funct Genom Unit, New Delhi, India..
    Bottinger, Erwin P.
    Charles Bronfman Inst Personalized Med, Icahn Sch Med, Mt Sinai, New York, NY USA..
    Cho, Yoon Shin
    Hallym Univ, Dept Biomed Sci, Chunchon, South Korea..
    Chandak, Giriraj R.
    CSIR, Ctr Cellular & Mol Biol, Hyderabad, Andhra Pradesh, India..
    Chan, Juliana Cn
    Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Peoples R China.;Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Hong Kong, Peoples R China.;Chinese Univ Hong Kong, Hong Kong Inst Diabet & Obes, Hong Kong, Peoples R China..
    Chia, Kee Seng
    Natl Univ Singapore, Natl Univ Hlth Syst, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore..
    Daly, Mark J.
    Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA USA..
    Ebrahim, Shah B.
    Ctr Chron Dis Control, New Delhi, India..
    Langenberg, Claudia
    Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England..
    Elliott, Paul
    Imperial Coll London, Dept Epidemiol & Biostat, London, England.;Imperial Coll London, MRC PHE Ctr Environm & Hlth, London, England..
    Jablonski, Kathleen A.
    George Washington Univ, Biostatist Ctr, Rockville, MD USA..
    Lehman, Donna M.
    Univ Texas Hlth Sci Ctr, Dept Med, San Antonio, TX USA..
    Jia, Weiping
    Shanghai Jiao Tong Univ, Shanghai Diabet Inst, Dept Endocrinol & Metab, Sixth Peoples Hosp, Shanghai, Peoples R China..
    Ma, Ronald Cw
    Boston Univ Sch Publ Hlth, Dept Biostatist, Boston, MA USA.;Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Peoples R China.;Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Hong Kong, Peoples R China.;Chinese Univ Hong Kong, Hong Kong Inst Diabet & Obes, Hong Kong, Peoples R China..
    Pollin, Toni I.
    Univ Maryland Sch Med, Div Endocrinol Diabet & Nutr, Dept Med, Baltimore, MD USA.;Univ Maryland Sch Med, Program Personalized Genom Med, Baltimore, MD USA..
    Sandhu, Manjinder
    Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, Cambridgeshire, England.;Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England..
    Tandon, Nikhil
    All India Inst Med Sci, Dept Endocrinol & Metab, New Delhi, India..
    Froguel, Philippe
    Univ Lille, Lille Pasteur Inst, CNRS UMR8199, Lille, France.;Imperial Coll London, Sch Publ Hlth, Dept Genom Common Dis, London, England..
    Barroso, Ines
    Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, Cambridgeshire, England.;Univ Cambridge, Inst Metab Sci, Metabol Res Labs, Cambridge, England..
    Teo, Yik Ying
    Natl Univ Singapore, Natl Univ Hlth Syst, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;Natl Univ Singapore, Inst Life Sci, Singapore, Singapore.;Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore, Singapore..
    Zeggini, Eleftheria
    Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, Cambridgeshire, England..
    Loos, Ruth J. F.
    Charles Bronfman Inst Personalized Med, Icahn Sch Med, Mt Sinai, New York, NY USA..
    Small, Kerrin S.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Ried, Janina S.
    German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany..
    DeFronzo, Ralph A.
    Univ Texas Hlth Sci Ctr, Dept Med, San Antonio, TX USA..
    Grallert, Harald
    German Ctr Diabet Res DZD, Munich, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol II, Neuherberg, Germany.;Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Germany..
    Glaser, Benjamin
    Hadassah Hebrew Univ Med Ctr, Endocrinol & Metab Serv, Jerusalem, Israel..
    Metspalu, Andres
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Wareham, Nicholas J.
    Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England..
    Walker, Mark
    Newcastle Univ, Inst Cellular Med, Sch Med, Newcastle Upon Tyne, Tyne & Wear, England..
    Banks, Eric
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Gieger, Christian
    German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol II, Neuherberg, Germany.;Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Germany..
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.
    Im, Hae Kyung
    Univ Chicago, Med Genet Sect, Dept Med, Chicago, IL USA..
    Illig, Thomas
    Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Neuherberg, Germany.;Hannover Med Sch, Hannover Unified Biobank, Hannover, NH, Germany.;Hannover Med Sch, Dept Human Genet, Hannover, NH, Germany..
    Franks, Paul W.
    Lund Univ, Lund Univ Diabet Ctr, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden.;Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Buck, Gemma
    Univ Oxford, Nuffield Dept Med, Oxford Genom Ctr, Wellcome Trust Ctr Human Genet, Oxford, England..
    Trakalo, Joseph
    Univ Oxford, Nuffield Dept Med, Oxford Genom Ctr, Wellcome Trust Ctr Human Genet, Oxford, England..
    Buck, David
    Univ Oxford, Nuffield Dept Med, Oxford Genom Ctr, Wellcome Trust Ctr Human Genet, Oxford, England..
    Prokopenko, Inga
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Imperial Coll London, Sch Publ Hlth, Dept Genom Common Dis, London, England..
    Magi, Reedik
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Farjoun, Yossi
    Broad Inst, Data Sci & Data Engn, Cambridge, MA USA..
    Owen, Katharine R.
    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England..
    Gloyn, Anna L.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England..
    Strauch, Konstantin
    German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Ludwig Maximilians Univ Munchen, IBE, Chair Genet Epidemiol, Fac Med, Munich, Germany..
    Tuomi, Tiinamaija
    Univ Helsinki, Abdominal Ctr Endocrinol, Helsinki, Finland.;Helsinki Univ Cent Hosp, Abdominal Ctr Endocrinol, Helsinki, Finland.;Folkhalsan Res Ctr, Helsinki, Finland.;Univ Helsinki, Res Programs Unit, Diabet & Obes, Helsinki, Finland.;Univ Helsinki, Finnish Inst Mol Med, Helsinki, Finland..
    Kooner, Jaspal Singh
    Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England.;Natl Heart & Lung Inst, Cardiovascular Sci, Imperial Coll London, Hammersmith Campus, London, England.;Imperial Coll London, Imperial Coll Healthcare NHS Trust, London, England..
    Lee, Jong-Young
    Korea Natl Inst Hlth, Ctr Genome Sci, Chungcheongbukdo, South Korea..
    Park, Taesung
    Seoul Natl Univ, Dept Stat, Seoul, South Korea.;Seoul Natl Univ, Interdisciplinary Program Bioinformat, Seoul, South Korea..
    Donnelly, Peter
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Dept Stat, Oxford, England..
    Morris, Andrew D.
    Ninewells Hosp & Med Sch, Ctr Mol Med, Clin Res Ctr, Dundee, Scotland.;Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland..
    Hattersley, Andrew T.
    Univ Exeter, Univ Exeter Med Sch, Exeter, Devon, England..
    Bowden, Donald W.
    Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA.;Wake Forest Sch Med, Dept Biochem, Winston Salem, NC USA..
    Collins, Francis S.
    NIH, Natl Human Genome Res Inst, Med Genom & Metab Genet Branch, Bethesda, MD USA..
    Atzmon, Gil
    Albert Einstein Coll Med, Dept Med, New York, NY USA.;Albert Einstein Coll Med, Dept Genet, New York, NY USA.;Univ Haifa, Dept Nat Sci, Haifa, Israel..
    Chambers, John C.
    Imperial Coll London, Dept Epidemiol & Biostat, London, England.;Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England.;Imperial Coll London, Imperial Coll Healthcare NHS Trust, London, England..
    Spector, Timothy D.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Laakso, Markku
    Univ Eastern Finland, Inst Clin Med, Fac Hlth Sci, Internal Med, Kuopio, Finland.;Kuopio Univ Hosp, Kuopio, Finland..
    Strom, Tim M.
    Helmholtz Zentrum Munchen, Inst Human Genet, German Res Ctr Environm Hlth, Neuherberg, Germany.;Tech Univ Munich, Inst Human Genet, Munich, Germany..
    Bell, Graeme I.
    Univ Chicago, Dept Med, Chicago, IL USA.;Univ Chicago, Dept Human Genet, Chicago, IL USA..
    Blangero, John
    Univ Texas Hlth Sci Ctr, San Antonio Univ Texas Rio Grande Valley, Reg Acad Hlth Ctr, South Texas Diabet & Obes Inst, Brownsville, TX USA..
    Duggirala, Ravindranath
    Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA..
    Tai, EShyong
    Natl Univ Singapore, Natl Univ Hlth Syst, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;Natl Univ Singapore, Natl Univ Hlth Syst, Yong Loo Lin Sch Med, Dept Med, Singapore, Singapore.;Duke NUS Med Sch Singapore, Cardiovascular Metab Disorders Program, Singapore, Singapore..
    McVean, Gilean
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Li Ka Shing Ctr Hlth Informat & Discovery, Oxford, England..
    Hanis, Craig L.
    Univ Texas Hlth Sci Ctr, Sch Publ Hlth, Ctr Human Genet, Houston, TX USA..
    Wilson, James G.
    Univ Mississippi Med Ctr, Dept Physiol & Biophys, Jackson, MS USA..
    Seielstad, Mark
    Univ Calif San Francisco, Dept Lab Med, Inst Human Genet, San Francisco, CA USA.;Blood Syst Res Inst, San Francisco, CA USA..
    Frayling, Timothy M.
    Univ Exeter, Univ Exeter Med Sch, Genet Complex Traits, Exeter, Devon, England..
    Meigs, James B.
    Harvard Med Sch, Massachusetts Gen Hosp, Div Gen Med, Boston, MA USA.;Harvard Med Sch, Dept Med, Boston, MA USA..
    Cox, Nancy J.
    Univ Chicago, Med Genet Sect, Dept Med, Chicago, IL USA..
    Sladek, Rob
    McGill Univ, Genome Quebec Innovat Ctr, Montreal, PQ H3A 2T5, Canada.;McGill Univ, Dept Human Genet, Montreal, PQ, Canada.;McGill Univ, Dept Med, Divis Endocrinol & Metab, Montreal, PQ, Canada..
    Lander, Eric S.
    MIT, Broad Inst, Cambridge, MA USA..
    Gabriel, Stacey
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Mohlke, Karen L.
    Univ N Carolina, Dept Genet, Chapel Hill, NC USA..
    Meitinger, Thomas
    Helmholtz Zentrum Munchen, Inst Human Genet, German Res Ctr Environm Hlth, Neuherberg, Germany.;Tech Univ Munich, Inst Human Genet, Munich, Germany..
    Groop, Leif
    Lund Univ, Dept Clin Sci Diabet & Endocrinol, Ctr Diabet, Malmo, Sweden.;Univ Helsinki, Finnish Inst Mol Med, Helsinki, Finland..
    Abecasis, Goncalo
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI USA..
    Scott, Laura J.
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI USA..
    Morris, Andrew P.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.;Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England..
    Kang, Hyun Min
    Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA USA..
    Altshuler, David
    Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA USA.;Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.;Harvard Med Sch, Dept Genet, Boston, MA USA.;Harvard Med Sch, Dept Med, Boston, MA USA.;Massachusetts Gen Hosp, Dept Med, Diabet Res Ctr Diabet Unit, Boston, MA USA.;MIT, Dept Biol, Cambridge, MA 02139 USA..
    Burtt, Noel P.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Florez, Jose C.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.;Massachusetts Gen Hosp, Dept Med, Ctr Genom Med, Boston, MA USA.;Harvard Med Sch, Dept Med, Boston, MA USA.;Massachusetts Gen Hosp, Dept Med, Diabet Res Ctr Diabet Unit, Boston, MA USA..
    Boehnke, Michael
    Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI USA..
    McCarthy, Mark I.
    Univ Oxford, Nuffield Dept Med, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England..
    Data Descriptor: Sequence data and association statistics from 12,940 type 2 diabetes cases and controls2017In: Scientific Data, E-ISSN 2052-4463, Vol. 4, article id 170179Article in journal (Refereed)
    Abstract [en]

    To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (> 80% of low-frequency coding variants in similar to ~82 K Europeans via the exome chip, and similar to ~90% of low-frequency non-coding variants in similar to ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.

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  • 73. Folkersen, Lasse
    et al.
    van't Hooft, Ferdinand
    Chernogubova, Ekaterina
    Agardh, Hanna E.
    Hansson, Göran K.
    Hedin, Ulf
    Liska, Jan
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Paulssson-Berne, Gabrielle
    Franco-Cereceda, Anders
    Hamsten, Anders
    Gabrielsen, Anders
    Eriksson, Per
    Association of genetic risk variants with expression of proximal genes identifies novel susceptibility genes for cardiovascular disease2010In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 3, no 4, p. 365-373Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Population-based genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with cardiovascular disease or its risk factors. Genes in close proximity to these risk-SNPs are often thought to be pathogenetically important based on their location alone. However, the actual connections between SNPs and disease mechanisms remain largely unknown.

    METHODS AND RESULTS:

    To identify novel susceptibility genes, we investigated how 166 SNPs previously found to be associated with increased cardiovascular risk and/or predisposing metabolic traits relate to the expression of nearby genes. Gene expression in 577 samples of aorta, liver, mammary artery, and carotid atherosclerotic plaque was measured using expression arrays. For 47 SNPs, the expression levels of proximal genes (located within 200 kb) were affected (P<0.005). More than 20 of these genes had not previously been identified as candidate genes for cardiovascular or related metabolic traits. SNP-associated gene effects were tissue-specific and the tissue specificity was phenotype-dependent.

    CONCLUSIONS:

    This study demonstrates several instances of association between risk-SNPs and genes immediately adjacent to them. It also demonstrates instances in which the associated gene is not the immediately proximal and obvious candidate gene for disease. This shows the necessity of careful studies of genetic marker data as a first step toward application of genome-wide association studies findings in a clinical setting.

  • 74.
    Foox, Jonathan
    et al.
    Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10021 USA.;Weill Cornell Med, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsau, New York, NY 10021 USA..
    Nordlund, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab. EATRIS ERIC European Infrastruct Translat Med, De Boelelaan 1118, NL-1081 HZ Amsterdam, Netherlands.
    Lalancette, Claudia
    Univ Michigan Med, BRCF Epigen Core, Ann Arbor, MI 48109 USA..
    Gong, Ting
    Univ Hawaii, Dept Quantitat Hlth Sci, John A Burns Sch Med, Honolulu, HI 96813 USA..
    Lacey, Michelle
    Tulane Univ, New Orleans, LA 70118 USA..
    Lent, Samantha
    AbbVie Genom Res Ctr, 1 N Waukegan Rd, N Chicago, IL 60036 USA..
    Langhorst, Bradley W.
    New England Biolabs Inc, Ipswich, MA 01938 USA..
    Ponnaluri, V. K. Chaithanya
    New England Biolabs Inc, Ipswich, MA 01938 USA..
    Williams, Louise
    New England Biolabs Inc, Ipswich, MA 01938 USA..
    Padmanabhan, Karthik Ramaswamy
    Univ Michigan Med, BRCF Epigen Core, Ann Arbor, MI 48109 USA..
    Cavalcante, Raymond
    Univ Michigan Med, BRCF Epigen Core, Ann Arbor, MI 48109 USA..
    Lundmark, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab. EATRIS ERIC European Infrastruct Translat Med, De Boelelaan 1118, NL-1081 HZ Amsterdam, Netherlands.
    Butler, Daniel
    Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10021 USA..
    Mozsary, Christopher
    Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10021 USA..
    Gurvitch, Justin
    Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10021 USA..
    Greally, John M.
    Albert Einstein Coll Med, Bronx, NY 10461 USA..
    Suzuki, Masako
    Albert Einstein Coll Med, Bronx, NY 10461 USA..
    Menor, Mark
    Univ Hawaii, Dept Quantitat Hlth Sci, John A Burns Sch Med, Honolulu, HI 96813 USA..
    Nasu, Masaki
    Univ Hawaii, Dept Quantitat Hlth Sci, John A Burns Sch Med, Honolulu, HI 96813 USA..
    Alonso, Alicia
    Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10021 USA..
    Sheridan, Caroline
    Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10021 USA.;Weill Cornell Med, Div Hematol Oncol, Dept Med, Epigen Core Facil, New York, NY USA..
    Scherer, Andreas
    EATRIS ERIC European Infrastruct Translat Med, De Boelelaan 1118, NL-1081 HZ Amsterdam, Netherlands.;Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland..
    Bruinsma, Stephen
    Illumina Inc, Madison, WI 53705 USA..
    Golda, Gosia
    Jagiellonian Univ, Fac Biochem Biophys & Biotechnol, Krakow, Poland..
    Muszynska, Agata
    Jagiellonian Univ, Malopolska Ctr Biotechnol, Krakow, Poland..
    Labaj, Pawel P.
    Jagiellonian Univ, Malopolska Ctr Biotechnol, Krakow, Poland..
    Campbell, Matthew A.
    New England Biolabs Inc, Ipswich, MA 01938 USA..
    Wos, Frank
    New York Genome Ctr, New York, NY 10013 USA..
    Raine, Amanda
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. EATRIS ERIC European Infrastruct Translat Med, De Boelelaan 1118, NL-1081 HZ Amsterdam, Netherlands.
    Liljedahl, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab. EATRIS ERIC European Infrastruct Translat Med, De Boelelaan 1118, NL-1081 HZ Amsterdam, Netherlands.
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab. EATRIS ERIC European Infrastruct Translat Med, De Boelelaan 1118, NL-1081 HZ Amsterdam, Netherlands.
    Wang, Charles
    Loma Linda Univ, Ctr Genom, Sch Med, Loma Linda, CA 92350 USA..
    Chen, Zhong
    Loma Linda Univ, Ctr Genom, Sch Med, Loma Linda, CA 92350 USA..
    Yang, Zhaowei
    Loma Linda Univ, Ctr Genom, Sch Med, Loma Linda, CA 92350 USA.;Guangzhou Med Univ, Guangzhou Inst Resp Hlth, Dept Allergy & Clin Immunol, State Key Lab Resp Dis,Affiliated Hosp 1, Guangzhou, Peoples R China..
    Li, Jing
    Loma Linda Univ, Ctr Genom, Sch Med, Loma Linda, CA 92350 USA.;Guangzhou Med Univ, Guangzhou Inst Resp Hlth, Dept Allergy & Clin Immunol, State Key Lab Resp Dis,Affiliated Hosp 1, Guangzhou, Peoples R China..
    Yang, Xiaopeng
    Zhengzhou Univ, Dept Neurol, Affiliated Hosp 2, Zhengzhou 450014, Peoples R China..
    Wang, Hongwei
    Univ Chicago, Dev Med, Chicago, IL 60637 USA..
    Melnick, Ari
    Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10021 USA..
    Guo, Shang
    Zhengzhou Univ, Affiliated Hosp 2, Shanghai 200233, Peoples R China..
    Blume, Alexander
    Max Delbrueck Ctr Mol Med, Berlin Inst Med Syst Biol, Bioinformat & Omics Data Sci Platform, Berlin, Germany..
    Franke, Vedran
    Max Delbrueck Ctr Mol Med, Berlin Inst Med Syst Biol, Bioinformat & Omics Data Sci Platform, Berlin, Germany..
    Ibanez de Caceres, Inmaculada
    EATRIS ERIC European Infrastruct Translat Med, De Boelelaan 1118, NL-1081 HZ Amsterdam, Netherlands.;IdiPAZ, Canc Epigenet Lab, INGEMM, Madrid, Spain..
    Rodriguez-Antolin, Carlos
    EATRIS ERIC European Infrastruct Translat Med, De Boelelaan 1118, NL-1081 HZ Amsterdam, Netherlands.;IdiPAZ, Canc Epigenet Lab, INGEMM, Madrid, Spain..
    Rosas, Rocio
    EATRIS ERIC European Infrastruct Translat Med, De Boelelaan 1118, NL-1081 HZ Amsterdam, Netherlands.;IdiPAZ, Canc Epigenet Lab, INGEMM, Madrid, Spain..
    Davis, Justin Wade
    AbbVie Genom Res Ctr, 1 N Waukegan Rd, N Chicago, IL 60036 USA..
    Ishii, Jennifer
    New York Genome Ctr, New York, NY 10013 USA..
    Megherbi, Dalila B.
    Univ Massachusetts Lowell, Francis Coll Engn, CMINDS Res Ctr, Lowell, MA 01854 USA..
    Xiao, Wenming
    US FDA, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA..
    Liao, Will
    New York Genome Ctr, New York, NY 10013 USA..
    Xu, Joshua
    US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA..
    Hong, Huixiao
    US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA..
    Ning, Baitang
    US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA..
    Tong, Weida
    US FDA, Div Bioinformat & Biostat, Natl Ctr Toxicol Res, 3900 NCTR Rd, Jefferson, AR 72079 USA..
    Akalin, Altuna
    Max Delbrueck Ctr Mol Med, Berlin Inst Med Syst Biol, Bioinformat & Omics Data Sci Platform, Berlin, Germany..
    Wang, Yunliang
    Zhengzhou Univ, Affiliated Hosp 2, Shanghai 200233, Peoples R China..
    Deng, Youping
    Univ Hawaii, Dept Quantitat Hlth Sci, John A Burns Sch Med, Honolulu, HI 96813 USA..
    Mason, Christopher E.
    Weill Cornell Med, Dept Physiol & Biophys, New York, NY 10021 USA.;Weill Cornell Med, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsau, New York, NY 10021 USA.;Feil Family Brain & Mind Res Inst, New York, NY 10065 USA.;Weill Cornell Med, WorldQuant Initiat Quantitat Predict, New York, NY 10021 USA..
    The SEQC2 epigenomics quality control (EpiQC) study2021In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 22, no 1, article id 332Article in journal (Refereed)
    Abstract [en]

    Background

    Cytosine modifications in DNA such as 5-methylcytosine (5mC) underlie a broad range of developmental processes, maintain cellular lineage specification, and can define or stratify types of cancer and other diseases. However, the wide variety of approaches available to interrogate these modifications has created a need for harmonized materials, methods, and rigorous benchmarking to improve genome-wide methylome sequencing applications in clinical and basic research. Here, we present a multi-platform assessment and cross-validated resource for epigenetics research from the FDA’s Epigenomics Quality Control Group.

    Results

    Each sample is processed in multiple replicates by three whole-genome bisulfite sequencing (WGBS) protocols (TruSeq DNA methylation, Accel-NGS MethylSeq, and SPLAT), oxidative bisulfite sequencing (TrueMethyl), enzymatic deamination method (EMSeq), targeted methylation sequencing (Illumina Methyl Capture EPIC), single-molecule long-read nanopore sequencing from Oxford Nanopore Technologies, and 850k Illumina methylation arrays. After rigorous quality assessment and comparison to Illumina EPIC methylation microarrays and testing on a range of algorithms (Bismark, BitmapperBS, bwa-meth, and BitMapperBS), we find overall high concordance between assays, but also differences in efficiency of read mapping, CpG capture, coverage, and platform performance, and variable performance across 26 microarray normalization algorithms.

    Conclusions

    The data provided herein can guide the use of these DNA reference materials in epigenomics research, as well as provide best practices for experimental design in future studies. By leveraging seven human cell lines that are designated as publicly available reference materials, these data can be used as a baseline to advance epigenomics research.

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    FULLTEXT01
  • 75.
    Fredriksson, Mona
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Barbany, Gisela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Liljedahl, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Hermanson, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics.
    Kataja, Matti
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Assessing hematopoietic chimerism after stem cell transplantation by multiplexed SNP genotyping using microarrays and quantitative analysis of SNP alleles2004In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 18, no 2, p. 255-266Article in journal (Refereed)
    Abstract [en]

    Single-nucleotide polymorphisms (SNPs) have the potential to be particularly useful as markers for monitoring of chimerism after stem cell transplantation (SCT) because they can be analyzed by accurate and robust methods. We used a two-phased minisequencing strategy for monitoring chimerism after SCT. First, informative SNPs with alleles differing between donor and recipient were identified using a multiplex microarray-based minisequencing system screening 51 SNPs to ensure that multiple informative SNPs were detected in each donor-recipient pair. Secondly, the development of chimerism was followed up after SCT by sensitive, quantitative analysis of individual informative SNPs by applying the minisequencing method in a microtiter plate format. Using this panel of SNPs, we identified multiple informative SNPs in nine unrelated and in 16 related donor-recipient pairs. Samples from nine of the donor-recipient pairs taken at time points ranging from 1 month to 8 years after transplantation were available for analysis. In these samples, we monitored the allelic ratios of two or three informative SNPs in individual minisequencing reactions. The results agreed well with the data obtained by microsatellite analysis. Thus, we conclude that the two-phased minisequencing strategy is a useful approach in the following up of patients after SCT.

  • 76.
    Fredriksson, Mona
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Barbany, Gisela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Liljedahl, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Hermanson, Monika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kataja, Matti
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Assessing hematopoietic chimerism after allogeneic stem cell transplantation by multiplexed SNP genotyping using microarrays and quantitative analysis of SNP alleles2004In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 18, no 2, p. 255-266Article in journal (Refereed)
    Abstract [en]

    Single-nucleotide polymorphisms (SNPs) have the potential to be particularly useful as markers for monitoring of chimerism after stem cell transplantation (SCT) because they can be analyzed by accurate and robust methods. We used a two-phased minisequencing strategy for monitoring chimerism after SCT. First, informative SNPs with alleles differing between donor and recipient were identified using a multiplex microarray-based minisequencing system screening 51 SNPs to ensure that multiple informative SNPs were detected in each donor–recipient pair. Secondly, the development of chimerism was followed up after SCT by sensitive, quantitative analysis of individual informative SNPs by applying the minisequencing method in a microtiter plate format. Using this panel of SNPs, we identified multiple informative SNPs in nine unrelated and in 16 related donor–recipient pairs. Samples from nine of the donor–recipient pairs taken at time points ranging from 1 month to 8 years after transplantation were available for analysis. In these samples, we monitored the allelic ratios of two or three informative SNPs in individual minisequencing reactions. The results agreed well with the data obtained by microsatellite analysis. Thus, we conclude that the two-phased minisequencing strategy is a useful approach in the following up of patients after SCT.

  • 77.
    Fuchsberger, Christian
    et al.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.;Med Univ Innsbruck, Dept Med Genet Mol & Clin Pharmacol, Div Genet Epidemiol, Innsbruck, Austria.;Univ Lubeck, European Acad Bolzano Bozen EURAC, Ctr Biomed, Bolzano, Italy..
    Flannick, Jason
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.;Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA..
    Teslovich, Tanya M.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Mahajan, Anubha
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England..
    Agarwala, Vineeta
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.;MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA..
    Gaulton, Kyle J.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England..
    Ma, Clement
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Fontanillas, Pierre
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Moutsianas, Loukas
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England..
    McCarthy, Davis J.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England.;Univ Oxford, Dept Stat, Oxford, England..
    Rivas, Manuel A.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England..
    Perry, John R. B.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England.;Univ Exeter, Sch Med, Genet Complex Traits, Exeter, Devon, England.;Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England.;Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Sim, Xueling
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Blackwell, Thomas W.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Robertson, Neil R.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Rayner, N. William
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, Cambs, England..
    Cingolani, Pablo
    McGill Univ, Sch Comp Sci, Montreal, PQ, Canada.;McGill Univ, Montreal, PQ, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ, Canada..
    Locke, Adam E.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Tajes, Juan Fernandez
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England..
    Highland, Heather M.
    Univ Texas Hlth Sci Ctr Houston, Univ Texas Grad Sch Biomed Sci Houston, Human Genet Ctr, Houston, TX 77030 USA..
    Dupuis, Josee
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA.;NHLBI, Framingham Heart Study, Framingham, MA USA..
    Chines, Peter S.
    NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA..
    Lindgren, Cecilia M.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.;Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England..
    Hartl, Christopher
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Jackson, Anne U.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Chen, Han
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA.;Harvard Sch Publ Hlth, Dept Biostat, Boston, MA USA..
    Huyghe, Jeroen R.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    van de Bunt, Martijn
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Pearson, Richard D.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England..
    Kumar, Ashish
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England.;Univ Basel, Swiss Trop & Publ Hlth Inst, Chron Dis Epidemiol, Basel, Switzerland..
    Mueller-Nurasyid, Martina
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany.;Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany.;Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany.;Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany..
    Grarup, Niels
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Stringham, Heather M.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Gamazon, Eric R.
    Univ Chicago, Dept Med, Med Genet Sect, 5841 S Maryland Ave, Chicago, IL 60637 USA..
    Lee, Jaehoon
    Seoul Natl Univ, Dept Stat, Seoul, South Korea..
    Chen, Yuhui
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England..
    Scott, Robert A.
    Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England..
    Below, Jennifer E.
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Human Genet Ctr, Houston, TX 77030 USA..
    Chen, Peng
    Natl Univ Hlth Syst, Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore..
    Huang, Jinyan
    Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA..
    Go, Min Jin
    Korea Natl Inst Hlth, Ctr Genome Sci, Cheongju, Chungcheongbuk, South Korea..
    Stitzel, Michael L.
    Jackson Lab Genom Med, Farmington, CT USA..
    Pasko, Dorota
    Univ Exeter, Sch Med, Genet Complex Traits, Exeter, Devon, England..
    Parker, Stephen C. J.
    Univ Michigan, Dept Computat Med, Ann Arbor, MI USA.;Univ Michigan, Dept Bioinformat & Human Genet, Ann Arbor, MI USA..
    Varga, Tibor V.
    Lund Univ, Genet & Mol Epidemiol Unit, Lund Univ Diabet Ctr, Dept Clin Sci, Malmo, Sweden..
    Green, Todd
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Beer, Nicola L.
    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Day-Williams, Aaron G.
    Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, Cambs, England..
    Ferreira, Teresa
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England..
    Fingerlin, Tasha
    Univ Colorado, Colorado Sch Publ Hlth, Dept Epidemiol, Aurora, CO USA..
    Horikoshi, Momoko
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Hu, Cheng
    Shanghai Jiao Tong Univ, Peoples Hosp 6, Shanghai Diabet Inst, Dept Endocrinol & Metab, Shanghai, Peoples R China..
    Huh, Iksoo
    Seoul Natl Univ, Dept Stat, Seoul, South Korea..
    Ikram, Mohammad Kamran
    Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Natl Univ Hlth Syst, Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore.;Duke NUS Grad Med Sch, Eye Acad Clin Programme, Singapore, Singapore..
    Kim, Bong-Jo
    Korea Natl Inst Hlth, Ctr Genome Sci, Cheongju, Chungcheongbuk, South Korea..
    Kim, Yongkang
    Seoul Natl Univ, Dept Stat, Seoul, South Korea..
    Kim, Young Jin
    Korea Natl Inst Hlth, Ctr Genome Sci, Cheongju, Chungcheongbuk, South Korea..
    Kwon, Min-Seok
    Seoul Natl Univ, Interdisciplinary Program Bioinformat, Seoul, South Korea..
    Lee, Juyoung
    Korea Natl Inst Hlth, Ctr Genome Sci, Cheongju, Chungcheongbuk, South Korea..
    Lee, Selyeong
    Seoul Natl Univ, Dept Stat, Seoul, South Korea..
    Lin, Keng-Han
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Maxwell, Taylor J.
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Human Genet Ctr, Houston, TX 77030 USA..
    Nagai, Yoshihiko
    McGill Univ, Montreal, PQ, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ, Canada.;McGill Univ, Dept Human Genet, Montreal, PQ, Canada.;McGill Univ Hlth Ctr, Res Inst, Montreal, PQ, Canada..
    Wang, Xu
    Natl Univ Hlth Syst, Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore..
    Welch, Ryan P.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Yoon, Joon
    Seoul Natl Univ, Interdisciplinary Program Bioinformat, Seoul, South Korea..
    Zhang, Weihua
    Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England.;Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England..
    Barzilai, Nir
    Albert Einstein Coll Med, Dept Med, New York, NY USA.;Albert Einstein Coll Med, Dept Genet, New York, NY USA..
    Voight, Benjamin F.
    Univ Penn, Perelman Sch Med, Dept Syst Pharmacol & Translat Therapeut, Philadelphia, PA 19104 USA.;Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA..
    Han, Bok-Ghee
    Korea Natl Inst Hlth, Ctr Genome Sci, Cheongju, Chungcheongbuk, South Korea..
    Jenkinson, Christopher P.
    Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA.;South Texas Vet Hlth Care Syst, Res, San Antonio, TX USA..
    Kuulasmaa, Teemu
    Univ Eastern Finland, Internal Med, Inst Clin Med, Fac Hlth Sci, Kuopio, Finland..
    Kuusisto, Johanna
    Univ Eastern Finland, Internal Med, Inst Clin Med, Fac Hlth Sci, Kuopio, Finland.;Kuopio Univ Hosp, Kuopio, Finland..
    Manning, Alisa
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Ng, Maggie C. Y.
    Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA..
    Palmer, Nicholette D.
    Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA.;Wake Forest Sch Med, Dept Biochem, Winston Salem, NC USA..
    Balkau, Beverley
    INSERM, Ctr Res Epidemiol & Populat Hlth, U1018, Villejuif, France..
    Stancakova, Alena
    Univ Eastern Finland, Internal Med, Inst Clin Med, Fac Hlth Sci, Kuopio, Finland..
    Abboud, Hanna E.
    Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA..
    Boeing, Heiner
    German Inst Human Nutr Potsdam Rehbrucke, Nuthetal, Germany..
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Prabhakaran, Dorairaj
    Ctr Chron Dis Control, New Delhi, India..
    Gottesman, Omri
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA..
    Scott, James
    Univ London Imperial Coll Sci Technol & Med, Cardiovasc Sci, Natl Heart & Lung Inst, Hammersmith Campus, London, England..
    Carey, Jason
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Kwan, Phoenix
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Grant, George
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Smith, Joshua D.
    Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA USA..
    Neale, Benjamin M.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.;Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Dept Med, Ctr Human Genet Res, Boston, MA 02114 USA..
    Purcell, Shaun
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.;Massachusetts Gen Hosp, Dept Med, Ctr Human Genet Res, Boston, MA 02114 USA.;Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Psychiat, New York, NY 10029 USA..
    Butterworth, Adam S.
    Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England..
    Howson, Joanna M. M.
    Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England..
    Lee, Heung Man
    Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China..
    Lu, Yingchang
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA..
    Kwak, Soo-Heon
    Seoul Natl Univ, Coll Med, Dept Internal Med, Seoul, South Korea..
    Zhao, Wei
    Univ Penn, Dept Med, Philadelphia, PA 19104 USA..
    Danesh, John
    Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, Cambs, England.;Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England.;Univ Cambridge, Dept Publ Hlth & Primary Care, NIHR Blood & Transplant Res Unit Donor Hlth & Gen, Cambridge, England..
    Lam, Vincent K. L.
    Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China..
    Park, Kyong Soo
    Seoul Natl Univ, Coll Med, Dept Internal Med, Seoul, South Korea.;Seoul Natl Univ, Grad Sch Convergence Sci & Technol, Dept Mol Med & Biopharmaceut Sci, Seoul, South Korea.;Seoul Natl Univ, Coll Med, Seoul, South Korea..
    Saleheen, Danish
    Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA.;Ctr Noncommunicable Dis, Karachi, Pakistan..
    So, Wing Yee
    Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China..
    Tam, Claudia H. T.
    Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China..
    Afzal, Uzma
    Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England..
    Aguilar, David
    Baylor Coll Med, Div Cardiovasc, Houston, TX 77030 USA..
    Arya, Rector
    Univ Texas Hlth Sci Ctr San Antonio, Dept Pediat, San Antonio, TX 78229 USA..
    Aung, Tin
    Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Natl Univ Hlth Syst, Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore.;Duke NUS Grad Med Sch, Eye Acad Clin Programme, Singapore, Singapore..
    Chan, Edmund
    Natl Univ Singapore, Natl Univ Hlth Syst, Yong Loo Lin Sch Med, Dept Med, Singapore, Singapore..
    Navarro, Carmen
    IMIB Arrixaca, Murcia Reg Hlth Council, Dept Epidemiol, Murcia, Spain.;Univ Murcia, CIBERESP, Murcia, Spain.;Univ Murcia, Sch Med, Unit Prevent Med & Publ Hlth, E-30001 Murcia, Spain..
    Cheng, Ching-Yu
    Natl Univ Hlth Syst, Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Natl Univ Hlth Syst, Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore.;Duke NUS Grad Med Sch, Eye Acad Clin Programme, Singapore, Singapore..
    Palli, Domenico
    Canc Res & Prevent Inst ISPO, Florence, Italy..
    Correa, Adolfo
    Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA..
    Curran, Joanne E.
    Univ Texas Rio Grande Valley, Reg Acad Hlth Ctr, South Texas Diabet & Obes Inst, Brownsville, TX USA..
    Rybin, Denis
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA..
    Farook, Vidya S.
    Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA..
    Fowler, Sharon P.
    Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA..
    Freedman, Barry I.
    Wake Forest Sch Med, Nephrol Sect, Dept Internal Med, Winston Salem, NC USA..
    Griswold, Michael
    Univ Mississippi, Med Ctr, Ctr Biostat & Bioinformat, Jackson, MS 39216 USA..
    Hale, Daniel Esten
    Univ Texas Hlth Sci Ctr San Antonio, Dept Pediat, San Antonio, TX 78229 USA..
    Hicks, Pamela J.
    Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA.;Wake Forest Sch Med, Dept Biochem, Winston Salem, NC USA..
    Khor, Chiea-Chuen
    Natl Univ Hlth Syst, Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Natl Univ Hlth Syst, Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore.;Natl Univ Singapore, Natl Univ Hlth Syst, Yong Loo Lin Sch Med, Dept Paediat, Singapore, Singapore.;ASTAR, Genome Inst Singapore, Div Human Genet, Singapore, Singapore..
    Kumar, Satish
    Univ Texas Rio Grande Valley, Reg Acad Hlth Ctr, South Texas Diabet & Obes Inst, Brownsville, TX USA..
    Lehne, Benjamin
    Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England..
    Thuillier, Dorothee
    Univ Lille, Lille Pasteur Inst, CNRS UMR8199, Lille, France..
    Lim, Wei Yen
    Natl Univ Hlth Syst, Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore..
    Liu, Jianjun
    Natl Univ Hlth Syst, Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;ASTAR, Genome Inst Singapore, Div Human Genet, Singapore, Singapore..
    van der Schouw, Yvonne T.
    Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands..
    Loh, Marie
    Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England.;Univ Oulu, Inst Hlth Sci, Oulu, Finland.;ASTAR, TLGM, Singapore, Singapore..
    Musani, Solomon K.
    Univ Mississippi, Med Ctr, Jackson Heart Study, Jackson, MS 39216 USA..
    Puppala, Sobha
    Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA..
    Scott, William R.
    Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England..
    Yengo, Loic
    Univ Lille, Lille Pasteur Inst, CNRS UMR8199, Lille, France..
    Tan, Sian-Tsung
    Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England.;Univ London Imperial Coll Sci Technol & Med, Cardiovasc Sci, Natl Heart & Lung Inst, Hammersmith Campus, London, England..
    Taylor, Herman A., Jr.
    Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA..
    Thameem, Farook
    Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA..
    Wilson, Gregory, Sr.
    Jackson State Univ, Coll Publ Serv, Jackson, MS USA..
    Wong, Tien Yin
    Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore.;Natl Univ Hlth Syst, Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Ophthalmol, Singapore, Singapore.;Duke NUS Grad Med Sch, Eye Acad Clin Programme, Singapore, Singapore..
    Njolstad, Pal Rasmus
    Univ Bergen, Dept Clin Sci, KG Jebsen Ctr Diabet Res, Bergen, Norway.;Haukeland Hosp, Dept Pediat, Bergen, Norway..
    Levy, Jonathan C.
    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Mangino, Massimo
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Bonnycastle, Lori L.
    NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA..
    Schwarzmayr, Thomas
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Human Genet, Neuherberg, Germany..
    Fadista, Joao
    Lund Univ, Ctr Diabet, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden..
    Surdulescu, Gabriela L.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Herder, Christian
    Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany.;German Ctr Diabet Res DZD, Neuherberg, Germany..
    Groves, Christopher J.
    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England..
    Wieland, Thomas
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Human Genet, Neuherberg, Germany..
    Bork-Jensen, Jette
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Brandslund, Ivan
    Univ Southern Denmark, Inst Reg Hlth Res, Odense, Denmark.;Vejle Hosp, Dept Clin Biochem, Vejle, Denmark..
    Christensen, Cramer
    Vejle Hosp, Dept Internal Med & Endocrinol, Vejle, Denmark..
    Koistinen, Heikki A.
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland.;Univ Helsinki, Abdominal Ctr Endocrinol, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Helsinki, Finland.;Minerva Fdn, Helsinki, Finland.;Univ Helsinki, Dept Med, Helsinki, Finland..
    Doney, Alex S. F.
    Ninewells Hosp & Med Sch, Med Res Inst, Div Cardiovasc & Diabet Med, Dundee, Scotland..
    Kinnunen, Leena
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland..
    Esko, Tonu
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.;Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.;Harvard Med Sch, Dept Genet, Boston, MA USA.;Boston Childrens Hosp, Div Endocrinol, Boston, MA USA..
    Farmer, Andrew J.
    Univ Oxford, Nuffield Dept Primary Care Hlth Sci, Oxford, England..
    Hakaste, Liisa
    Univ Helsinki, Abdominal Ctr Endocrinol, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Helsinki, Finland.;Folkhalsan Res Ctr, Helsinki, Finland.;Univ Helsinki, Res Programs Unit, Diabet & Obes, Helsinki, Finland..
    Hodgkiss, Dylan
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Kravic, Jasmina
    Lund Univ, Ctr Diabet, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden..
    Lyssenko, Valeriya
    Lund Univ, Ctr Diabet, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden..
    Hollensted, Mette
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Jorgensen, Marit E.
    Steno Diabet Ctr, Gentofte, Denmark..
    Jorgensen, Torben
    Capital Reg Denmark, Res Ctr Prevent & Hlth, Glostrup, Denmark.;Univ Copenhagen, Inst Hlth Sci, Dept Publ Hlth, Copenhagen, Denmark.;Aalborg Univ, Med, Aalborg, Denmark..
    Ladenvall, Claes
    Lund Univ, Ctr Diabet, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden..
    Justesen, Johanne Marie
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Karajamaki, Annemari
    Vaasa Cent Hosp, Dept Primary Hlth Care, Vaasa, Finland.;Vaasa Hlth Care Ctr, Ctr Diabet, Vaasa, Finland..
    Kriebel, Jennifer
    German Ctr Diabet Res DZD, Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany..
    Rathmann, Wolfgang
    Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Biometr & Epidemiol, Dusseldorf, Germany..
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lauritzen, Torsten
    Aarhus Univ, Sect Gen Practice, Dept Publ Hlth, Aarhus, Denmark..
    Narisu, Narisu
    NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA..
    Linneberg, Allan
    Capital Reg Denmark, Res Ctr Prevent & Hlth, Glostrup, Denmark.;Rigshosp, Dept Clin Expt Res, Glostrup, Denmark.;Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark..
    Melander, Olle
    Lund Univ, Dept Clin Sci Hypertens & Cardiovasc, Malmo, Sweden..
    Milani, Lili
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Neville, Matt
    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England..
    Orho-Melander, Marju
    Lund Univ, Dept Clin Sci Diabet & Cardiovasc Dis, Genet Epidemiol, Malmo, Sweden..
    Qi, Lu
    Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA..
    Qi, Qibin
    Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, New York, NY USA..
    Roden, Michael
    Univ Dusseldorf, Leibniz Ctr Diabet Res, German Diabet Ctr, Inst Clin Diabetol, Dusseldorf, Germany.;German Ctr Diabet Res DZD, Neuherberg, Germany.;Univ Dusseldorf, Fac Med, Dept Endocrinol & Diabetol, Dusseldorf, Germany..
    Rolandsson, Olov
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Swift, Amy
    NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA..
    Rosengren, Anders H.
    Lund Univ, Ctr Diabet, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden..
    Stirrups, Kathleen
    Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, Cambs, England..
    Wood, Andrew R.
    Univ Exeter, Sch Med, Genet Complex Traits, Exeter, Devon, England..
    Mihailov, Evelin
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Blancher, Christine
    Univ Oxford, Nuffield Dept Med, Oxford Genom Ctr, High Throughput Genom,Wellcome Trust Ctr Human Ge, Oxford, England..
    Carneiro, Mauricio O.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Maguire, Jared
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Poplin, Ryan
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Shakir, Khalid
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Fennell, Timothy
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    DePristo, Mark
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    de Angelis, Martin Hrabe
    German Ctr Diabet Res DZD, Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Expt Genet, Neuherberg, Germany.;Tech Univ Munich, Ctr Life & Food Sci Weihenstephan, Freising Weihenstephan, Germany..
    Deloukas, Panos
    Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, London, England.;King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah, Saudi Arabia..
    Gjesing, Anette P.
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Jun, Goo
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA.;Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Human Genet Ctr, Houston, TX 77030 USA..
    Nilsson, Peter
    Lund Univ, Dept Clin Sci, Med, Malmo, Sweden..
    Murphy, Jacquelyn
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Onofrio, Robert
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Thorand, Barbara
    German Ctr Diabet Res DZD, Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany..
    Hansen, Torben
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark.;Univ Southern Denmark, Fac Hlth Sci, Odense, Denmark..
    Meisinger, Christa
    German Ctr Diabet Res DZD, Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany..
    Hu, Frank B.
    Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA.;Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA..
    Isomaa, Bo
    Folkhalsan Res Ctr, Helsinki, Finland.;Dept Social Serv & Hlth Care, Pietarsaari, Finland..
    Karpe, Fredrik
    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England..
    Liang, Liming
    Harvard Sch Publ Hlth, Dept Biostat, Boston, MA USA.;Harvard Sch Publ Hlth, Dept Epidemiol, Boston, MA USA..
    Peters, Annette
    Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany.;German Ctr Diabet Res DZD, Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany..
    Huth, Cornelia
    German Ctr Diabet Res DZD, Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany..
    O'Rahilly, Stephen P.
    Univ Cambridge, Inst Metab Sci, Metab Res Labs, Cambridge, England..
    Palmer, Colin N. A.
    Univ Dundee, Ninewells Hosp & Med Sch, Pat Macpherson Ctr Pharmacogenet & Pharmacogen, Dundee, Scotland..
    Pedersen, Oluf
    Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark..
    Rauramaa, Rainer
    Kuopio Res Inst Exercise Med, Fdn Res Hlth Exercise & Nutr, Kuopio, Finland..
    Tuomilehto, Jaakko
    Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland.;Danube Univ Krems, Ctr Vasc Prevent, Krems, Austria.;King Abdulaziz Univ, Diabet Res Grp, Jeddah, Saudi Arabia.;Autonomous Univ Madrid, Univ Hosp LaPaz, Inst Invest Sanitaria Hosp Univ LaPaz IdiPAZ, Madrid, Spain.;Natl Inst Hlth & Welf, Helsinki, Finland..
    Salomaa, Veikko
    Natl Inst Hlth & Welf, Helsinki, Finland..
    Watanabe, Richard M.
    Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA.;Univ Southern Calif, Keck Sch Med, Dept Physiol & Biophys, Los Angeles, CA USA.;Univ Southern Calif, Keck Sch Med, Dabet & Obes Res Inst, Los Angeles, CA USA..
    Syvanen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bergman, Richard N.
    Cedars Sinai Diabet & Obes Res Inst, Los Angeles, CA USA..
    Bharadwaj, Dwaipayan
    CSIR IGIB, Funct Genom Unit, New Delhi, India..
    Bottinger, Erwin P.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA..
    Cho, Yoon Shin
    Hallym Univ, Dept Biomed Sci, Chunchon, South Korea..
    Chandak, Giriraj R.
    CSIR Ctr Cellular & Mol Biol, Hyderabad, Telangana, India..
    Chan, Juliana C. N.
    Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China.;Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Hong Kong, Hong Kong, Peoples R China.;Chinese Univ Hong Kong, Hong Kong Inst Diabet & Obes, Hong Kong, Hong Kong, Peoples R China..
    Chia, Kee Seng
    Natl Univ Hlth Syst, Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore..
    Daly, Mark J.
    Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA..
    Ebrahim, Shah B.
    Ctr Chron Dis Control, New Delhi, India..
    Langenberg, Claudia
    Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England..
    Elliott, Paul
    Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England.;Imperial Coll London, MRC PHE Ctr Environm & Hlth, London, England..
    Jablonski, Kathleen A.
    George Washington Univ, Biostat Ctr, Rockville, MD USA..
    Lehman, Donna M.
    Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA..
    Jia, Weiping
    Shanghai Jiao Tong Univ, Peoples Hosp 6, Shanghai Diabet Inst, Dept Endocrinol & Metab, Shanghai, Peoples R China..
    Ma, Ronald C. W.
    Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China.;Chinese Univ Hong Kong, Li Ka Shing Inst Hlth Sci, Hong Kong, Hong Kong, Peoples R China.;Chinese Univ Hong Kong, Hong Kong Inst Diabet & Obes, Hong Kong, Hong Kong, Peoples R China..
    Pollin, Toni I.
    Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA.;Univ Maryland, Sch Med, Program Personalized & Genom Med, Baltimore, MD 21201 USA..
    Sandhu, Manjinder
    Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, Cambs, England.;Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England..
    Tandon, Nikhil
    All India Inst Med Sci, Dept Endocrinol & Metab, New Delhi, India..
    Froguel, Philippe
    Univ Lille, Lille Pasteur Inst, CNRS UMR8199, Lille, France.;Imperial Coll London, Sch Publ Hlth, Dept Genom Common Dis, London, England..
    Barroso, Ines
    Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, Cambs, England.;Univ Cambridge, Inst Metab Sci, Metab Res Labs, Cambridge, England..
    Teo, Yik Ying
    Natl Univ Hlth Syst, Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;Natl Univ Singapore, Inst Life Sci, Singapore, Singapore.;Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore, Singapore..
    Zeggini, Eleftheria
    Wellcome Trust Sanger Inst, Dept Human Genet, Hinxton, Cambs, England..
    Loos, Ruth J. F.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA..
    Small, Kerrin S.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Ried, Janina S.
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany..
    DeFronzo, Ralph A.
    Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA..
    Grallert, Harald
    German Ctr Diabet Res DZD, Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany..
    Glaser, Benjamin
    Hadassah Hebrew Univ Med Ctr, Endocrinol & Metab Serv, Jerusalem, Israel..
    Metspalu, Andres
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Wareham, Nicholas J.
    Univ Cambridge, Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England..
    Walker, Mark
    Newcastle Univ, Inst Cellular Med, Sch Med, Newcastle Upon Tyne, Tyne & Wear, England..
    Banks, Eric
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Gieger, Christian
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Epidemiol 2, Neuherberg, Germany.;Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany..
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England..
    Im, Hae Kyung
    Univ Chicago, Dept Med, Med Genet Sect, 5841 S Maryland Ave, Chicago, IL 60637 USA..
    Illig, Thomas
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Res Unit Mol Epidemiol, Neuherberg, Germany.;Hannover Med Sch, Hannover Unified Biobank, Hannover, NH, Germany.;Hannover Med Sch, Inst Human Genet, Hannover, NH, Germany..
    Franks, Paul W.
    Lund Univ, Genet & Mol Epidemiol Unit, Lund Univ Diabet Ctr, Dept Clin Sci, Malmo, Sweden.;Harvard Sch Publ Hlth, Dept Nutr, Boston, MA USA.;Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Buck, Gemma
    Univ Oxford, Nuffield Dept Med, Oxford Genom Ctr, High Throughput Genom,Wellcome Trust Ctr Human Ge, Oxford, England..
    Trakalo, Joseph
    Univ Oxford, Nuffield Dept Med, Oxford Genom Ctr, High Throughput Genom,Wellcome Trust Ctr Human Ge, Oxford, England..
    Buck, David
    Univ Oxford, Nuffield Dept Med, Oxford Genom Ctr, High Throughput Genom,Wellcome Trust Ctr Human Ge, Oxford, England..
    Prokopenko, Inga
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Imperial Coll London, Sch Publ Hlth, Dept Genom Common Dis, London, England..
    Magi, Reedik
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Farjoun, Yossi
    Broad Inst, Data Sci & Data Engn, Cambridge, MA USA..
    Owen, Katharine R.
    Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England..
    Gloyn, Anna L.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England..
    Strauch, Konstantin
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany.;Univ Munich, Chair Genet Epidemiol, Inst Med Informat Biometry & Epidemiol, Munich, Germany..
    Tuomi, Tiinamaija
    Univ Helsinki, Abdominal Ctr Endocrinol, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Helsinki, Finland.;Folkhalsan Res Ctr, Helsinki, Finland.;Univ Helsinki, Res Programs Unit, Diabet & Obes, Helsinki, Finland.;Univ Helsinki, FIMM, Helsinki, Finland..
    Kooner, Jaspal Singh
    Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England.;Univ London Imperial Coll Sci Technol & Med, Cardiovasc Sci, Natl Heart & Lung Inst, Hammersmith Campus, London, England.;Imperial Coll London, Imperial Coll Healthcare NHS Trust, London, England..
    Lee, Jong-Young
    Korea Natl Inst Hlth, Ctr Genome Sci, Cheongju, Chungcheongbuk, South Korea..
    Park, Taesung
    Seoul Natl Univ, Dept Stat, Seoul, South Korea.;Seoul Natl Univ, Interdisciplinary Program Bioinformat, Seoul, South Korea..
    Donnelly, Peter
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England.;Univ Oxford, Dept Stat, Oxford, England..
    Morris, Andrew D.
    Ninewells Hosp & Med Sch, Ctr Mol Med, Clin Res Ctr, Dundee, Scotland.;Univ Edinburgh, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland..
    Hattersley, Andrew T.
    Univ Exeter, Sch Med, Exeter, Devon, England..
    Bowden, Donald W.
    Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Winston Salem, NC USA.;Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA.;Wake Forest Sch Med, Dept Biochem, Winston Salem, NC USA..
    Collins, Francis S.
    NHGRI, Med Genom & Metab Genet Branch, NIH, Bethesda, MD 20892 USA..
    Atzmon, Gil
    Albert Einstein Coll Med, Dept Med, New York, NY USA.;Albert Einstein Coll Med, Dept Genet, New York, NY USA.;Univ Haifa, Dept Nat Sci, Haifa, Israel..
    Chambers, John C.
    Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London, England.;Ealing Hosp NHS Trust, Dept Cardiol, Southall, Middx, England.;Imperial Coll London, Imperial Coll Healthcare NHS Trust, London, England..
    Spector, Timothy D.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Laakso, Markku
    Univ Eastern Finland, Internal Med, Inst Clin Med, Fac Hlth Sci, Kuopio, Finland.;Kuopio Univ Hosp, Kuopio, Finland..
    Strom, Tim M.
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Human Genet, Neuherberg, Germany.;Tech Univ Munich, Inst Human Genet, Munich, Germany..
    Bell, Graeme I.
    Univ Chicago, Dept Med Genet, Chicago, IL 60637 USA.;Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA..
    Blangero, John
    Univ Texas Rio Grande Valley, Reg Acad Hlth Ctr, South Texas Diabet & Obes Inst, Brownsville, TX USA..
    Duggirala, Ravindranath
    Texas Biomed Res Inst, Dept Genet, San Antonio, TX USA..
    Tai, E. Shyong
    Natl Univ Hlth Syst, Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;Natl Univ Singapore, Natl Univ Hlth Syst, Yong Loo Lin Sch Med, Dept Med, Singapore, Singapore.;Duke NUS Med Sch Singapore, Cardiovasc & Metab Disorders Program, Singapore, Singapore..
    McVean, Gilean
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England.;Univ Oxford, Li Ka Shing Ctr Hlth Informat & Discovery, Oxford, England..
    Hanis, Craig L.
    Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Human Genet Ctr, Houston, TX 77030 USA..
    Wilson, James G.
    Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA..
    Seielstad, Mark
    Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA.;Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94143 USA.;Blood Syst Res Inst, San Francisco, CA USA..
    Frayling, Timothy M.
    Univ Exeter, Sch Med, Genet Complex Traits, Exeter, Devon, England..
    Meigs, James B.
    Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA.;Harvard Med Sch, Dept Med, Boston, MA USA..
    Cox, Nancy J.
    Univ Chicago, Dept Med, Med Genet Sect, 5841 S Maryland Ave, Chicago, IL 60637 USA..
    Sladek, Rob
    McGill Univ, Montreal, PQ, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ, Canada.;McGill Univ, Dept Human Genet, Montreal, PQ, Canada.;McGill Univ, Dept Med, Div Endocrinol & Metab, Montreal, PQ, Canada..
    Lander, Eric S.
    Broad Inst MIT & Harvard, Cambridge, MA USA..
    Gabriel, Stacey
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Burtt, Noel P.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Mohlke, Karen L.
    Univ N Carolina, Dept Genet, Chapel Hill, NC USA..
    Meitinger, Thomas
    Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Inst Human Genet, Neuherberg, Germany.;Tech Univ Munich, Inst Human Genet, Munich, Germany..
    Groop, Leif
    Lund Univ, Ctr Diabet, Dept Clin Sci Diabet & Endocrinol, Malmo, Sweden.;Univ Helsinki, FIMM, Helsinki, Finland..
    Abecasis, Goncalo
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Florez, Jose C.
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.;Massachusetts Gen Hosp, Dept Med, Ctr Human Genet Res, Boston, MA 02114 USA.;Harvard Med Sch, Dept Med, Boston, MA USA.;Massachusetts Gen Hosp, Dept Med, Diabet Unit, Diabet Res Ctr, Boston, MA 02114 USA..
    Scott, Laura J.
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Morris, Andrew P.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England.;Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.;Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England..
    Kang, Hyun Min
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Boehnke, Michael
    Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA..
    Altshuler, David
    Broad Inst, Program Med & Populat Genet, Cambridge, MA USA.;Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA.;Harvard Med Sch, Dept Genet, Boston, MA USA.;Harvard Med Sch, Dept Med, Boston, MA USA.;Massachusetts Gen Hosp, Dept Med, Diabet Unit, Diabet Res Ctr, Boston, MA 02114 USA.;MIT, Dept Biol, Cambridge, MA USA..
    McCarthy, Mark I.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Nuffield Dept Med, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Oxford Univ Hosp Trust, Oxford NIHR Biomed Res Ctr, Oxford, England..
    The genetic architecture of type 2 diabetes2016In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 536, no 7614, p. 41-47Article in journal (Refereed)
    Abstract [en]

    The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.

  • 78. Gateva, Vesela
    et al.
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Hom, Geoff
    Taylor, Kimberly E.
    Chung, Sharon A.
    Sun, Xin
    Ortmann, Ward
    Kosoy, Roman
    Ferreira, Ricardo C.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gunnarsson, Iva
    Svenungsson, Elisabet
    Padyukov, Leonid
    Sturfelt, Gunnar
    Jönsen, Andreas
    Bengtsson, Anders A.
    Rantapää-Dahlqvist, Solbritt
    Baechler, Emily C.
    Brown, Elizabeth E.
    Alarcón, Graciela S.
    Edberg, Jeffrey C.
    Ramsey-Goldman, Rosalind
    McGwin, Gerald
    Reveille, John D.
    Vilá, Luis M.
    Kimberly, Robert P.
    Manzi, Susan
    Petri, Michelle A.
    Lee, Annette
    Gregersen, Peter K.
    Seldin, Michael F.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Criswell, Lindsey A.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Behrens, Timothy W.
    Graham, Robert R.
    A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus2009In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 41, no 11, p. 1228-1233Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies have recently identified at least 15 susceptibility loci for systemic lupus erythematosus (SLE). To confirm additional risk loci, we selected SNPs from 2,466 regions that showed nominal evidence of association to SLE (P < 0.05) in a genome-wide study and genotyped them in an independent sample of 1,963 cases and 4,329 controls. This replication effort identified five new SLE susceptibility loci (P < 5 x 10(-8)): TNIP1 (odds ratio (OR) = 1.27), PRDM1 (OR = 1.20), JAZF1 (OR = 1.20), UHRF1BP1 (OR = 1.17) and IL10 (OR = 1.19). We identified 21 additional candidate loci with P< or = 1 x 10(-5). A candidate screen of alleles previously associated with other autoimmune diseases suggested five loci (P < 1 x 10(-3)) that may contribute to SLE: IFIH1, CFB, CLEC16A, IL12B and SH2B3. These results expand the number of confirmed and candidate SLE susceptibility loci and implicate several key immunologic pathways in SLE pathogenesis.

  • 79. Gertow, Karl
    et al.
    Sennblad, Bengt
    Strawbridge, Rona J
    Ohrvik, John
    Zabaneh, Delilah
    Shah, Sonia
    Veglia, Fabrizio
    Fava, Cristiano
    Kavousi, Maryam
    McLachlan, Stela
    Kivimäki, Mika
    Bolton, Jennifer L
    Folkersen, Lasse
    Gigante, Bruna
    Leander, Karin
    Vikström, Max
    Larsson, Malin
    Silveira, Angela
    Deanfield, John
    Voight, Benjamin F
    Fontanillas, Pierre
    Sabater-Lleal, Maria
    Colombo, Gualtiero I
    Kumari, Meena
    Langenberg, Claudia
    Wareham, Nick J
    Uitterlinden, André G
    Gabrielsen, Anders
    Hedin, Ulf
    Franco-Cereceda, Anders
    Nyyssönen, Kristiina
    Rauramaa, Rainer
    Tuomainen, Tomi-Pekka
    Savonen, Kai
    Smit, Andries J
    Giral, Philippe
    Mannarino, Elmo
    Robertson, Christine M
    Talmud, Philippa J
    Hedblad, Bo
    Hofman, Albert
    Erdmann, Jeanette
    Reilly, Muredach P
    O'Donnell, Christopher J
    Farrall, Martin
    Clarke, Robert
    Franzosi, Maria Grazia
    Seedorf, Udo
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hansson, Göran K
    Eriksson, Per
    Samani, Nilesh J
    Watkins, Hugh
    Price, Jacqueline F
    Hingorani, Aroon D
    Melander, Olle
    Witteman, Jacqueline C M
    Baldassarre, Damiano
    Tremoli, Elena
    de Faire, Ulf
    Humphries, Steve E
    Hamsten, Anders
    Identification of the BCAR1-CFDP1-TMEM170A Locus as a Determinant of Carotid Intima-Media Thickness and Coronary Artery Disease Risk2012In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 5, no 6, p. 656-665Article in journal (Refereed)
    Abstract [en]

    Background

    Carotid intima-media thickness (cIMT) is a widely accepted marker of subclinical atherosclerosis. To date, large-scale investigations of genetic determinants of cIMT are sparse.

    Methods and Results

    To identify cIMT-associated genes and genetic variants, a discovery analysis using the Illumina 200K CardioMetabochip was conducted in 3430 subjects with detailed ultrasonographic determinations of cIMT from the IMPROVE (Carotid Intima Media Thickness [IMT] and IMT-Progression as Predictors of Vascular Events in a High Risk European Population) study. Segment-specific IMT measurements of common carotid, bifurcation, and internal carotid arteries, and composite IMT variables considering the whole carotid tree (IMTmean, IMTmax, and IMTmean-max), were analyzed. A replication stage investigating 42 single-nucleotide polymorphisms for association with common carotid IMT was undertaken in 5 independent European cohorts (total n=11 590). A locus on chromosome 16 (lead single-nucleotide polymorphism rs4888378, intronic in CFDP1) was associated with cIMT at significance levels passing multiple testing correction at both stages (array-wide significant discovery P=6.75×10−7 for IMTmax; replication P=7.24×10−6 for common cIMT; adjustments for sex, age, and population substructure where applicable; minor allele frequency 0.43 and 0.41, respectively). The protective minor allele was associated with lower carotid plaque score in a replication cohort (P=0.04, n=2120) and lower coronary artery disease risk in 2 case-control studies of subjects with European ancestry (odds ratio [95% confidence interval] 0.83 [0.77–0.90], P=6.53×10−6, n=13 591; and 0.95 [0.92–0.98], P=1.83×10−4, n=82 297, respectively). Queries of human biobank data sets revealed associations of rs4888378 with nearby gene expression in vascular tissues (n=126–138).

    Conclusions

    This study identified rs4888378 in the BCAR1-CFDP1-TMEM170A locus as a novel genetic determinant of cIMT and coronary artery disease risk in individuals of European descent.

  • 80. Ghotbi, Roza
    et al.
    Gomez, Alvin
    Milani, Lili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Tybring, Gunnel
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Bertilsson, Leif
    Ingelman-Sundberg, Magnus
    Aklillu, Eleni
    Allele-specific expression and gene methylation in the control of CYP1A2 mRNA level in human livers2009In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 9, no 3, p. 208-217Article in journal (Refereed)
    Abstract [en]

    The basis for interindividual variation in the CYP1A2 gene expression is not fully understood and the known genetic polymorphisms in the gene provide no explanation. We investigated whether the CYP1A2 gene expression is regulated by DNA methylation and displays allele-specific expression (ASE) using 65 human livers. Forty-eight percent of the livers displayed ASE not associated to the CYP1A2 mRNA levels. The extent of DNA methylation of a CpG island including 17 CpG sites, close to the translation start site, inversely correlated with hepatic CYP1A2 mRNA levels (P=0.018). The methylation of two separate core CpG sites was strongly associated with the CYP1A2 mRNA levels (P=0.005) and ASE phenotype (P=0.01), respectively. The CYP1A2 expression in hepatoma B16A2 cells was strongly induced by treatment with 5-aza-2'-deoxycytidine. In conclusion, the CYP1A2 gene expression is influenced by the extent of DNA methylation and displays ASE, mechanisms contributing to the large interindividual differences in CYP1A2 gene expression.

  • 81.
    Giedraitis, Vilmantas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Degerman-Gunnarsson, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sundelöf, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Glaser, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Genetic analysis of Alzheimer's disease in the Uppsala Longitudinal Study of Adult Men2009In: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, E-ISSN 1421-9824, Vol. 27, no 1, p. 59-68Article in journal (Refereed)
    Abstract [en]

    BACKGROUND/AIMS:

    Genetic factors influencing common complex conditions have proven difficult to identify, and data from numerous investigations have provided incomplete conclusions as to the identity of these genes. Here we aimed to identify susceptibility genes for late-onset Alzheimer's disease (AD).

    METHODS:

    The case-control analysis included samples from 86 AD patients and 404 cognitively healthy controls selected from the Uppsala Longitudinal Study of Adult Men (ULSAM). In the incidence analysis, all 1,088 genotyped ULSAM participants were included. DNA samples from ULSAM participants were analyzed for 2,578 single nucleotide polymorphisms (SNP) within 368 genes. The selection of genes tested for association to AD within this cohort was based on genes previously implicated in conditions with relevance to ULSAM, such as dementia, cardiovascular disease, diabetes and metabolic syndrome, osteoporosis, and cancer.

    RESULTS/CONCLUSION:

    Association analysis revealed 82 genes containing at least 1 significant SNP at p < 0.05 with association to AD. Only 20 genes remained significant after a permutation test to correct for multiple comparisons within individual genes. Using publicly available data from 2 genome-wide association (GWA) studies and linkage disequilibrium data from HapMap, we attempted to replicate the AD association identified in ULSAM. In addition to apolipoprotein E, we were able to replicate 5 other genes in both GWA studies at p < 0.05.

  • 82. Gorgen, Sabrina
    et al.
    Ostberg, Therese
    Salomonsson, Stina
    Ding, Bo
    Eliasson, Hakan
    Malarstig, Anders
    Alfredsson, Lars
    Klareskog, Lars
    Hamsten, Anders
    Olsson, Tomas
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Gadler, Fredrik
    Jonzon, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Sonesson, Sven-Erik
    Kockum, Ingrid
    Wahren-Herlenius, Marie
    The HLA Locus Contains Novel Foetal Susceptibility Alleles For Congenital Heart Block with Significant Paternal Influence2013In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 72, no S1, p. A56-A56Article in journal (Other academic)
  • 83. Graham, R. Robert
    et al.
    Kyogoku, Chieko
    Sigurdsson, Snaevar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Vlasova, Irina A.
    Davies, Leela R.L.
    Baechler, Emily C.
    Plenge, Robert M.
    Koeuth, Thearith
    Ortmann, Ward A.
    Hom, Geoffrey
    Bauer, Jason W.
    Gillett, Clarence
    Burtt, Noel
    Cunninghame Graham, Deborah S.
    Onofrio, Robert
    Petri, Michelle
    Gunnarsson, Iva
    Svenungsson, Elisabeth
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gregersen, Peter K.
    Moser, Kathy
    Gaffney, Patrick M.
    Criswell, Lindsey A.
    Vyse, Timothy J.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Altshuler, David M.
    Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus2007In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 104, no 16, p. 6758-6763Article in journal (Refereed)
    Abstract [en]

    Systematic genome-wide studies to map genomic regions associated with human diseases are becoming more practical. Increasingly, efforts will be focused on the identification of the specific functional variants responsible for the disease. The challenges of identifying causal variants include the need for complete ascertainment of genetic variants and the need to consider the possibility of multiple causal alleles. We recently reported that risk of systemic lupus erythematosus (SLE) is strongly associated with a common SNP in IFN regulatory factor 5 (IRF5), and that this variant altered spicing in a way that might provide a functional explanation for the reproducible association to SLE risk. Here, by resequencing and genotyping in patients with SLE, we find evidence for three functional alleles of IRF5: the previously described exon 1B splice site variant, a 30-bp in-frame insertion/deletion variant of exon 6 that alters a proline-, glutamic acid-, serine- and threonine-rich domain region, and a variant in a conserved polyA+ signal sequence that alters the length of the 3' UTR and stability of IRF5 mRNAs. Haplotypes of these three variants define at least three distinct levels of risk to SLE. Understanding how combinations of variants influence IRF5 function may offer etiological and therapeutic insights in SLE; more generally, IRF5 and SLE illustrates how multiple common variants of the same gene can together influence risk of common disease.

  • 84.
    Granroth, Sofie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kurland, L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Genetic variation in the ddah-1 gene in relation to adma levels and endothelial function2010In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 28, no Suppl. A, p. E124-E125Article in journal (Other academic)
    Abstract [en]

    Background:

    Asymmetric dimethylarginine (ADMA), an endogenous methylated amino acid, has been identified as a competitive inhibitor of nitric oxide synthase (NOS). Elevated ADMA levels have been demonstrated in cardiovascular disorders and many studies have reported an inverse correlation between ADMA and endothelial function. The majority of ADMA is metabolized by dimethylarginine dimethylaminohydrolases (DDAH-1 and DDAH-2). Our aim was to study the genetic variation in the DDAH-1 gene in relation to ADMA levels and endothelial function.

    Methods:

    A total of 959 individuals, aged 70, from the community based Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study were included. Plasma concentrations of ADMA were measured by high performance liquid chromatography. Endothelial function was evaluated with both the invasive forearm technique (measuring endothelial dependent vasodilation in resistance arteries) and with brachial artery ultrasound (measuring flow mediated dilation in a conduit artery). Forty common single nucleotide polymorphisms (SNPs) in the DDAH-1 gene were analyzed.

    Results:

    There were significant associations between DDAH-1 genotype and ADMA levels in 20 of the 40 selected SNPs. However, no associations were seen between DDAH-1 genotype and endothelial function.

    Conclusion:

    These results indicate that genetic variation in the DDAH-1 gene has an impact on ADMA concentration in plasma. However, it does not seem to have a major influence on endothelial function.

  • 85.
    Gronroos, Toni
    et al.
    Tampere Univ, Fac Med & Hlth Technol, Tampere Ctr Child Hlth Res, Tampere, Finland..
    Makinen, Artturi
    Tampere Univ, Fac Med & Hlth Technol, Tampere Ctr Child Hlth Res, Tampere, Finland.;Tampere Univ Hosp, Dept Pathol, Fimlab Labs, Tampere, Finland..
    Laukkanen, Saara
    Tampere Univ, Fac Med & Hlth Technol, Tampere Ctr Child Hlth Res, Tampere, Finland..
    Mehtonen, Juha
    Univ Eastern Finland, Inst Biomed, Sch Med, Kuopio, Finland..
    Nikkila, Atte
    Tampere Univ, Fac Med & Hlth Technol, Tampere Ctr Child Hlth Res, Tampere, Finland..
    Oksa, Laura
    Tampere Univ, Fac Med & Hlth Technol, Tampere Ctr Child Hlth Res, Tampere, Finland..
    Rounioja, Samuli
    Tampere Univ Hosp, Dept Hematol, Fimlab Labs, Tampere, Finland..
    Marincevic-Zuniga, Yanara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nordlund, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pohjolainen, Virva
    Tampere Univ Hosp, Dept Pathol, Fimlab Labs, Tampere, Finland..
    Paavonen, Timo
    Tampere Univ Hosp, Dept Pathol, Fimlab Labs, Tampere, Finland.;Tampere Univ, Fac Med & Hlth Technol, Dept Pathol, Tampere, Finland..
    Heinaniemi, Merja
    Lohi, Olli
    Tampere Univ, Fac Med & Hlth Technol, Tampere Ctr Child Hlth Res, Tampere, Finland.;Tampere Univ Hosp, Dept Pediat, Tampere, Finland..
    Clinicopathological features and prognostic value of SOX11 in childhood acute lymphoblastic leukemia2020In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 2043Article in journal (Refereed)
    Abstract [en]

    Acute lymphoblastic leukemia is marked by aberrant transcriptional features that alter cell differentiation, self-renewal, and proliferative features. We sought to identify the transcription factors exhibiting altered and subtype-specific expression patterns in B-ALL and report here that SOX11, a developmental and neuronal transcription factor, is aberrantly expressed in the ETV6-RUNX1 and TCF3-PBX1 subtypes of acute B-cell leukemias. We show that a high expression of SOX11 leads to alterations of gene expression that are typically associated with cell adhesion, migration, and differentiation. A high expression is associated with DNA hypomethylation at the SOX11 locus and a favorable outcome. The results indicate that SOX11 expression marks a group of patients with good outcomes and thereby prompts further study of its use as a biomarker.

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  • 86. Grundberg, Elin
    et al.
    Meduri, Eshwar
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Hedman, Asa K.
    Keildson, Sarah
    Buil, Alfonso
    Busche, Stephan
    Yuan, Wei
    Nisbet, James
    Sekowska, Magdalena
    Wilk, Alicja
    Barrett, Amy
    Small, Kerrin S.
    Ge, Bing
    Caron, Maxime
    Shin, So-Youn
    Lathrop, Mark
    Dermitzakis, Emmanouil T.
    McCarthy, Mark I.
    Spector, Timothy D.
    Bell, Jordana T.
    Deloukas, Panos
    Global Analysis of DNA Methylation Variation in Adipose Tissue from Twins Reveals Links to Disease-Associated Variants in Distal Regulatory Elements2013In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 93, no 5, p. 876-890Article in journal (Refereed)
    Abstract [en]

    Epigenetic modifications such as DNA methylation play a key role in gene regulation and disease susceptibility. However, little is known about the genome-wide frequency, localization, and function of methylation variation and how it is regulated by genetic and environmental factors. We utilized the Multiple Tissue Human Expression Resource (MuTHER) and generated Illumina 450K adipose methylome data from 648 twins. We found that individual CpGs had low variance and that variability was suppressed in promoters. We noted that DNA methylation variation was highly heritable (h(median)(2) = 0.34) and that shared environmental effects correlated with metabolic phenotype-associated CpGs. Analysis of methylation quantitative-trait loci (metQTL) revealed that 28% of CpGs were associated with nearby SNPs, and when overlapping them with adipose expression quantitative-trait loci (eQTL) from the same individuals, we found that 6% of the loci played a role in regulating both gene expression and DNA methylation. These associations were bidirectional, but there were pronounced negative associations for promoter CpGs. Integration of metQTL with adipose reference epigenomes and disease associations revealed significant enrichment of metQTL overlapping metabolic-trait or disease loci in enhancers (the strongest effects were for high-density lipoprotein cholesterol and body mass index [BMI]). We followed up with the BMI SNP rs713586, a cg01884057 metQTL that overlaps an enhancer upstream of ADCY3, and used bisulphite sequencing to refine this region. Our results showed widespread population invariability yet sequence dependence on adipose DNA methylation but that incorporating maps of regulatory elements aid in linking CpG variation to gene regulation and disease risk in a tissue-dependent manner.

  • 87. Grundberg, Elin
    et al.
    Meduri, Eshwar
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hedman, Åsa K.
    Wellcome Trust Centre for Human Genetics, University of Oxford, OX37BN Oxford, UK.
    Keildson, Sarah
    Buil, Alfonso
    Busche, Stephan
    Yuan, Wei
    Nisbet, James
    Sekowska, Magdalena
    Wilk, Alicja
    Barrett, Amy
    Small, Kerrin S.
    Ge, Bing
    Caron, Maxime
    Shin, So-Youn
    Lathrop, Mark
    Dermitzakis, Emmanouil T.
    McCarthy, Mark I.
    Spector, Timothy D.
    Bell, Jordana T.
    Deloukas, Panos
    Global Analysis of DNA Methylation Variation in Adipose Tissue from Twins Reveals Links to Disease-Associated Variants in Distal Regulatory Elements2013In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 93, no 5, p. 876-890Article in journal (Refereed)
    Abstract [en]

    Epigenetic modifications such as DNA methylation play a key role in gene regulation and disease susceptibility. However, little is known about the genome-wide frequency, localization, and function of methylation variation and how it is regulated by genetic and environmental factors. We utilized the Multiple Tissue Human Expression Resource (MuTHER) and generated Illumina 450K adipose methylome data from 648 twins. We found that individual CpGs had low variance and that variability was suppressed in promoters. We noted that DNA methylation variation was highly heritable (h(median)(2) = 0.34) and that shared environmental effects correlated with metabolic phenotype-associated CpGs. Analysis of methylation quantitative-trait loci (metQTL) revealed that 28% of CpGs were associated with nearby SNPs, and when overlapping them with adipose expression quantitative-trait loci (eQTL) from the same individuals, we found that 6% of the loci played a role in regulating both gene expression and DNA methylation. These associations were bidirectional, but there were pronounced negative associations for promoter CpGs. Integration of metQTL with adipose reference epigenomes and disease associations revealed significant enrichment of metQTL overlapping metabolic-trait or disease loci in enhancers (the strongest effects were for high-density lipoprotein cholesterol and body mass index [BMI]). We followed up with the BMI SNP rs713586, a cg01884057 metQTL that overlaps an enhancer upstream of ADCY3, and used bisulphite sequencing to refine this region. Our results showed widespread population invariability yet sequence dependence on adipose DNA methylation but that incorporating maps of regulatory elements aid in linking CpG variation to gene regulation and disease risk in a tissue-dependent manner.

  • 88.
    Gunnarsson, Rebeqa
    et al.
    Lund Univ, Dept Lab Med, Div Clin Genet, Lund, Sweden.
    DiLorenzo, Sebastian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundin-Ström, Kristina B.
    Lund Univ, Dept Lab Med, Div Clin Genet, Lund, Sweden.
    Olsson, Linda
    Lund Univ, Dept Lab Med, Div Clin Genet, Lund, Sweden;Dept Clin Genet & Pathol, Div Lab Med, Lund, Sweden.
    Biloglav, Andrea
    Lund Univ, Dept Lab Med, Div Clin Genet, Lund, Sweden.
    Lilljebjörn, Henrik
    Lund Univ, Dept Lab Med, Div Clin Genet, Lund, Sweden.
    Rissler, Marianne
    Lund Univ, Dept Lab Med, Div Clin Genet, Lund, Sweden.
    Wahlberg, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundmark, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Castor, Anders
    Skane Univ Hosp, Dept Pediat, Lund, Sweden.
    Behrendtz, Mikael
    Linkoping Univ Hosp, Dept Pediat, Linkoping, Sweden.
    Fioretos, Thoas
    Lund Univ, Dept Lab Med, Div Clin Genet, Lund, Sweden;Dept Clin Genet & Pathol, Div Lab Med, Lund, Sweden.
    Paulsson, Kajsa
    Lund Univ, Dept Lab Med, Div Clin Genet, Lund, Sweden.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Johansson, Bertil
    Lund Univ, Dept Lab Med, Div Clin Genet, Lund, Sweden;Dept Clin Genet & Pathol, Div Lab Med, Lund, Sweden.
    Mutation, methylation, and gene expression profiles in dup(1q)-positive pediatric B-cell precursor acute lymphoblastic leukemia2018In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 32, no 10, p. 2117-2125Article in journal (Refereed)
    Abstract [en]

    High-throughput sequencing was applied to investigate the mutation/methylation patterns on 1q and gene expression profiles in pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL) with/without (w/wo) dup(1q). Sequencing of the breakpoint regions and all exons on 1q in seven dup(1q)-positive cases revealed non-synonymous somatic single nucleotide variants (SNVs) in BLZF1, FMN2, KCNT2, LCE1C, NES, and PARP1. Deep sequencing of these in a validation cohort w (n = 17)/wo (n = 94) dup(1q) revealed similar SNV frequencies in the two groups (47% vs. 35%; P = 0.42). Only 0.6% of the 36,259 CpGs on 1q were differentially methylated between cases w (n = 14)/wo (n = 13) dup(1q). RNA sequencing of high hyperdiploid (HeH) and t(1;19)(q23;p13)-positive cases w (n = 14)/wo (n = 52) dup(1q) identified 252 and 424 differentially expressed genes, respectively; only seven overlapped. Of the overexpressed genes in the HeH and t(1;19) groups, 23 and 31%, respectively, mapped to 1q; 60-80% of these encode nucleic acid/protein binding factors or proteins with catalytic activity. We conclude that the pathogenetically important consequence of dup(1q) in BCP ALL is a gene-dosage effect, with the deregulated genes differing between genetic subtypes, but involving similar molecular functions, biological processes, and protein classes.

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  • 89.
    Gupta, Manu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Milani, Lili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Hermansson, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Simonsson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Markekvarn, B
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Barbany, Gisela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Expression of BCR-ABL1 oncogene relative to ABL1 gene changes overtime in chronic myeloid leukemia2008In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 366, no 3, p. 848-851Article in journal (Other (popular science, discussion, etc.))
    Abstract [en]

    Using a quantitative single nucleotide polymorphism (SNP) assay we have investigated the changes in the expression of the BCR-ABL1 oncogene relative to the wild-type ABL1 and BCR alleles in cells from chronic myeloid leukemia (CML) patients not responding to therapy. The results show a progressive increase in the BCR-ABL1 oncogene expression at the expense of decreased expression of the ABL1 allele, not involved in the fusion. No relative changes in the expression of the two BCR alleles were found. These results demonstrate that allele-specific charities in gene expression, with selective, progressive silencing of the wild-type A BL1 allele in favor of the oncogenic BCR-ABL1 allele occur in CML patients with therapy-resistant disease.

  • 90.
    Guy, Lionel
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Jernberg, Cecilia
    Norling, Jenny Arven
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Ivarsson, Sofie
    Hedenstrom, Ingela
    Melefors, Ojar
    Liljedahl, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Engstrand, Lars
    Andersson, Siv G. E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Adaptive Mutations and Replacements of Virulence Traits in the Escherichia coli O104:H4 Outbreak Population2013In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 5, p. e63027-Article in journal (Refereed)
    Abstract [en]

    The sequencing of highly virulent Escherichia coli O104:H4 strains isolated during the outbreak of bloody diarrhea and hemolytic uremic syndrome in Europe in 2011 revealed a genome that contained a Shiga toxin encoding prophage and a plasmid encoding enteroaggregative fimbriae. Here, we present the draft genome sequence of a strain isolated in Sweden from a patient who had travelled to Tunisia in 2010 (E112/10) and was found to differ from the outbreak strains by only 38 SNPs in non-repetitive regions, 16 of which were mapped to the branch to the outbreak strain. We identified putatively adaptive mutations in genes for transporters, outer surface proteins and enzymes involved in the metabolism of carbohydrates. A comparative analysis with other historical strains showed that E112/10 contained Shiga toxin prophage genes of the same genotype as the outbreak strain, while these genes have been replaced by a different genotype in two otherwise very closely related strains isolated in the Republic of Georgia in 2009. We also present the genome sequences of two enteroaggregative E. coli strains affiliated with phylogroup A (C43/90 and C48/93) that contain the agg genes for the AAF/I-type fimbriae characteristic of the outbreak population. Interestingly, C43/90 also contained a tet/mer antibiotic resistance island that was nearly identical in sequence to that of the outbreak strain, while the corresponding island in the Georgian strains was most similar to E. coli strains of other serotypes. We conclude that the pan-genome of the outbreak population is shared with strains of the A phylogroup and that its evolutionary history is littered with gene replacement events, including most recently independent acquisitions of antibiotic resistance genes in the outbreak strains and its nearest neighbors. The results are summarized in a refined evolutionary model for the emergence of the O104:H4 outbreak population.

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  • 91.
    Hagberg, Niklas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Joelsson, Martin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Leonard, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Reid, Sarah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mo, John
    AstraZeneca, Resp Inflammat & Autoimmun, IMED Biotech Unit, Gothenburg, Sweden.
    Nilsson, Magnus K.
    AstraZeneca, Resp Inflammat & Autoimmun, IMED Biotech Unit, Gothenburg, Sweden.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bryceson, Yenan T.
    Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, Karolinska Univ Hosp Huddinge, Stockholm, Sweden;Univ Bergen, Dept Clin Sci, Broegelmann Res Lab, Bergen, Norway.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The STAT4 SLE risk allele rs7574865[T] is associated with increased IL-12-induced IFN-γ production in T cells from patients with SLE2018In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, no 7, p. 1070-1077Article in journal (Refereed)
    Abstract [en]

    Objectives Genetic variants in the transcription factor STAT4 are associated with increased susceptibility to systemic lupus erythematosus (SLE) and a more severe disease phenotype. This study aimed to clarify how the SLE-associated intronic STAT4 risk allele rs7574865[T] affects the function of immune cells in SLE.

    Methods Peripheral blood mononuclear cells (PBMCs) were isolated from 52 genotyped patients with SLE. Phosphorylation of STAT4 (pSTAT4) and STAT1 (pSTAT1) in response to interferon (IFN)-α, IFN-γ or interleukin (IL)-12, total levels of STAT4, STAT1 and T-bet, and frequency of IFN-γ+ cells on IL-12 stimulation were determined by flow cytometry in subsets of immune cells before and after preactivation of cells with phytohaemagglutinin (PHA) and IL-2. Cellular responses and phenotypes were correlated to STAT4 risk allele carriership. Janus kinase inhibitors (JAKi) selective for TYK2 (TYK2i) or JAK2 (JAK2i) were evaluated for inhibition of IL-12 or IFN-γ-induced activation of SLE PBMCs.

    Results In resting PBMCs, the STAT4 risk allele was neither associated with total levels of STAT4 or STAT1, nor cytokine-induced pSTAT4 or pSTAT1. Following PHA/IL-2 activation, CD8+ T cells from STAT4 risk allele carriers displayed increased levels of STAT4 resulting in increased pSTAT4 in response to IL-12 and IFN-α, and an augmented IL-12-induced IFN-γ production in CD8+ and CD4+ T cells. The TYK2i and the JAK2i efficiently blocked IL-12 and IFN-γ-induced activation of PBMCs from STAT4 risk patients, respectively.

    Conclusions T cells from patients with SLE carrying the STAT4 risk allele rs7574865[T] display an augmented response to IL-12 and IFN-α. This subset of patients may benefit from JAKi treatment.

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  • 92. Haldorsen, Karstein
    et al.
    Appel, Silke
    Le Hellard, Stephanie
    Bruland, Ove
    Brun, Johan G.
    Omdal, Roald
    Kristjansdottir, Gudlaug
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Theander, Elke
    Fernandes, Carla P. D.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Kvarnstrom, Marika
    Eriksson, Per
    Ronnblom, Lars
    Herlenius, Marie Wahren
    Jonsson, Roland
    Bolstad, Anne Isine
    No Association of Primary Sjogren's Syndrome with Fcγ?Receptor Gene Variants2012In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 76, no 2, p. 198-198Article in journal (Other academic)
  • 93.
    Hallberg, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Ibanez, Luisa
    Univ Autonoma Barcelona, Hosp Univ Vall dHebron, Fundacio Inst Catala Farmacol, E-08193 Barcelona, Spain..
    Bondon-Guitton, Emmanuelle
    Univ Toulouse, Serv Pharmacol Med & Clin, Ctr Hosp Univ, Fac Med, Toulouse, France..
    Kreutz, Reinhold
    Charite, Inst Klin Pharmakol & Toxikol, D-13353 Berlin, Germany..
    Carvajal, Alfonso
    Univ Valladolid, Ctr Estudios Seguridad Medicamentos, Valladolid, Spain..
    Isabel Lucena, M.
    Univ Malaga, Hosp Univ Virgen de la Victoria, Inst Invest Biomed Malaga, Farmacol Clin S, E-29071 Malaga, Spain.;Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain..
    Sancho Ponce, Esther
    Hosp Gen Cataluna, Serv Hematol & Banc Sang, Sant Cugat Del Valles, Spain..
    Molokhia, Mariam
    Guys & St Thomas NHS Fdn Trust, Res Biomed Res Ctr, Natl Inst Hlth, Dept Primary Care & Publ Hlth Sci, London, England.;Kings Coll London, London WC2R 2LS, England..
    Martin, Javier
    CSIC, Inst Parasitol & Biomed Lopez Neyra, Granada, Spain..
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Yue, Qun-Ying
    Med Prod Agcy, Uppsala, Sweden..
    Magnusson, Patrik K. E.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Swedish Twin Registry, Stockholm, Sweden..
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genetic variants associated with antithyroid drug-induced agranulocytosis: a genome-wide association study in a European population2016In: The Lancet Diabetes and Endocrinology, ISSN 2213-8587, E-ISSN 2213-8595, Vol. 4, no 6, p. 507-516Article in journal (Refereed)
    Abstract [en]

    Background: Drug-induced agranulocytosis is a potentially life-threatening adverse reaction. Genome-wide association studies (GWASs) in ethnic Chinese people in Taiwan and Hong Kong have shown an association between agranulocytosis induced by antithyroid drugs and the HLA alleles HLA-B*38:02 and HLA-DRB1*08:03. We aimed to identify genetic variants associated with antithyroid drug-induced agranulocytosis in a white European population.

    Methods: We did a GWAS in 234 European adults with any non-chemotherapy drug-induced agranulocytosis (absolute neutrophil count <= 0.5 x 10(9)/L [<= 500/mu L]) and 5170 population controls. 39 of the 234 patients had agranulocytosis that was induced by antithyroid drugs (thiamazole [methimazole], carbimazole, or propylthiouracil). After imputation and HLA allele prediction, 9 380 034 single nucleotide polymorphisms (SNPs) and 180 HLA alleles were tested for association. The genome-wide significance threshold was p<5 x 10(-8).

    Findings: Agranulocytosis induced by non-chemotherapy drugs in general was significantly associated with the HLA region on chromosome 6, with odds ratios (ORs) of 3.24 (95% CI 2.31-4.55, p = 1.20 x 10(-11)) for HLA-B*27:05 and 3.57 (2.61-4.90, p = 2.32 x 10(-15)) for the top SNP (rs114291795). Drug-specific analysis showed that the association with HLA-B*27: 05 was largely driven by cases induced by antithyroid drugs. In a multiple logistic regression model, the OR for HLA-B*27: 05 was 7.30 (3.81-13.96) when antithyroid drug-induced agranulocytosis was compared with population controls (p= 1.91 x 10(-9)) and 16.91 (3.44-83.17) when compared with a small group of hyperthyroid controls (p = 5.04 x 10(-4)). Three SNPs were strongly associated with antithyroid drug-induced agranulocytosis: rs652888 (OR 4.73, 95% CI 3.00-7.44, p= 1.92 x 10(-11)) and rs199564443 (17.42, 7.38-41.12, p = 7.04 x 10(-11)), which were independent of HLA-B*27:05, and rs1071816 (5.27, 3.06-9.10, p = 2.35 x 10(-9)) which was in moderate linkage disequilibrium with HLA-B*27:05. In heterozygous carriers of all three SNPs, the predicted probability of antithyroid drug-induced agranulocytosis was about 30% (OR 753, 95% CI 105-6812). To avoid one case of agranulocytosis, based on the possible risk reduction if all three SNPs are genotyped and carriers are treated or monitored differently from non-carriers, roughly 238 patients would need to be genotyped.

    Interpretation: In white European people, antithyroid drug-induced agranulocytosis was associated with HLA-B* 27: 05 and with other SNPs on chromosome 6. In the future, carriers of these variants could be placed under intensified monitoring or offered alternative treatment for hyperthyroidism.

  • 94.
    Hallberg, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Karlsson, J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Kurland, L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kahan, Thomas
    Malmqvist, K.
    Öhman, K. P.
    Nyström, F.
    Liljedahl, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gender-specific association between preproendothelin-1 genotype and reduction of systolic blood pressure during antihypertensive treatment: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA)2004In: Clinical Cardiology, ISSN 0160-9289, E-ISSN 1932-8737, Vol. 27, no 5, p. 287-290Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Studies suggest that endothelin-1 contributes to the pathogenesis of hypertension. A G5665T gene polymorphism of preproendothelin-1 has been shown to be associated with higher blood pressure in overweight patients. No study has yet determined the effect of this polymorphism on the change in blood pressure during antihypertensive treatment.

    HYPOTHESIS:

    This study aimed to determine this effect in hypertensive patients with left ventricular (LV) hypertrophy during antihypertensive treatment with either irbesartan or atenolol.

    METHODS:

    We determined the preproendothelin-1 genotype using minisequencing in 102 patients with essential hypertension and LV hypertrophy verified by echocardiography, randomized in a double-blind fashion to treatment with either the AT1-receptor antagonist irbesartan or the beta1-adrenoceptor antagonist atenolol.

    RESULTS:

    The change in systolic blood pressure (SBP) after 12 weeks of treatment was related to the preproendothelin-1 genotype in men; after adjustment for potential covariates (age, blood pressure, and LV mass index at study entry, dose of irbesartan/atenolol, and type of treatment), those carrying the T-allele responded on average with a more than two-fold greater reduction than those with the G/G genotype (-21.9 mmHg [13.9] vs. -8.9 [2.3], p = 0.007). No significant differences in blood pressure change between G/G and carriers of the T-allele were seen among women.

    CONCLUSIONS:

    Our finding suggests a gender-specific relationship between the G5665T preproendothelin-1 polymorphism and change in SBP in response to antihypertensive treatment with irbesartan or atenolol, suggesting the endothelin pathway to be a common mechanism included in the hypertensive action of the drugs.

  • 95.
    Hallberg, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Kurland, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kahan, Thomas
    Malmqvist, Karin
    Öhman, Karl Peter
    Nyström, Fredrik
    Liljedahl, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Adipocyte-derived leucine aminopeptidase genotype and response to antihypertensive therapy2003In: BMC Cardiovascular Disorders, ISSN 1471-2261, E-ISSN 1471-2261, Vol. 18, no 3, p. 11-Article in journal (Refereed)
    Abstract [en]

    Background

    Adipocyte-derived leucine aminopeptidase (ALAP) is a recently identified member of the M1 family of zinc-metallopeptidases and is thought to play a role in blood pressure control through inactivation of angiotensin II and/or generation of bradykinin. The enzyme seems to be particularly abundant in the heart. Recently, the Arg528-encoding allele of the ALAP gene was shown to be associated with essential hypertension.

    Methods

    We evaluated the influence of this polymorphism on the change in left ventricular mass index in 90 patients with essential hypertension and echocardiographically diagnosed left ventricular hypertrophy, randomised in a double-blind study to receive treatment with either the angiotensin II type I receptor antagonist irbesartan or the beta1-adrenoceptor blocker atenolol for 48 weeks. Genyotyping was performed using minisequencing.

    Results

    After adjustment for potential covariates (blood pressure and left ventricular mass index at baseline, blood pressure change, age, sex, dose and added antihypertensive treatment), there was a marked difference between the Arg/Arg and Lys/Arg genotypes in patients treated with irbesartan; those with the Arg/Arg genotype responded on average with an almost two-fold greater regression of left ventricular mass index than patients with the Lys/Arg genotype (-30.1 g/m2 [3.6] vs -16.7 [4.5], p = 0.03).

    Conclusions

    The ALAP genotype seems to determine the degree of regression of left ventricular hypertrophy during antihypertensive treatment with the angiotensin II type I receptor antagonist irbesartan in patients with essential hypertension and left ventricular hypertrophy. This is the first report of a role for ALAP/aminopeptidases in left ventricular mass regulation, and suggests a new potential target for antihypertensive drugs.

  • 96.
    Hallberg, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Persson, Matilda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cavalli, Marco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Norling, Pia
    Sickla Hlth Ctr, Nacka, Sweden..
    Johansson, Hans-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Yue, Qun-Ying
    Med Prod Agcy, Uppsala, Sweden..
    Magnusson, Patrik K. E.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Swedish Twin Registry, Stockholm, Sweden..
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genetic variants associated with angiotensin-converting enzyme inhibitor-induced cough: a genome-wide association study in a Swedish population2017In: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 18, no 3, p. 201-213Article in journal (Refereed)
    Abstract [en]

    Aim: We conducted a genome-wide association study on angiotensin-converting enzyme inhibitor-induced cough and used our dataset to replicate candidate genes iden-tified in previous studies. Patients & methods: A total of 124 patients and 1345 treated controls were genotyped using Illumina arrays. The genome-wide significance level was set to p < 5 x 10(-8). Results: We identified nearly genome-wide significant associations in CLASP1, PDE11A, KCNMB2, TGFA, SLC38A6 and MMP16. The strongest association was with rs62151109 in CLASP1 (odds ratio: 3.97; p = 9.44 x 10(-8)). All top hits except two were located in intronic or noncoding DNA regions. None of the candidate genes were significantly associated in our study. Conclusion: Angiotensin-converting enzyme inhibitor-induced cough is potentially associated with genes that are independent of bradykinin pathways.

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  • 97.
    Halldorsdottir, Anna Margret
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Kanduri, Meena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Marincevic, Millaray
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Göransson, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Agarwal, Prasoon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Jernberg-Wiklund, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Stamatopoulos, Kostas
    Sander, Birgitta
    Ehrencrona, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Mantle cell lymphoma displays a homogenous methylation profile: A comparative analysis with chronic lymphocytic leukemia2012In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 87, no 4, p. 361-367Article in journal (Refereed)
    Abstract [en]

    Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) are mature CD5(+) B-cell malignancies with different biological/clinical characteristics. We recently reported an association between different prognostic subgroups of CLL (i.e., IGHV mutated and unmutated) and genomic methylation pattern. However, the relationship between DNA methylation and prognostic markers, such as the proliferation gene expression signature, has not been investigated in MCL. We applied high-resolution methylation microarrays (27,578 CpG sites) to assess the global DNA methylation profiles in 20 MCL (10 each with high/low proliferation signature) and 30 CLL (15 poor-prognostic IGHV unmutated subset #1 and 15 good-prognostic IGHV mutated subset #4) samples. Notably, MCL and each CLL subset displayed distinct genomic methylation profiles. After unsupervised hierarchical clustering, 17/20 MCL cases formed a cluster separate from CLL, while CLL subsets #1 and #4 formed subclusters. Surprisingly, few differentially methylated genes (n = 6) were identified between high vs. low proliferation MCL. In contrast, distinct methylation profiles were demonstrated for MCL and CLL. Importantly, certain functional classes of genes were preferentially methylated in either disease. For instance, developmental genes, in particular homeobox transcription factor genes (e.g., HLXB9, HOXA13), were more highly methylated in MCL, whereas apoptosis-related genes were enriched among targets methylated in CLL (e.g., CYFIP2, NR4A1). Results were validated using pyrosequencing, RQ-PCR and reexpression of specific genes. In summary, the methylation profile of MCL was homogeneous and no correlation with the proliferation signature was observed. Compared to CLL, however, marked differences were discovered such as the preferential methylation of homeobox genes in MCL.

  • 98.
    Halldórsdóttir, Anna Margrét
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Kanduri, Meena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Marincevic, Millaray
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Göransson, H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Agarwal, Prasoon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Jernberg-Wiklund, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Stamatopoulos, K.
    4Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece.
    Sander, B.
    Ehrencrona, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Mantle Cell Lymphoma is Characterized by a Strikingly Homogenous Methylation Profile: a comparative analysis with chronic lymphocytic leukemia2011In: PLOS ONE, E-ISSN 1932-6203Article in journal (Refereed)
  • 99.
    Hallström, Helena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Uppsala Clinical Research Center (UCR).
    Glynn, Anders
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Uppsala Clinical Research Center (UCR).
    Coffee consumption and CYP1A2 genotype in relation to bone mineral density of the proximal femur in elderly men and women: a cohort study2010In: Nutrition & Metabolism, E-ISSN 1743-7075, Vol. 7, p. 12-Article in journal (Refereed)
    Abstract [en]

    ABSTRACT: BACKGROUND: Drinking coffee has been linked to reduced calcium conservation, but it is less clear whether it leads to sustained bone mineral loss and if individual predisposition for caffeine metabolism might be important in this context. Therefore, the relation between consumption of coffee and bone mineral density (BMD) at the proximal femur in men and women was studied, taking into account, for the first time, genotypes for cytochrome P450 1A2 (CYP1A2) associated with metabolism of caffeine. METHODS: Dietary intakes of 359 men and 358 women (aged 72 years), participants of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS), were assessed by a 7-day food diary. Two years later, BMD for total proximal femur, femoral neck and trochanteric regions of the proximal femur were measured by Dual-energy X-ray absorptiometry (DXA). Genotypes of CYP1A2 were determined. Adjusted means of BMD for each category of coffee consumption were calculated. RESULTS: Men consuming 4 cups of coffee or more per day had 4% lower BMD at the proximal femur (p = 0.04) compared with low or non-consumers of coffee. This difference was not observed in women. In high consumers of coffee, those with rapid metabolism of caffeine (C/C genotype) had lower BMD at the femoral neck (p = 0.01) and at the trochanter (p = 0.03) than slow metabolizers (T/T and C/T genotypes). Calcium intake did not modify the relation between coffee and BMD. CONCLUSION: High consumption of coffee seems to contribute to a reduction in BMD of the proximal femur in elderly men, but not in women. BMD was lower in high consumers of coffee with rapid metabolism of caffeine, suggesting that rapid metabolizers of caffeine may constitute a risk group for bone loss induced by coffee.

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  • 100. Harrison, Seamus C.
    et al.
    Zabaneh, Delilah
    Asselbergs, Folkert W.
    Drenos, Fotios
    Jones, Gregory T.
    Shah, Sonia
    Gertow, Karl
    Sennblad, Bengt
    Strawbridge, Rona J.
    Gigante, Bruna
    Holewijn, Suzanne
    De Graaf, Jacqueline
    Vermeulen, Sita
    Folkersen, Lasse
    van Rij, Andre M.
    Baldassarre, Damiano
    Veglia, Fabrizio
    Talmud, Philippa J.
    Deanfield, John E.
    Agu, Obi
    Kivimaki, Mika
    Kumari, Meena
    Bown, Matthew J.
    Nyyssonen, Kristiina
    Rauramaa, Rainer
    Smit, Andries J.
    Franco-Cereceda, Anders
    Giral, Philippe
    Mannarino, Elmo
    Silveira, Angela
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    de Borst, Gert J.
    van der Graaf, Yolanda
    de Faire, Ulf
    Baas, Annette F.
    Blankensteijn, Jan D.
    Wareham, Nicholas J.
    Fowkes, Gerry
    Tzoulaki, Ionna
    Price, Jacqueline F.
    Tremoli, Elena
    Hingorani, Aroon D.
    Eriksson, Per
    Hamsten, Anders
    Humphries, Steve E.
    A gene-centric study of common carotid artery remodelling2013In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 226, no 2, p. 440-446Article in journal (Refereed)
    Abstract [en]

    Background: Expansive remodelling is the process of compensatory arterial enlargement in response to atherosclerotic stimuli. The genetic determinants of this process are poorly characterized. Methods: Genetic association analyses of inter-adventitial common carotid artery diameter (ICCAD) in the IMPROVE study (n = 3427) using the Illumina 200k Metabochip was performed. Single nucleotide polymorphisms (SNPs) that met array-wide significance were taken forward for analysis in three further studies (n = 5704), and tested for association with Abdominal Aortic Aneurysm (AAA). Results: rs3768445 on Chromosome 1q24.3, in a cluster of protein coding genes (DNM3, PIGC, C1orf105) was associated with larger ICCAD in the IMPROVE study. For each copy of the rare allele carried, ICCAD was on average 0.13 mm greater (95% CI 0.08-0.18 mm, P = 8.2 x 10(-8)). A proxy SNP (rs4916251, R-2 = 0.99) did not, however, show association with ICCAD in three follow-up studies (P for replication = 0.29). There was evidence of interaction between carotid intima-media thickness (CIMT) and rs4916251 on ICCAD in two of the cohorts studies suggesting that it plays a role in the remodelling response to atherosclerosis. In meta-analysis of 5 case-control studies pooling data from 5007 cases and 43,630 controls, rs4916251 was associated with presence of AAA 1.10, 95% CI 1.03-1.17, p = 2.8 x 10(-3), I-2 = 18.8, Q = 0.30). A proxy SNP, rs4916251 was also associated with increased expression of PIGC in aortic tissue, suggesting that this may the mechanism by which this locus affects vascular remodelling. Conclusions: Common variation at 1q24.3 is associated with expansive vascular remodelling and risk of AAA. These findings support a hypothesis that pathways involved in systemic vascular remodelling play a role in AAA development.

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