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  • 251. Strawbridge, Rona J.
    et al.
    Dupuis, Josee
    Prokopenko, Inga
    Barker, Adam
    Ahlqvist, Emma
    Rybin, Denis
    Petrie, John R.
    Travers, Mary E.
    Bouatia-Naji, Nabila
    Dimas, Antigone S.
    Nica, Alexandra
    Wheeler, Eleanor
    Chen, Han
    Voight, Benjamin F.
    Taneera, Jalal
    Kanoni, Stavroula
    Peden, John F.
    Turrini, Fabiola
    Gustafsson, Stefan
    Zabena, Carina
    Almgren, Peter
    Barker, David J. P.
    Barnes, Daniel
    Dennison, Elaine M.
    Eriksson, Johan G.
    Eriksson, Per
    Eury, Elodie
    Folkersen, Lasse
    Fox, Caroline S.
    Frayling, Timothy M.
    Goel, Anuj
    Gu, Harvest F.
    Horikoshi, Momoko
    Isomaa, Bo
    Jackson, Anne U.
    Jameson, Karen A.
    Kajantie, Eero
    Kerr-Conte, Julie
    Kuulasmaa, Teemu
    Kuusisto, Johanna
    Loos, Ruth J. F.
    Luan, Jian'an
    Makrilakis, Konstantinos
    Manning, Alisa K.
    Teresa Martinez-Larrad, Maria
    Narisu, Narisu
    Mannila, Maria Nastase
    Ohrvik, John
    Osmond, Clive
    Pascoe, Laura
    Payne, Felicity
    Sayer, Avan A.
    Sennblad, Bengt
    Silveira, Angela
    Stancakova, Alena
    Stirrups, Kathy
    Swift, Amy J.
    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.
    Tuomi, Tiinamaija
    van 't Hooft, Ferdinand M.
    Walker, Mark
    Weedon, Michael N.
    Xie, Weijia
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ongen, Halit
    Malarstig, Anders
    Hopewell, Jemma C.
    Saleheen, Danish
    Chambers, John
    Parish, Sarah
    Danesh, John
    Kooner, Jaspal
    Ostenson, Claes-Goran
    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.
    Cooper, Cyrus C.
    Serrano-Rios, Manuel
    Ferrannini, Ele
    Forsen, Tom J.
    Clarke, Robert
    Franzosi, Maria Grazia
    Seedorf, Udo
    Watkins, Hugh
    Froguel, Philippe
    Johnson, Paul
    Deloukas, Panos
    Collins, Francis S.
    Laakso, Markku
    Dermitzakis, Emmanouil T.
    Boehnke, Michael
    McCarthy, Mark I.
    Wareham, Nicholas J.
    Groop, Leif
    Pattou, Francois
    Gloyn, Anna L.
    Dedoussis, George V.
    Lyssenko, Valeriya
    Meigs, James B.
    Barroso, Ines
    Watanabe, Richard M.
    Ingelsson, Erik
    Langenberg, Claudia
    Hamsten, Anders
    Florez, Jose C.
    Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes2011In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 60, no 10, p. 2624-2634Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE-Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired beta-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS-We have conducted a meta-analysis of genome-wide association tests of similar to 2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS-Nine SNPs at eight loci were associated with proinsulin levels (P < 5 x 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC3OA8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 x 10(-4)), improved beta-cell function (P = 1.1 x 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 x 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS-We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis. 

  • 252.
    Strawbridge, Rona J.
    et al.
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    Hilding, Agneta
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Silveira, Angela
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    Österholm, Cecilia
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Nova Southeastern Univ, Cell Therapy Inst, Ft Lauderdale, FL USA..
    Sennblad, Bengt
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden.;Karolinska Inst, Sci Life Lab, Stockholm, Sweden..
    McLeod, Olga
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    Tsikrika, Panagiota
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    Foroogh, Fariba
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    Tremoli, Elena
    Univ Milan, Dipartimento Sci Farmacol & Biomol, Milan, Italy.;Ist Ricovero & Cura Carattere Sci, Ctr Cardiol Monzino, Milan, Italy..
    Baldassarre, Damiano
    Univ Milan, Dipartimento Sci Farmacol & Biomol, Milan, Italy.;Ist Ricovero & Cura Carattere Sci, Ctr Cardiol Monzino, Milan, Italy..
    Veglia, Fabrizio
    Ist Ricovero & Cura Carattere Sci, Ctr Cardiol Monzino, Milan, Italy..
    Rauramaa, Rainer
    Fdn Res Hlth Exercise & Nutr, Kuopio Res Inst Exercise Med, Kuopio, Finland.;Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, Kuopio, Finland..
    Smit, Andries J.
    Univ Med Ctr Groningen, Dept Med, Groningen, Netherlands..
    Giral, Phillipe
    Grp Hosp Pitie Salpetriere, Assistance Publ Hop Paris, Serv Endocrinol Metab, Unites Prevent Cardiovasc, Paris, France..
    Kurl, Sudhir
    Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio Campus, Kuopio, Finland..
    Mannarino, Elmo
    Univ Perugia, Dept Clin & Expt Med, Internal Med Angiol & Arteriosclerosis Dis, Perugia, Italy..
    Grossi, Enzo
    Bracco Med Dept, Milan, Italy..
    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.
    Humphries, Steve E.
    UCL, Ctr Cardiovasc Genet, London, England..
    de Faire, Ulf
    Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Cardiol, Stockholm, Sweden..
    Östenson, Claes-Goran
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Maegdefessel, Lars
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    Hamsten, Anders
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Cardiol, Stockholm, Sweden..
    Backlund, Alexandra
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    Soluble CD93 Is Involved in Metabolic Dysregulation but Does Not Influence Carotid Intima-Media Thickness2016In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 65, no 10, p. 2888-2899Article in journal (Refereed)
    Abstract [en]

    Type 2 diabetes and cardiovascular disease are complex disorders involving metabolic and inflammatory mechanisms. Here we investigated whether sCD93, a group XIV c-type lectin of the endosialin family, plays a role in metabolic dysregulation or carotid intima-media thickness (IMT). Although no association was observed between sCD93 and IMT, sCD93 levels were significantly lower in subjects with type 2 diabetes (n = 901, mean 6 SD 156.6 +/- 40.0 ng/mL) compared with subjects without diabetes (n = 2,470, 164.1 +/- 44.8 ng/mL, P < 0.0001). Genetic variants associated with diabetes risk (DIAGRAM Consortium) did not influence sCD93 levels (individually or combined in a single nucleotide polymorphism score). In a prospective cohort, lower sCD93 levels preceded the development of diabetes. Consistent with this, a cd93-deficient mouse model (in addition to apoe deficiency) demonstrated no difference in atherosclerotic lesion development compared with apoe(-/-) cd93-sufficient littermates. However, cd93-deficient mice showed impaired glucose clearance and insulin sensitivity (compared with littermate controls) after eating a high-fat diet. The expression of cd93 was observed in pancreatic islets, and leaky vessels were apparent in cd93-deficient pancreases. We further demonstrated that stress-induced release of sCD93 is impaired by hyperglycemia. Therefore, we propose CD93 as an important component in glucometabolic regulation.

  • 253.
    Strawbridge, Rona J.
    et al.
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden.;Univ Glasgow, Inst Mental Hlth & Wellbeing, Mental Hlth & Wellbeing, Glasgow, Lanark, Scotland.;Univ Glasgow, Dept Hlth & Wellbeing, Glasgow G12 8RZ, Lanark, Scotland..
    Silveira, Angela
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    den Hoed, Marcel
    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.
    Gustafsson, Stefan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Luan, Jian'an
    Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Cambridge, England..
    Rybin, Denis
    Boston Univ, Data Coordinating Ctr, Boston, MA 02215 USA..
    Dupuis, Josee
    Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA.;Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA..
    Li-Gao, Ruifang
    Leiden Univ, Dept Clin Epidemiol, Med Ctr, Leiden, Netherlands..
    Kavousi, Maryam
    Univ Med Ctr Rotterdam, Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Dehghan, Abbas
    Univ Med Ctr Rotterdam, Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Imperial Coll London, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, London, England..
    Haljas, Kadri
    Univ Helsinki, Fac Med, Dept Psychol & Logoped, Helsinki, Finland..
    Lahti, Jari
    Univ Helsinki, Fac Med, Dept Psychol & Logoped, Helsinki, Finland.;Folkhalsan Res Ctr, Helsinki, Finland..
    Gadin, Jesper R.
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    Backlund, Alexandra
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    de Faire, Ulf
    Karolinska Inst, Inst Environm Med, Div Cardiovasc Epidemiol, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Cardiol, Stockholm, Sweden..
    Gertow, Karl
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    Giral, Phillipe
    Grp Hosp Pitie Salpetriere, AP HP, Serv Endocrinol Metab, Unites Prevent Cardiovasc, Paris, France..
    Goel, Anuj
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Radcliffe Dept Med, Div Cardiovasc Med, Oxford, England..
    Humphries, Steve E.
    UCL, Inst Cardiovasc Sci, Ctr Cardiovasc Genet, London, England..
    Kurl, Sudhir
    Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio Campus, Kuopio, Finland..
    Langenberg, Claudia
    Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Cambridge, England.;Imperial Coll London, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, London, England..
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Cambridge, England.;Imperial Coll London, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, London, England..
    Lindgren, Cecilia C. M.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Mannarino, Elmo
    Univ Perugia, Dept Clin & Expt Med Internal Med Angiol & Arteri, Perugia, Italy..
    Mook-Kanamori, Dennis O.
    Leiden Univ, Med Ctr, Dept Publ Hlth & Primary Care, Leiden, Netherlands..
    Morris, Andrew P.
    Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England..
    de Mutsert, Renee
    Univ Helsinki, Fac Med, Dept Psychol & Logoped, Helsinki, Finland..
    Rauramaa, Rainer
    Kuopio Res Inst Exercise Med, Fdn Res Hlth Exercise & Nutr, Kuopio, Finland.;Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, Kuopio, Finland..
    Saliba-Gustafsson, Peter
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    Sennblad, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden.
    Smit, Andries J.
    Univ Med Ctr Groningen, Dept Med, Groningen, Netherlands.;Univ Groningen, Univ Med Ctr Groningen, Dept Med, Groningen, Netherlands..
    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.
    Tremoli, Elena
    Univ Milan, Dipartimento Sci Farmacolog & Biomol, Milan, Italy.;IRCCS, Ctr Cardiolog Monzino, Milan, Italy..
    Veglia, Fabrizio
    IRCCS, Ctr Cardiolog Monzino, Milan, Italy..
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bjorck, Hanna M.
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    Eriksson, Johan G.
    Folkhalsan Res Ctr, Helsinki, Finland.;Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland.;Helsinki Univ Hosp, Helsinki, Finland.;Natl Inst Hlth & Welf, Helsinki, Finland..
    Hofman, Albert
    Harvard T H Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA..
    Franco, Oscar H.
    Watkins, Hugh
    Jukema, J. Wouter
    Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands.;Interuniv Cardiol Inst Netherlands, Utrecht, Netherlands..
    Florez, Jose C.
    Massachusetts Gen Hosp, Diabet Unit, Boston, MA USA.;Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA USA.;Broad Inst, Programs Metab & Med & Populat Genet, Cambridge, MA USA.;Harvard Med Sch, Dept Med, Cambridge, MA USA..
    Wareham, Nicholas J.
    Univ Cambridge, Sch Clin Med, MRC Epidemiol Unit, Cambridge, England..
    Meigs, James B.
    Broad Inst, Programs Metab & Med & Populat Genet, Cambridge, MA USA.;Harvard Med Sch, Dept Med, Cambridge, MA USA.;Massachusetts Gen Hosp, Gen Med Div, Boston, MA USA..
    Ingelsson, Erik
    Stanford Univ, Sch Med, Div Cardiovasc Med, Dept Med, Stanford, CA USA..
    Baldassarre, Damiano
    Univ Milan, Dipartimento Sci Farmacolog & Biomol, Milan, Italy.;Univ Milan, Dept Med Biotechnol & Translat Med, Milan, Italy..
    Hamsten, Anders
    Identification of a novel proinsulin-associated SNP and demonstration that proinsulin is unlikely to be a causal factor in subclinical vascular remodelling using Mendelian randomisation2017In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 266, p. 196-204Article in journal (Refereed)
    Abstract [en]

    Background and aims: Increased proinsulin relative to insulin levels have been associated with subclinical atherosclerosis (measured by carotid intima-media thickness (cIMT)) and are predictive of future cardiovascular disease (CVD), independently of established risk factors. The mechanisms linking proinsulin to atherosclerosis and CVD are unclear. A genome-wide meta-analysis has identified nine loci associated with circulating proinsulin levels. Using proinsulin-associated SNPs, we set out to use a Mendelian randomisation approach to test the hypothesis that proinsulin plays a causal role in subclinical vascular remodelling.

    Methods: We studied the high CVD-risk IMPROVE cohort (n = 3345), which has detailed biochemical phenotyping and repeated, state-of-the-art, high-resolution carotid ultrasound examinations. Genotyping was performed using Illumina Cardio-Metabo and Immuno arrays, which include reported proinsulin-associated loci. Participants with type 2 diabetes (n = 904) were omitted from the analysis. Linear regression was used to identify proinsulin-associated genetic variants.

    Results: We identified a proinsulin locus on chromosome 15 (rs8029765) and replicated it in data from 20,003 additional individuals. An 11-SNP score, including the previously identified and the chromosome 15 proinsulin-associated loci, was significantly and negatively associated with baseline IMTmean and IMTmax (the primary cIMT phenotypes) but not with progression measures. However, MR-Eggers refuted any significant effect of the proinsulin-associated 11-SNP score, and a non-pleiotropic SNP score of three variants (including rs8029765) demonstrated no effect on baseline or progression cIMT measures.

    Conclusions: We identified a novel proinsulin-associated locus and demonstrated that whilst proinsulin levels are associated with cIMT measures, proinsulin per se is unlikely to have a causative effect on cIMT.

  • 254.
    Stålberg, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Wang, Shu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Larsson, Catharina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Weber, Günther
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Gobl, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Suppression of the neoplastic phenotype by transfection of phospholipase C3 to neuroendocrine tumor cells1999In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 450, no 3, p. 210-216Article in journal (Refereed)
    Abstract [en]

    The expression of phospholipase C beta 3 (PLCB3) is low or absent in several neuroendocrine neoplasias. To investigate the role of PLCB3 in the neuroendocrine tumorigenesis, we transfected a PLCB3 construct to three neuroendocrine tumor cell lines with a low PLCB3 expression. The growth rate and tumorigenicity were assessed in vitro by [3H]thymidine incorporation and cell counting, in vivo, by xenografting to nude mice. In vitro, PLCB3 expressing clones showed a significant growth inhibition. The tumor weight was reduced for one of the two xenografted PLCB3-transfected cell lines and in both, a reduced number of proliferating (Ki-67 positive) cells was observed. This study implies an essential role for PLCB3 in the neuroendocrine tumorigenesis.

  • 255. Surakka, Ida
    et al.
    Whitfield, John B
    Perola, Markus
    Visscher, Peter M
    Montgomery, Grant W
    Falchi, Mario
    Willemsen, Gonneke
    de Geus, Eco J C
    Magnusson, Patrik K E
    Christensen, Kaare
    Sørensen, Thorkild I A
    Pietiläinen, Kirsi H
    Rantanen, Taina
    Silander, Kaisa
    Widén, Elisabeth
    Muilu, Juha
    Rahman, Iffat
    Liljedahl, Ulrika
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Palotie, Aarno
    Kaprio, Jaakko
    Kyvik, Kirsten O
    Pedersen, Nancy L
    Boomsma, Dorret I
    Spector, Tim
    Martin, Nicholas G
    Ripatti, Samuli
    Peltonen, Leena
    A Genome-Wide Association Study of Monozygotic Twin-Pairs Suggests a Locus Related to Variability of Serum High-Density Lipoprotein Cholesterol2012In: Twin Research and Human Genetics, ISSN 1832-4274, E-ISSN 1839-2628, Vol. 15, no 6, p. 691-699Article in journal (Refereed)
    Abstract [en]

    Genome-wide association analysis on monozygotic twin-pairs offers a route to discovery of gene-environment interactions through testing for variability loci associated with sensitivity to individual environment/lifestyle. We present a genome-wide scan of loci associated with intra-pair differences in serum lipid and apolipoprotein levels. We report data for 1,720 monozygotic female twin-pairs from GenomEUtwin project with 2.5 million SNPs, imputed or genotyped, and measured serum lipid fractions for both twins. We found one locus associated with intra-pair differences in high-density lipoprotein cholesterol, rs2483058 in an intron of SRGAP2, where twins carrying the C allele are more sensitive to environmental factors (P = 3.98 × 10-8). We followed up the association in further genotyped monozygotic twins (N = 1,261), which showed a moderate association for the variant (P = 0.200, same direction of an effect). In addition, we report a new association on the level of apolipoprotein A-II (P = 4.03 × 10-8).

  • 256. Svenungsson, Elisabet
    et al.
    Gustafsson, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Leonard, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sandling, Johanna
    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.
    Jönsen, Andreas
    Bengtsson, Anders A
    Sturfelt, Gunnar
    Rantapää-Dahlqvist, Solbritt
    Elvin, Kerstin
    Sundin, Ulf
    Garnier, Sophie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Simard, Julia F
    Sigurdsson, Snaevar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Padyukov, Leonid
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    A STAT4 risk allele is associated with ischaemic cerebrovascular events and anti-phospholipid antibodies in systemic lupus erythematosus2010In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 69, no 5, p. 834-840Article in journal (Refereed)
    Abstract [en]

    Objective

    To investigate whether the risk allele for systemic lupus erythematosus (SLE) in the signal transducer and activator of transcription factor 4 (STAT4) gene, defined by the single nucleotide polymorphism (SNP) rs10181656(G), is associated with vascular events and/or presence of prothrombotic anti-phospholipid antibodies (aPL) in patients with SLE.

    Methods

    Two independent groups of unrelated patients with SLE of Swedish ethnicity (n=424 and 154) were genotyped, and occurrence of previous manifestations of ischaemic heart disease (IHD), ischaemic cerebrovascular disease (ICVD) and venous thromboembolic events (VTE) was tabulated. aPL values were measured by ELISA. Matched controls (n=492 and 194) were genotyped.

    Results

    The STAT4 risk allele was more frequent in patients with SLE with previous arterial events (combined OR (ORc)=1.5, 95% CI 1.1 to 2.0) compared to patients without such events. The association was mainly attributable to an accumulation of the risk allele among patients with ICVD (ORc=2.3, CI 1.6 to 3.3). There was no association with IHD or VTE. The presence of two or more aPLs was associated with the risk allele (ORc=1.6, 95% CI 1.2 to 2.0). In multivariable-adjusted logistic regression analyses treatment for hypertension, at least one STAT4 risk allele, older age, IgG anti-cardiolipin antibodies and longer SLE duration remained independently associated with previous ICVD (p≤0.02 for all).

    Conclusion

    Patients with SLE with the STAT4 risk allele had a strikingly increased risk of ICVD, comparable in magnitude to that of hypertension. The results imply that a genetic predisposition is an important and previously unrecognised risk factor for ICVD in SLE, and that aPLs may be one underlying mechanism.

  • 257.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    From gels to chips: "Minisequencing" primer extension for analysis of point mutations and single nucleotide polymorphisms1999In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 13, no 1, p. 1-10Article in journal (Refereed)
    Abstract [en]

    In the minisequencing primer extension reaction, a DNA polymerase is used specifically to extend a primer that anneals immediately adjacent to the nucleotide position to be analyzed with a single labeled nucleoside triphospate complementary to the nucleotide at the variant site. The reaction allows highly specific detection of point mutations and single nucleotide polymorphisms (SNPs). Because all SNPs can be analyzed with high specificty at the same reaction conditions, minisequencing is a promising reaction principle for multiplex high-throughput genotyping assays. It is also a useful tool for accurate quantitative PCR-based analysis. This review discusses the different approaches, ranging from traditional gel-based formats to multiplex detection on microarrays that have been developed and applied to minisequencing assays.

  • 258.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Microarrays: Use in Mutation Detection2003In: Nature encyclopedia of the human genome / [ed] David N. Cooper, London: Nature Publishing Group, 2003, 5 vol, p. 940-944Chapter in book (Other (popular science, discussion, etc.))
  • 259.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Toward genome-wide SNP genotyping2005In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 37 Suppl, p. S5-S10Article in journal (Other academic)
    Abstract [en]

    Genome-wide association studies with SNP markers are expected to allow identification of genes that underlie complex disorders. Hundreds of thousands of SNP markers will be required for comprehensive genome-wide association studies. The development of microarray-based methods for SNP genotyping on this scale remains a demanding task, despite many recent advances in technology for the production of high-density microarrays. A key technical obstacle is the PCR amplification step, which is required to reduce the complexity of and gain sufficient sensitivity for genotyping SNPs in large, diploid genomes. The multiplexing level that can be achieved in PCR does not match that of current microarray-based methods, making PCR the limiting step in the assays. Highly multiplexed microarray systems for SNP genotyping have recently been developed by combining well-known reaction principles for DNA amplification and SNP genotyping in clever ways. These new methods offer the potential of genome-wide SNP mapping of genes involved in complex diseases in the foreseeable future, provided that issues related to selection of the optimal SNP markers, sample throughput and the cost of the assays can be addressed.

  • 260.
    Syvänen, Ann-Christine
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Söderlund, Hans
    DNA sandwiches with silver and gold2002In: Nature Biotechnology, ISSN 1087-0156, E-ISSN 1546-1696, Vol. 20, no 4, p. 349-350Article in journal (Other academic)
  • 261.
    Syvänen, Ann-Christine
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Taylor, Graham R
    Approaches for analyzing human mutations and nucleotide sequence variation: a report from the Seventh International Mutation Detection meeting, 20032004In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 23, no 5, p. 401-405Article in journal (Other academic)
    Abstract [en]

    The Seventh International Symposium on Mutations in the Human Genome, Mutation Detection 2003, was held during 2–6 July 2003 in Palm Cove near Cairns, Australia. The meeting was organized under the auspices of the Human Genome Organisation (HUGO) as a satellite meeting of the International World Congress of Genetics, held in Melbourne the following week. Meeting participants reported on advances in mutation detection technologies, including advances in high-throughput detection systems for SNP genotyping applicable to the international haplotype mapping project (HapMap); and bioinformatics tools, including databases for handling and processing growing amounts of genome variation data.

  • 262.
    Sætre, Glenn-Peter
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Evolutionary Biology.
    Borge, Thomas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Evolutionary Biology.
    Lindroos, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Haavie, Jon
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Evolutionary Biology.
    Sheldon, Ben C
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology.
    Primmer, Craig
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Sex chromosome evolution and speciation in Ficedula flycatchers2003In: Proceedings of the Royal Society of London. Biological Sciences, ISSN 0962-8452, E-ISSN 1471-2954, Vol. 270, no 1510, p. 53-59Article in journal (Other academic)
    Abstract [en]

    Speciation is the combination of evolutionary processes that leads to the reproductive isolation of different populations. We investigate the significance of sex-chromosome evolution on the development of post- and prezygotic isolation in two naturally hybridizing Ficedula flycatcher species. Applying a tag-array-based mini-sequencing assay to genotype single nucleotide polymorphisms (SNPs) and interspecific substitutions, we demonstrate rather extensive hybridization and backcrossing in sympatry. However, gene flow across the partial postzygotic barrier (introgression) is almost exclusively restricted to autosomal loci, suggesting strong selection against introgression of sex-linked genes. In addition to this partial postzygotic barrier, character displacement of male plumage characteristics has previously been shown to reinforce prezygotic isolation in these birds. We show that male plumage traits involved in reinforcing prezygotic isolation are sex linked. These results suggest a major role of sex-chromosome evolution in mediating post- and prezygotic barriers to gene flow and point to a causal link in the development of the two forms of reproductive isolation.

  • 263. 't Hoen, Peter A C
    et al.
    Friedländer, Marc R
    Almlöf, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sammeth, Michael
    Pulyakhina, Irina
    Anvar, Seyed Yahya
    Laros, Jeroen F J
    Buermans, Henk P J
    Karlberg, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Brännvall, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    den Dunnen, Johan T
    van Ommen, Gert-Jan B
    Gut, Ivo G
    Guigó, Roderic
    Estivill, Xavier
    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.
    Dermitzakis, Emmanouil T
    Lappalainen, Tuuli
    Reproducibility of high-throughput mRNA and small RNA sequencing across laboratories2013In: Nature Biotechnology, ISSN 1087-0156, E-ISSN 1546-1696, Vol. 31, no 11, p. 1015-1022Article in journal (Refereed)
    Abstract [en]

    RNA sequencing is an increasingly popular technology for genome-wide analysis of transcript sequence and abundance. However, understanding of the sources of technical and interlaboratory variation is still limited. To address this, the GEUVADIS consortium sequenced mRNAs and small RNAs of lymphoblastoid cell lines of 465 individuals in seven sequencing centers, with a large number of replicates. The variation between laboratories appeared to be considerably smaller than the already limited biological variation. Laboratory effects were mainly seen in differences in insert size and GC content and could be adequately corrected for. In small-RNA sequencing, the microRNA (miRNA) content differed widely between samples owing to competitive sequencing of rRNA fragments. This did not affect relative quantification of miRNAs. We conclude that distributing RNA sequencing among different laboratories is feasible, given proper standardization and randomization procedures. We provide a set of quality measures and guidelines for assessing technical biases in RNA-seq data.

  • 264.
    Tasa, Tonis
    et al.
    Univ Tartu, Inst Comp Sci, EE-50409 Tartu, Estonia;Univ Tartu, Inst Genom, Estonian Genome Ctr, EE-51010 Tartu, Estonia.
    Krebs, Kristi
    Univ Tartu, Inst Genom, Estonian Genome Ctr, EE-51010 Tartu, Estonia.
    Kals, Mart
    Univ Tartu, Inst Genom, Estonian Genome Ctr, EE-51010 Tartu, Estonia.
    Mägi, Reedik
    Univ Tartu, Inst Genom, Estonian Genome Ctr, EE-51010 Tartu, Estonia.
    Lauschke, Volker M.
    Karolinska Inst, Dept Physiol & Pharmacol, Sect Pharmacogenet, S-17177 Stockholm, Sweden.
    Haller, Toomas
    Univ Tartu, Inst Genom, Estonian Genome Ctr, EE-51010 Tartu, Estonia.
    Puurand, Tarmo
    Univ Tartu, Inst Mol & Cell Biol, Dept Bioinformat, EE-51010 Tartu, Estonia.
    Remm, Maido
    Univ Tartu, Inst Mol & Cell Biol, Dept Bioinformat, EE-51010 Tartu, Estonia.
    Esko, Tonu
    Univ Tartu, Inst Genom, Estonian Genome Ctr, EE-51010 Tartu, Estonia.
    Metspalu, Andres
    Univ Tartu, Inst Genom, Estonian Genome Ctr, EE-51010 Tartu, Estonia.
    Vilo, Jaak
    Univ Tartu, Inst Comp Sci, EE-50409 Tartu, Estonia.
    Milani, Lili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Tartu, Inst Genom, Estonian Genome Ctr, EE-51010 Tartu, Estonia.
    Genetic variation in the Estonian population: pharmacogenomics study of adverse drug effects using electronic health records2019In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, no 3, p. 442-454Article in journal (Refereed)
    Abstract [en]

    Pharmacogenomics aims to tailor pharmacological treatment to each individual by considering associations between genetic polymorphisms and adverse drug effects (ADEs). With technological advances, pharmacogenomic research has evolved from candidate gene analyses to genome-wide association studies. Here, we integrate deep whole-genome sequencing (WGS) information with drug prescription and ADE data from Estonian electronic health record (EHR) databases to evaluate genome- and pharmacome-wide associations on an unprecedented scale. We leveraged WGS data of 2240 Estonian Biobank participants and imputed all single-nucleotide variants (SNVs) with allele counts over 2 for 13,986 genotyped participants. Overall, we identified 41 (10 novel) loss-of-function and 567 (134 novel) missense variants in 64 very important pharmacogenes. The majority of the detected variants were very rare with frequencies below 0.05%, and 6 of the novel lossof-function and 99 of the missense variants were only detected as single alleles (allele count = 1). We also validated documented pharmacogenetic associations and detected new independent variants in known gene-drug pairs. Specifically, we found that CTNNA3 was associated with myositis and myopathies among individuals taking nonsteroidal anti-inflammatory oxicams and replicated this finding in an extended cohort of 706 individuals. These findings illustrate that population-based WGS-coupled EHRs are a useful tool for biomarker discovery.

  • 265.
    Tay, Nicole
    et al.
    Kings Coll London, Ctr Populat Neurosci & Stratified Med, Inst Psychiat, London, England;Kings Coll London, SGDP Ctr, Inst Psychiat, London, England.
    Macare, Christine
    Kings Coll London, Ctr Populat Neurosci & Stratified Med, Inst Psychiat, London, England;Kings Coll London, SGDP Ctr, Inst Psychiat, London, England.
    Liu, Yun
    Fudan Univ, Dept Biochem & Mol Biol, MOE Key Lab Metab & Mol Med, Sch Basic Med Sci, Shanghai, Peoples R China.
    Ruggeri, Barbara
    Kings Coll London, Ctr Populat Neurosci & Stratified Med, Inst Psychiat, London, England;Kings Coll London, SGDP Ctr, Inst Psychiat, London, England.
    Jia, Tianye
    Kings Coll London, Ctr Populat Neurosci & Stratified Med, Inst Psychiat, London, England;Kings Coll London, SGDP Ctr, Inst Psychiat, London, England;Fudan Univ, Inst Sci & Technol Brain Inspired Intelligen, Shanghai, Peoples R China;Fudan Univ, Key Lab Computat Neurosci & Brain Inspired Intell, Minist Educ, Shanghai, Peoples R China.
    Chu, Congying
    Kings Coll London, Ctr Populat Neurosci & Stratified Med, Inst Psychiat, London, England;Kings Coll London, SGDP Ctr, Inst Psychiat, London, England.
    Biondo, Francesca
    Kings Coll London, Ctr Populat Neurosci & Stratified Med, Inst Psychiat, London, England;Kings Coll London, SGDP Ctr, Inst Psychiat, London, England.
    Ing, Alex
    Kings Coll London, Ctr Populat Neurosci & Stratified Med, Inst Psychiat, London, England;Kings Coll London, SGDP Ctr, Inst Psychiat, London, England.
    Luo, Qiang
    Fudan Univ, Sch Life Sci, Shanghai, Peoples R China;Fudan Univ, Inst Sci & Technol Brain Inspired Intelligence, Shanghai, Peoples R China.
    Sarkisyan, Daniil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Banaschewski, Tobias
    Heidelberg Univ, Dept Child & Adolescent Psychiat & Psychotherapy, Cent Inst Mental Hlth, Mannheim, Germany.
    Barker, Gareth J.
    Kings Coll London, Ctr Populat Neurosci & Stratified Med, Inst Psychiat, London, England;Kings Coll London, SGDP Ctr, Inst Psychiat, London, England.
    Bokde, Arun L. W.
    Trinity Coll Dublin, Discipline Psychiat, Sch Med, Dublin, Ireland;Trinity Coll Dublin, Trinity Coll, Inst Neurosci, Dublin, Ireland.
    Bromberg, Uli
    Univ Med Ctr Hamburg Eppendorf, Hamburg, Germany.
    Büchel, Christian
    Univ Med Ctr Hamburg Eppendorf, Hamburg, Germany.
    Quinlan, Erin Burke
    Kings Coll London, Ctr Populat Neurosci & Stratified Med, Inst Psychiat, London, England;Kings Coll London, SGDP Ctr, Inst Psychiat, London, England.
    Desrivieres, Sylvane
    Kings Coll London, Ctr Populat Neurosci & Stratified Med, Inst Psychiat, London, England;Kings Coll London, SGDP Ctr, Inst Psychiat, London, England.
    Flor, Herta
    Heidelberg Univ, Dept Cognit & Clin Neurosci, Cent Inst Mental Hlth, Med Fac Mannheim, Mannheim, Germany;Univ Mannheim, Dept Psychol, Sch Social Sci, Mannheim, Germany.
    Frouin, Vincent
    Univ Paris Saclay, NeuroSpin, Gif Sur Yvette, France.
    Garavan, Hugh
    Univ Vermont, Dept Psychiat, Burlington, VT USA;Univ Vermont, Dept Psychol, Burlington, VT 05405 USA.
    Gowland, Penny
    Univ Nottingham, Sir Peter Mansfield Imaging Ctr Sch Phys, Nottingham, England.
    Heinz, Andreas
    Univ Med Berlin, Charite, Dept Psychiat & Psychotherapy, Campus Charite Mitte, Berlin, Germany.
    Ittermann, Bernd
    Phys Tech Bundesanstalt, Berlin, Germany.
    Martinot, Jean-Luc
    Univ Paris 05, Univ Paris Sud Paris Saclay, Unit 1000 Neuroimaging & Psychiat, DIGITEO Labs,INSERM, Gif Sur Yvette, France;Cochin Hosp, Maison Solenn, Paris, France.
    Artiges, Eric
    Univ Paris Saclay, Univ Paris Sud, DIGITEO Labs, INSERM, Gif Sur Yvette, France;Orsay Hosp, Dept Psychiat, Orsay, France.
    Nees, Frauke
    Trinity Coll Dublin, Discipline Psychiat, Sch Med, Dublin, Ireland;Trinity Coll Dublin, Trinity Coll, Inst Neurosci, Dublin, Ireland;Heidelberg Univ, Dept Cognit & Clin Neurosci, Cent Inst Mental Hlth, Med Fac Mannheim, Mannheim, Germany;Heidelberg Univ, Dept Child & Adolescent Psychiat & Psychotherapy, Cent Inst Mental Hlth, Med Fac Mannheim, Mannheim, Germany;Nees German Res Fdn, Bonn, Germany.
    Orfanos, Dimitri Papadopoulos
    Univ Paris Saclay, NeuroSpin, Gif Sur Yvette, France.
    Paus, Tomas
    Univ Toronto, Bloorview Res Inst, Holland Bloorview Kids Rehabil, Hosp & Dept Psychol, Toronto, ON, Canada;Univ Toronto, Bloorview Res Inst, Holland Bloorview Kids Rehabil, Dept Psychiat, Toronto, ON, Canada.
    Poustka, Luise
    Univ Med Ctr Gottingen, Dept Child & Adolescent Psychiat & Psychotherapy, Gottingen, Germany;Med Univ Vienna, Clin Child & Adolescent Psychiat, Vienna, Austria.
    Hohmann, Sarah
    Heidelberg Univ, Dept Child & Adolescent Psychiat & Psychotherapy, Cent Inst Mental Hlth, Mannheim, Germany.
    Fröhner, Juliane H.
    Tech Univ Dresden, Dept Psychiat, Dresden, Germany;Tech Univ Dresden, Neuroimaging Ctr, Dresden, Germany.
    Smolka, Michael N.
    Tech Univ Dresden, Dept Psychiat, Dresden, Germany;Tech Univ Dresden, Neuroimaging Ctr, Dresden, Germany.
    Walter, Henrik
    Univ Med Berlin, Charite, Dept Psychiat & Psychotherapy, Campus Charite Mitte, Berlin, Germany.
    Whelan, Robert
    Trinity Coll Dublin, Sch Psychol, Dublin, Ireland;Trinity Coll Dublin, Global Brain Hlth Inst, Dublin, Ireland.
    Frieling, Helge
    Hannover Med Sch, Dept Psychiat Social Psychiat & Psychotherapy, Hannover, Germany.
    Bleich, Stefan
    Hannover Med Sch, Dept Psychiat Social Psychiat & Psychotherapy, Hannover, Germany.
    Barker, Edward D.
    Kings Coll London, Ctr Neuroimaging Sci, Inst Psychiat Psychol & Neurosci, London, England.
    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.
    Rüegg, Joelle
    Karolinska Inst, Dept Clin Neurosci, Ctr Mol Med, Stockholm, Sweden.
    Ekström, Tomas J.
    Karolinska Inst, Dept Clin Neurosci, Ctr Mol Med, Stockholm, Sweden.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Schumann, Gunter
    Kings Coll London, Ctr Populat Neurosci & Stratified Med, Inst Psychiat, London, England;Kings Coll London, SGDP Ctr, Inst Psychiat, London, England.
    Allele-Specific Methylation of SPDEF: A Novel Moderator of Psychosocial Stress and Substance Abuse2019In: American Journal of Psychiatry, ISSN 0002-953X, E-ISSN 1535-7228, Vol. 176, no 2, p. 146-155Article in journal (Refereed)
    Abstract [en]

    Objective: Psychosocial stress is a key risk factor for substance abuse among adolescents. Recently, epigenetic processes such as DNA methylation have emerged as potential mechanisms that could mediate this relationship. The authors conducted a genome-wide methylation analysis to investigate whether differentially methylated regions are associated with psychosocial stress in an adolescent population.

    Methods: A methylome-wide analysis of differentially methylated regions was used to examine a sample of 1,287 14-year-old adolescents (50.7% of them female) from the European IMAGEN study. The Illumina 450k array was used to assess DNA methylation, pyrosequencing was used for technical replication, and linear regression analyses were used to identify associations with psychosocial stress and substance use (alcohol and tobacco). Findings were replicated by pyrosequencing a test sample of 413 participants from the IMAGEN study.

    Results: Hypermethylation in the sterile alpha motif/pointed domain containing the ETS transcription factor (SPDEF) gene locus was associated with a greater number of stressful life events in an allele-dependent way. Among individuals with the minor G-allele, SPDEF methylation moderated the association between psychosocial stress and substance abuse. SPDEF methylation interacted with lifetime stress in gray matter volume in the right cuneus, which in turn was associated with the frequency of alcohol and tobacco use. SPDEF was involved in the regulation of trans-genes linked to substance use.

    Conclusions: Taken together, the study findings describe a novel epigenetic mechanism that helps explain how psychosocial stress exposure influences adolescent substance abuse.

  • 266.
    Teppo, Susanna
    et al.
    Univ Tampere, Tampere Ctr Child Hlth Res, Tampere 33520, Finland.;Tampere Univ Hosp, Tampere 33520, Finland..
    Laukkanen, Saara
    Univ Tampere, Tampere Ctr Child Hlth Res, Tampere 33520, Finland.;Tampere Univ Hosp, Tampere 33520, Finland..
    Liuksiala, Thomas
    Univ Tampere, Tampere Ctr Child Hlth Res, Tampere 33520, Finland.;Tampere Univ Hosp, Tampere 33520, Finland.;Univ Tampere, Inst Biosci & Med Technol, Tampere 33520, Finland..
    Nordlund, Jessica
    Uppsala Univ, Dept Med Sci, Mol Med & Sci Life Lab, S-75105 Uppsala, Sweden..
    Oittinen, Mikko
    Univ Tampere, Tampere Ctr Child Hlth Res, Tampere 33520, Finland.;Tampere Univ Hosp, Tampere 33520, Finland..
    Teittinen, Kaisa
    Univ Tampere, Tampere Ctr Child Hlth Res, Tampere 33520, Finland.;Tampere Univ Hosp, Tampere 33520, Finland..
    Gronroos, Toni
    Univ Tampere, Tampere Ctr Child Hlth Res, Tampere 33520, Finland.;Tampere Univ Hosp, Tampere 33520, Finland..
    St-Onge, Pascal
    Univ Montreal, CHU St Justine Res Ctr, Montreal, PQ H3T 1J4, Canada..
    Sinnett, Daniel
    Univ Montreal, CHU St Justine Res Ctr, Montreal, PQ H3T 1J4, Canada.;Univ Montreal, Fac Med, Dept Pediat, Montreal, PQ H3T 1J4, Canada..
    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.
    Nykter, Matti
    Univ Tampere, Inst Biosci & Med Technol, Tampere 33520, Finland.;Tampere Univ Technol, Dept Signal Proc, Tampere 33720, Finland..
    Viiri, Keijo
    Univ Tampere, Tampere Ctr Child Hlth Res, Tampere 33520, Finland.;Tampere Univ Hosp, Tampere 33520, Finland..
    Heinaniemi, Merja
    Univ Eastern Finland, Inst Biomed, Sch Med, Kuopio 70211, Finland..
    Lohi, Olli
    Univ Tampere, Tampere Ctr Child Hlth Res, Tampere 33520, Finland.;Tampere Univ Hosp, Tampere 33520, Finland..
    Genome-wide repression of eRNA and target gene loci by the ETV6-RUNX1 fusion in acute leukemia2016In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 26, no 11, p. 1468-1477Article in journal (Refereed)
    Abstract [en]

    Approximately 20%-25% of childhood acute lymphoblastic leukemias carry the ETV6-RUNX1 (E/R) fusion gene, a fusion of two central hematopoietic transcription factors, ETV6 (TEL) and RUNX1 (AML1). Despite its prevalence, the exact genomic targets of E/R have remained elusive. We evaluated gene loci and enhancers targeted by E/R genome-wide in precursor B acute leukemia cells using global run-on sequencing (GRO-seq). We show that expression of the E/R fusion leads to widespread repression of RUNX1 motif-containing enhancers at its target gene loci. Moreover, multiple super-enhancers from the CD19(+)/CD20(+)-lineage were repressed, implicating a role in impediment of lineage commitment. In effect, the expression of several genes involved in B cell signaling and adhesion was down-regulated, and the repression depended on the wild-type DNA-binding Runt domain of RUNX1. We also identified a number of E/R-regulated annotated and de novo noncoding genes. The results provide a comprehensive genome-wide mapping between E/R-regulated key regulatory elements and genes in precursor B cell leukemia that disrupt normal B lymphopoiesis.

  • 267. Tyden, Eva
    et al.
    Dahlberg, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Karlberg, Olof
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Hoglund, Johan
    Deep amplicon sequencing of preselected isolates of Parascaris equorum in beta-tubulin codons associated with benzimidazole resistance in other nematodes2014In: Parasites & Vectors, ISSN 1756-3305, E-ISSN 1756-3305, Vol. 7, p. 410-Article in journal (Refereed)
    Abstract [en]

    Background: The development of anthelmintic resistance (AR) to macrocyclic lactones in the equine roundworm Parascaris equorum has resulted in benzimidazoles now being the most widely used substance to control Parascaris infections. However, over-reliance on one drug class is a risk factor for the development of AR. Consequently, benzimidazole resistance is widespread in several veterinary parasites, where it is associated with single nucleotide polymorphisms (SNPs) in drug targets encoded by the beta-tubulin genes. The importance of these SNPs varies between different parasitic nematodes, but it has been hypothesised that they occur, at low allele frequencies, even in unselected populations. This study investigated whether these SNPs exist in the P. equorum population and tested the hypothesis that BZ resistance can develop from pre-existing SNPs in codons 167, 198 and 200 of the beta-tubulin isotype 1 and 2 genes, reported to be associated with AR in strongylids. The efficacy of the oral paste formula fenbendazole on 11 farms in Sweden was also assessed. Methods: Two isotype-specific primer pairs were designed, one on either side of the codon 167 and one on either side of codons 198 and 200. A pool of 100 000 larvae was sequenced using deep amplicon sequencing by Illumina HiSeq. Faecal egg count reduction test was used to assess the efficacy of fenbendazole. Results: No SNPs were observed in codons 167, 198 or 200 of the beta-tubulin isotype 1 or 2 genes of P. equorum, even though 100 000 larvae were sequenced. Faecal egg count reduction testing of fenbendazole showed that this anthelmintic was still 100% effective, meaning that the likelihood of finding high allele frequency of SNPs associated with benzimidazoles resistance in P. equorum was low. Unexpectedly, the allele frequencies observed in single worms were comparable to those in pooled samples. Conclusions: We concluded that fenbendazole does not exert selection pressure on the beta-tubulin genes of isotypes 1 and 2 in P. equorum. The fact that no pre-existing SNPs were found in codons 167, 198 and 200 in P. equorum also illustrates the difficulties in generalising about AR mechanisms between different taxonomic groups of nematodes.

  • 268.
    Täpp, Ida
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Malmberg, Lovisa
    Rennel, Emma
    Majstin, Wik
    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.
    Homogeneous scoring of single nucleotide polymorphisms: The 5’-nuclease ”TaqMan” assay versus Molecular beacon probes2000In: BioTechniques, ISSN 0736-6205, E-ISSN 1940-9818, Vol. 28, no 4, p. 732-738Article in journal (Refereed)
    Abstract [en]

    Homogeneous assays based on real-time fluorescence monitoring during PCR are relevant alternatives for large-scale genotyping of single-nucleotide polymorphisms (SNPs). We compared the performance of the homogeneous TaqMan 5'-nuclease assay and the Molecular Beacon assay using three SNPs in the human estrogen receptor gene as targets. When analyzing a panel of 90 DNA samples, both assays yielded a comparable power of discrimination between the genotypes of a C-to-T transition in codon 10 and a G-to-A transition in codon 594 of the estrogen receptor gene. The Molecular Beacon probes distinguished better than the TaqMan probes between homozygous and heterozygous genotypes of a C-to-G transversion in codon 325. The sensitivity of detecting one allele, present as a minority in a mixed sample, varied between the SNPs and was similar for both assays. With the Molecular Beacon assay, the measured signal ratios were proportional to the amount of the minor allele over a wider range than with the TaqMan assay at all three SNPs.

  • 269. Uronen, Riikka-Liisa
    et al.
    Lundmark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Orho-Melander, Marju
    Jauhiainen, Matti
    Larsson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Melander, Olle
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Ikonen, Elina
    Niemann-Pick C1 modulates hepatic triglyceride metabolism and its genetic variation contributes to serum triglyceride levels2010In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 30, no 8, p. 1614-1620Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    To study how Niemann-Pick disease type C1 (NPC1) influences hepatic triacylglycerol (TG) metabolism and to determine whether this is reflected in circulating lipid levels.

    METHODS AND RESULTS:

     In Npc1−/− mice, the hepatic cholesterol content is increased but the TG content is decreased. We investigated lipid metabolism in Npc1−/− mouse hepatocytes and the association of NPC1 single-nucleotide polymorphisms with circulating TGs in humans. TGs were reduced in Npc1−/− mouse serum and hepatocytes. In Npc1−/− hepatocytes, the incorporation of [3H]oleic acid and [3H]acetate into TG was decreased, but shunting of oleic acid- or acetate-derived [3H]carbons into cholesterol was increased. Inhibition of cholesterol synthesis normalized TG synthesis, content, and secretion in Npc1−/− hepatocytes, suggesting increased hepatic cholesterol neogenesis as a cause for the reduced TG content and secretion. We found a significant association between serum TG levels and 5 common NPC1 single-nucleotide polymorphisms in a cohort of 1053 men, with the lowest P=8.7×10−4 for the single-nucleotide polymorphism rs1429934. The association between the rs1429934 A allele and higher TG levels was replicated in 2 additional cohorts, which included 8041 individuals.

    CONCLUSIONS:

    This study provides evidence of the following: (1) in mice, loss of NPC1 function reduces hepatocyte TG content and secretion by increasing the metabolic flux of carbons into cholesterol synthesis; and (2) common variation in NPC1 contributes to serum TG levels in humans.

  • 270.
    Varenhorst, Christoph
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Johansson, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Barratt, Bryan J.
    Hagström, Emil
    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 Surgical Sciences, Endocrine Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Åkerblom, Axel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Becker, Richard C.
    James, Stefan K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Katus, Hugo A.
    Husted, Steen
    Steg, Ph. Gabriel
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Voora, Deepak
    Teng, Renli
    Storey, Robert F.
    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.
    Effect of genetic variations on ticagrelor plasma levels and clinical outcomes2015In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 36, no 29, p. 1901-1912Article in journal (Refereed)
    Abstract [en]

    Aims Ticagrelor, a direct-acting P2Y(12)-receptor antagonist, is rapidly absorbed and partly metabolized to the major metabolite AR-C124910XX (ARC). To identify single-nucleotide polymorphisms (SNPs) associated with pharmacokinetics of ticagrelor and clinical outcomes, we performed a genome-wide association study (GWAS) in patients treated with ticagrelor in the PLATO trial. Methods and results A two-stage design was used for the GWAS with discovery (discovery phase: n = 1812) and replication cohorts (replication phase: n = 1941). The steady-state area under the curve (AUCss) values, estimated by the population pharmacokinetic (PK) models, were log transformed and analysed on a genome-wide scale using linear regression. SNPs were analysed against clinical events using Cox-regression in 4990 patients. An SNP (rs113681054) in SLCO1B1 was associated with levels of ticagrelor (P = 1.1 x 10(-6)) and ARC (P = 4.6 x 10(-13)). This SNP is in linkage disequilibrium with a functional variant (rs4149056) that results in decreased OATP1B1 transporter activity. Ticagrelor levels were also associated with two independent SNPs (rs62471956, P = 7.7 x 10(-15) and rs56324128, P = 9.7 x 10(-12)) in the CYP3A4 region. Further, ARC levels were associated with rs61361928 (P = 3.0 x 10(-14)) in UGT2B7. At all loci, the effects were small. None of the identified SNPs that affected ticagrelor PK were associated with the primary composite outcome (cardiovascular death myocardial infarction, and stroke), non-CABG-related bleeds or investigator-reported dyspnoea. Conclusion In patients with ACS, ticagrelor pharmacokinetics is influenced by three genetic loci (SLCO1B1, UGT2B7, and CYP3A4). However, the modest genetic effects on ticagrelor plasma levels did not translate into any detectable effect on efficacy or safety during ticagrelor treatment.

  • 271.
    Virtanen, Anders
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Henriksson, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Nilsson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Lindell, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Mechanism of processive and cap-stimulated mRNA poly(A) tail degradation2012In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26, p. 950.3-Article in journal (Other academic)
  • 272. Vuong, Mai Tuyet
    et al.
    Gunnarsson, Iva
    Lundberg, Sigrid
    Svenungsson, Elisabet
    Wramner, Lars
    Fernström, Anders
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Do, Lieu Thi
    Jacobson, Stefan H.
    Padyukov, Leonid
    Genetic risk factors in lupus nephritis and IgA nephropathy: no support of an overlap2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 5, p. e10559-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    IgA nephropathy (IgAN) and nephritis in Systemic Lupus Erythematosus (SLE) are two common forms of glomerulonephritis in which genetic findings are of importance for disease development. We have recently reported an association of IgAN with variants of TGFB1. In several autoimmune diseases, particularly in SLE, IRF5, STAT4 genes and TRAF1-C5 locus have been shown to be important candidate genes. The aim of this study was to compare genetic variants from the TGFB1, IRF5, STAT4 genes and TRAF1-C5 locus with susceptibility to IgAN and lupus nephritis in two Swedish cohorts.

    PATIENTS AND METHODS:

    We genotyped 13 single nucleotide polymorphisms (SNPs) in four genetic loci in 1252 DNA samples from patients with biopsy proven IgAN or with SLE (with and without nephritis) and healthy age- and sex-matched controls from the same population in Sweden.

    RESULTS:

    Genotype and allelic frequencies for SNPs from selected genes did not differ significantly between lupus nephritis patients and SLE patients without nephritis. In addition, haplotype analysis for seven selected SNPs did not reveal a difference for the SLE patient groups with and without nephritis. Moreover, none of these SPNs showed a significant difference between IgAN patients and healthy controls. IRF5 and STAT4 variants remained significantly different between SLE cases and healthy controls. In addition, the data did not show an association of TRAF1-C5 polymorphism with susceptibility to SLE in this Swedish population.

    CONCLUSION:

    Our data do not support an overlap in genetic susceptibility between patients with IgAN or SLE and reveal no specific importance of SLE associated SNPs for the presence of lupus nephritis.

  • 273.
    Wadelius, Mia
    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, 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. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kreutz, Reinhold
    Universitätsmedizin Berlin, Institut für Klinische Pharmakologie und Toxikologie, Berlin, Germany.
    Bondon-Guitton, Emmanuelle
    Service de Pharmacologie Médicale et Clinique, Centre Hospitalier Universitaire, Faculté de Médecine de l'Université de Toulouse, Toulouse, France.
    Ibañez, Luisa
    Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Fundació Institut Català de Farmacologia, Barcelona, Spain.
    Carvajal, Alfonso
    Centro de Estudios sobre la Seguridad de los Medicamentos, Universidad de Valladolid, Valladolid, Spain.
    Lucena, M Isabel
    S Farmacologia Clinica, Instituto de Investigación Biomedica de Málaga (IBIMA), H Universitario Virgen de la Victoria, Universidad de Málaga, CIBERehd, Madrid, Spain.
    Sancho Ponce, Esther
    Servei d'Hematologia i Banc de Sang, Hospital General de Catalunya, Sant Cugat del Vallès, Spain.
    Molokhia, Mariam
    NIHR Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London Department of Primary Care and Public Health Sciences, London, U.
    Martin, Javier
    Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Granada, Spain.
    Axelsson, Tomas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Kohnke, Hugo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Yue, Qun-Ying
    Medical Products Agency, Uppsala, Sweden.
    Magnusson, Patrik K E
    Swedish Twin Registry, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Bengtsson, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hallberg, Pär
    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.
    Sulfasalazine-Induced Agranulocytosis Is Associated With the Human Leukocyte Antigen Locus.2018In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 103, no 5, p. 843-853Article in journal (Refereed)
    Abstract [en]

    Agranulocytosis is a serious, although rare, adverse reaction to sulfasalazine, which is used to treat inflammatory joint and bowel disease. We performed a genome‐wide association study comprising 9,380,034 polymorphisms and 180 HLA alleles in 36 cases of sulfasalazine‐induced agranulocytosis and 5,170 population controls. Sulfasalazine‐induced agranulocytosis was significantly associated with the HLA region on chromosome 6. The top hit (rs9266634) was located close to HLA‐B, odds ratio (OR) 5.36 (95% confidence interval (CI) (2.97, 9.69) P = 2.55 × 10−8). We HLA‐sequenced a second cohort consisting of 40 cases and 142 treated controls, and confirmed significant associations with HLA‐B*08:01, OR = 2.25 (95% CI (1.02, 4.97) P = 0.0439), in particular the HLA‐B*08:01 haplotype HLA‐DQB1*02:01‐DRB1*03:01‐B*08:01‐C*07:01, OR = 3.79 (95% CI (1.63, 8.80) P = 0.0019), and with HLA‐A*31:01, OR = 4.81 (95% CI (1.52, 15.26) P = 0.0077). The number needed to test for HLA‐B*08:01 and HLA‐A*31:01 to avoid one case was estimated to be 1,500. We suggest that intensified monitoring or alternative treatment should be considered for known carriers of HLA‐B*08:01 or HLA‐A*31:01.

  • 274.
    Wahl, Simone
    et al.
    Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Inst Epidemiol II, German Res Ctr Environm Hlth, Helmholtz Zentrum M nchen, Neuherberg, Germany.;German Ctr Diabet Res DZD, Neuherberg, Germany.;Univ Alexandria, Med Res Inst, Clin & Expt Surg Dept, Hadara, Alexandria 21561, Egypt..
    Drong, Alexander
    Univ Oxford, Wellcome Trust Ctr Human Genet, Roosevelt Dr, Oxford OX3 7BN, England..
    Lehne, Benjamin
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostatist, MRC PHE Ctr Environm & Hlth, London W2 1PG, England..
    Loh, Marie
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostatist, MRC PHE Ctr Environm & Hlth, London W2 1PG, England.;Inst Hlth Sci, POB 5000, FI-90014 Oulu, Finland.;Translat Lab Genet Med TLGM, Agcy Sci, Technol & Res ASTAR, 8A Biomed Grove, Singapore 138648, Singapore..
    Scott, William R.
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostatist, MRC PHE Ctr Environm & Hlth, London W2 1PG, England.;Imperial Coll London, Natl Heart & Lung Inst, London W12 0NN, England..
    Kunze, Sonja
    Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Inst Epidemiol II, German Res Ctr Environm Hlth, Helmholtz Zentrum M nchen, Neuherberg, Germany..
    Tsai, Pei-Chien
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England..
    Ried, Janina S.
    German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany..
    Zhang, Weihua
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostatist, MRC PHE Ctr Environm & Hlth, London W2 1PG, England.;Imperial Coll London, Natl Heart & Lung Inst, London W12 0NN, England.;Ealing Hosp NHS Trust, Middlesex UB1 3HW, England..
    Yang, Youwen
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostatist, MRC PHE Ctr Environm & Hlth, London W2 1PG, England..
    Tan, Sili
    Fiorito, Giovanni
    Human Genet Fdn Torino, Turin, Italy.;Univ Torino, Dept Med Sci, Turin, Italy..
    Franke, Lude
    Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands.;Univ Groningen, NL-9700 AB Groningen, Netherlands..
    Guarrera, Simonetta
    Human Genet Fdn Torino, Turin, Italy.;Univ Torino, Dept Med Sci, Turin, Italy..
    Kasela, Silva
    Univ Tartu, Estonian Genome Ctr, Riia 23b, EE-51010 Tartu, Estonia.;Univ Tartu, Inst Mol & Cell Biol, Dept Biotechnol, Riia 23, EE-51010 Tartu, Estonia..
    Kriebel, Jennifer
    Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Inst Epidemiol II, German Res Ctr Environm Hlth, Helmholtz Zentrum M nchen, Neuherberg, Germany.;German Ctr Diabet Res DZD, Neuherberg, Germany..
    Richmond, Rebecca C.
    Univ Bristol, Sch Social & Community Med, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England..
    Adamo, Marco
    Univ Coll London Hosp, UCLH Bariatr Ctr Weight Loss, Weight Management & Metab & Endocrine Surg, Ground Floor West Wing,250 Euston Rd, London NW1 2PG, England..
    Afzal, Uzma
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostatist, MRC PHE Ctr Environm & Hlth, London W2 1PG, England.;Imperial Coll London, Natl Heart & Lung Inst, London W12 0NN, England.;Ealing Hosp NHS Trust, Middlesex UB1 3HW, England..
    Ala-Korpela, Mika
    Univ Oulu & Biocenter Oulu, Computat Med, Fac Med, Oulu, Finland.;Univ Eastern Finland, Sch Pharm, NMR Metabol Lab, Kuopio, Finland.;Univ Bristol & Med Res Council Integrat Epidemiol, Univ Bristol, Sch Social & Community Med, Computat Med, Bristol, Avon, England..
    Albetti, Benedetta
    Univ Studi Milano & Fondazione IRCCS CaGranda Osp, Dept Clin Sci & Community Hlth, EPIGET Lab, Milan, Italy..
    Ammerpohl, Ole
    Univ Hosp Schleswig Holstein, Inst Human Genet, Kiel Campus, Kiel, Germany..
    Apperley, Jane F.
    Imperial Coll London, Dept Med, Centre Haematol, Fac Med, Hammersmith Campus, London W12 0NN, England..
    Beekman, Marian
    Leiden Univ Med Ctr, Mol Epidemiol, NL-2333 ZC Leiden, Netherlands..
    Bertazzi, Pier Alberto
    Univ Studi Milano & Fondazione IRCCS CaGranda Osp, Dept Clin Sci & Community Hlth, EPIGET Lab, Milan, Italy..
    Black, S. Lucas
    Imperial Coll London, Dept Med, Sect Infect Dis & Immun, London W12 0NN, England..
    Blancher, Christine
    Bonder, Marc-Jan
    Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands.;Univ Groningen, NL-9700 AB Groningen, Netherlands..
    Brosch, Mario
    Univ Oxford, High Throughput Genom Oxford Genom Ctr, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England.;Tech Univ Dresden, Univ Hosp, Med Dept 1, Dresden, Germany..
    Carstensen-Kirberg, Maren
    Heinrich Heine Univ Dusseldorf, German Diabet Ctr, Leibniz Ctr Diabet Res, Inst Clin Diabetol, Dusseldorf, Germany..
    de Craen, Anton J. M.
    Leiden Univ Med Ctr, Gerontol & Geriatr, NL-2300 RC Leiden, Netherlands..
    de Lusignan, Simon
    Univ Surrey, Dept Clin & Expt Med, Guildford GU2 7PX, Surrey, England..
    Dehghan, Abbas
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Elkalaawy, Mohamed
    Univ Coll London Hosp, UCLH Bariatr Ctr Weight Loss, Weight Management & Metab & Endocrine Surg, Ground Floor West Wing,250 Euston Rd, London NW1 2PG, England.;Univ Alexandria, Med Res Inst, Clin & Expt Surg Dept, Hadara, Alexandria 21561, Egypt..
    Fischer, Krista
    Univ Tartu, Estonian Genome Ctr, Riia 23b, EE-51010 Tartu, Estonia..
    Franco, Oscar H.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Gaunt, Tom R.
    Univ Bristol, Sch Social & Community Med, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England..
    Hampe, Jochen
    Univ Oxford, High Throughput Genom Oxford Genom Ctr, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England..
    Hashemi, Majid
    Univ Coll London Hosp, UCLH Bariatr Ctr Weight Loss, Weight Management & Metab & Endocrine Surg, Ground Floor West Wing,250 Euston Rd, London NW1 2PG, England..
    Isaacs, Aaron
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Jenkinson, Andrew
    Univ Coll London Hosp, UCLH Bariatr Ctr Weight Loss, Weight Management & Metab & Endocrine Surg, Ground Floor West Wing,250 Euston Rd, London NW1 2PG, England..
    Jha, Sujeet
    Dept Endocrinol, Diabet & Obes, Max Healthcare, New Delhi 110017, India..
    Kato, Norihiro
    Res Inst, Natl Ctr Global Hlth & Med, Dept Gene Diagnost & Therapeut, Tokyo 1628655, Japan..
    Krogh, Vittorio
    Epidemiol & Prevent Unit, Fondazione IRCSS Ist Nazl Tumori, Milan, Italy..
    Laffan, Michael
    Imperial Coll London, Dept Med, Centre Haematol, Fac Med, Hammersmith Campus, London W12 0NN, England..
    Meisinger, Christa
    Inst Epidemiol II, German Res Ctr Environm Hlth, Helmholtz Zentrum M nchen, Neuherberg, Germany..
    Meitinger, Thomas
    German Res Ctr Environm Hlth, Int Human Genet, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Tech Univ Munich, Inst Human Genet, Munich, Germany.;Partner site Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany..
    Mok, Zuan Yu
    Natl Univ Singapore, Cancer Sci Inst Singapore, Singapore, Singapore..
    Motta, Valeria
    Univ Studi Milano & Fondazione IRCCS CaGranda Osp, Dept Clin Sci & Community Hlth, EPIGET Lab, Milan, Italy.;Partner site Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany..
    Ng, Hong Kiat
    Natl Univ Singapore, Cancer Sci Inst Singapore, Singapore, Singapore..
    Nikolakopoulou, Zacharoula
    Natl Heart & Lung Inst, London SW3 6LY, England..
    Nteliopoulos, Georgios
    Imperial Coll London, Dept Med, Centre Haematol, Fac Med, Hammersmith Campus, London W12 0NN, England..
    Panico, Salvatore
    Dipartmento Med Clin Chirurgia Federio II Univ, Naples, Italy..
    Pervjakova, Natalia
    Univ Tartu, Estonian Genome Ctr, Riia 23b, EE-51010 Tartu, Estonia.;Univ Tartu, Inst Mol & Cell Biol, Dept Biotechnol, Riia 23, EE-51010 Tartu, Estonia..
    Prokisch, Holger
    Tech Univ Munich, Inst Human Genet, Munich, Germany..
    Rathmann, Wolfgang
    Heinrich Heine Univ Dusseldorf, German Diabet Ctr, Leibniz Ctr Diabet Res, Inst Biometr & Epidemiol, Dusseldorf, Germany..
    Roden, Michael
    German Ctr Diabet Res DZD, Neuherberg, Germany.;Heinrich Heine Univ Dusseldorf, German Diabet Ctr, Leibniz Ctr Diabet Res, Inst Clin Diabetol, Dusseldorf, Germany.;Heinrich Heine Univ Hosp Dusseldorf, Fac Med, Dept Endocrinol & Diabetol, Dusseldorf, Germany..
    Rota, Federica
    Univ Studi Milano & Fondazione IRCCS CaGranda Osp, Dept Clin Sci & Community Hlth, EPIGET Lab, Milan, Italy..
    Rozario, Michelle Ann
    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. Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton, England..
    Schafmayer, Clemens
    Univ Hosp Schleswig Holstein, Dept Visceral & Thorac Surg, Kiel Campus, Kiel, Germany..
    Schramm, Katharina
    Tech Univ Munich, Inst Human Genet, Munich, Germany..
    Siebert, Reiner
    Univ Hosp Schleswig Holstein, Inst Human Genet, Kiel Campus, Kiel, Germany.;Univ Hosp Ulm, Inst Human Genet, Albert Einstein Allee 11, D-89081 Ulm, Germany..
    Slagboom, P. Eline
    Leiden Univ Med Ctr, Mol Epidemiol, NL-2333 ZC Leiden, Netherlands..
    Soininen, Pasi
    Univ Oulu & Biocenter Oulu, Computat Med, Fac Med, Oulu, Finland.;Univ Eastern Finland, Sch Pharm, NMR Metabol Lab, Kuopio, Finland..
    Stolk, Lisette
    Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    Strauch, Konstantin
    German Res Ctr Environm Hlth, Inst Genet Epidemiol, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Ludwig Maximilians Univ Munchen, Inst Med Informat, Biometry & Epidemiol, Chair Genet Epidemiol, Munich, Germany..
    Tai, E-Shyong
    Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore 119228, Singapore.;Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117597, Singapore.;Duke Natl Univ, Singapore Grad Med Sch, Singapore 169857, Singapore..
    Tarantini, Letizia
    Univ Studi Milano & Fondazione IRCCS CaGranda Osp, Dept Clin Sci & Community Hlth, EPIGET Lab, Milan, Italy..
    Thorand, Barbara
    Inst Epidemiol II, German Res Ctr Environm Hlth, Helmholtz Zentrum M nchen, Neuherberg, Germany.;German Ctr Diabet Res DZD, Neuherberg, Germany..
    Tigchelaar, Ettje F.
    Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands.;Univ Groningen, NL-9700 AB Groningen, Netherlands..
    Tumino, Rosario
    Cancer Registry & Histopathol Unit, Civile MP Arezzo Hosp, ASP 7, Ragusa, Italy..
    Uitterlinden, Andre G.
    Erasmus MC, Dept Internal Med & Epidemiol, Rotterdam, Netherlands..
    van Duijn, Cornelia
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    van Meurs, Joyce B. J.
    Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    Vineis, Paolo
    Imperial Coll London, Epidemiol & Publ Hlth, London, England..
    Wickremasinghe, Ananda Rajitha
    Univ Kelaniya, Dept Publ Hlth, Fac Med, Box 6,Thalagolla Rd, Ragama 11010, Sri Lanka..
    Wijmenga, Cisca
    Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands.;Univ Groningen, NL-9700 AB Groningen, Netherlands..
    Yang, Tsun-Po
    Yuan, Wei
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England.;Inst Canc Res, Surrey SM2 5NG, England..
    Zhernakova, Alexandra
    Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands.;Univ Groningen, NL-9700 AB Groningen, Netherlands..
    Batterham, Rachel L.
    Univ Coll London Hosp, UCLH Bariatr Ctr Weight Loss, Weight Management & Metab & Endocrine Surg, Ground Floor West Wing,250 Euston Rd, London NW1 2PG, England.;UCL, Rayne Inst, Dept Med, Ctr Obes Res, London WC1E 6JJ, England..
    Smith, George Davey
    Univ Bristol, Sch Social & Community Med, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England..
    Deloukas, Panos
    Queen Mary Univ London, William Harvey Res Inst, Barts & London Sch Med & Dent, London EC1M 6BQ, England.;King Abdulaziz Univ, Princess Jawhara Brahim Ctr Excellence Res Heredi, Jeddah 21589, Saudi Arabia..
    Heijmans, Bastiaan T.
    Herder, Christian
    German Ctr Diabet Res DZD, Neuherberg, Germany.;Heinrich Heine Univ Dusseldorf, German Diabet Ctr, Leibniz Ctr Diabet Res, Inst Clin Diabetol, Dusseldorf, Germany..
    Hofman, Albert
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Lindgren, Cecilia M.
    Broad Inst, Massachusetts Inst Technol & Harvard Univ, Cambridge, MA 02142 USA..
    Milani, Lili
    Univ Tartu, Estonian Genome Ctr, Riia 23b, EE-51010 Tartu, Estonia..
    van der Harst, Pim
    Univ Med Ctr Groningen, Dept Cardiol, Univ Groningen, NL-9700 RB Groningen, Netherlands.;ICIN Netherlands Heart Inst, Durrer Ctr Cardiogenet Res, NL-3511 GC Utrecht, Netherlands..
    Peters, Annette
    German Ctr Diabet Res DZD, Neuherberg, Germany.;Partner site Munich Heart Alliance, DZHK German Ctr Cardiovasc Res, Munich, Germany..
    Illig, Thomas
    Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Hannover Med Sch, Hannover Unified Biobank, Feodor Lynen St 15, Hannover, Germany.;Hannover Med Sch, Inst Human Genet, Carl Neuberg St 1, Hannover, Germany..
    Relton, Caroline L.
    Univ Bristol, Sch Social & Community Med, MRC Integrat Epidemiol Unit, Bristol BS8 2BN, Avon, England..
    Waldenberger, Melanie
    Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Inst Epidemiol II, German Res Ctr Environm Hlth, Helmholtz Zentrum M nchen, Neuherberg, Germany..
    Jaervelin, Marjo-Riitta
    Imperial Coll London, Sch Publ Hlth, MRC Hlth Protect Agcy HPE Ctr Environm & Hlth, Dept Epidemiol & Biostatist, London, England.;Univ Oulu, Bioctr Oulu, POB 5000, Oulu, Finland.;Univ Oulu, Ctr Life Course Epidemiol, Fac Med, POB 5000, Oulu 90014, Finland.;Oulu Univ Hosp, Unit Primary Care, Kajaanintie 50,Box 20, Oulu, Finland..
    Bollati, Valentina
    Univ Studi Milano & Fondazione IRCCS CaGranda Osp, Dept Clin Sci & Community Hlth, EPIGET Lab, Milan, Italy..
    Soong, Richie
    Natl Univ Singapore, Cancer Sci Inst Singapore, Singapore, Singapore.;Natl Univ Singapore Hosp, Dept Pathol, Singapore, Singapore..
    Spector, Tim D.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England..
    Scott, James
    Imperial Coll London, Natl Heart & Lung Inst, London W12 0NN, England..
    McCarthy, Mark I.
    Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.;Oxford NIHR Biomed Res Ctr, Churchill Hosp, Oxford OX3 7LJ, England..
    Elliott, Paul
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostatist, MRC PHE Ctr Environm & Hlth, London W2 1PG, England..
    Bell, Jordana T.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England..
    Matullo, Giuseppe
    Human Genet Fdn Torino, Turin, Italy.;Univ Torino, Dept Med Sci, Turin, Italy..
    Gieger, Christian
    Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Inst Epidemiol II, German Res Ctr Environm Hlth, Helmholtz Zentrum M nchen, Neuherberg, Germany..
    Kooner, Jaspal S.
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostatist, MRC PHE Ctr Environm & Hlth, London W2 1PG, England.;Imperial Coll London, Natl Heart & Lung Inst, London W12 0NN, England.;Ealing Hosp NHS Trust, Middlesex UB1 3HW, England.;Imperial Coll Healthcare NHS Trust, London W12 0HS, England..
    Grallert, Harald
    Res Unit Mol Epidemiol, German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Neuherberg, Germany.;Inst Epidemiol II, German Res Ctr Environm Hlth, Helmholtz Zentrum M nchen, Neuherberg, Germany.;German Ctr Diabet Res DZD, Neuherberg, Germany.;Imperial Coll London, Natl Heart & Lung Inst, London W12 0NN, England..
    Chambers, John C.
    Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostatist, MRC PHE Ctr Environm & Hlth, London W2 1PG, England.;Imperial Coll London, Natl Heart & Lung Inst, London W12 0NN, England.;Ealing Hosp NHS Trust, Middlesex UB1 3HW, England.;Imperial Coll Healthcare NHS Trust, London W12 0HS, England.;Nanyang Technol Univ, Lee Kong Chian Sch Med, Singapore, Singapore..
    Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity2017In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 541, no 7635, p. 81-+Article in journal (Refereed)
    Abstract [en]

    Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type (2) diabetes, cardiovascular disease and related metabolic and inflammatory disturbances(1,2). Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation(3-6), a key regulator of gene expression and molecular phenotype(7). Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P < 1 x 10(-7), range P = 9.2 x 10(-8) to 6.0 x 10(-46); n = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P < 9.0 x 10(-6), range P = 5.5 x 10(-6) to 6.1 x 10(-35), n = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07-2.56); P = 1.1 x 10(-54)). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type 2 diabetes and other adverse clinical consequences of obesity.

  • 275.
    Wahlberg, Per
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. 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.
    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.
    Busche, Stephan
    McGill Univ, Dept Human Genet, Montreal, PQ, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ, Canada..
    Raine, Amanda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tandre, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Sinnett, Daniel
    St Justine Univ Hlth Ctr, Res Ctr, Montreal, PQ, Canada.;Univ Montreal, Dept Pediat, Montreal, PQ, Canada..
    Forestier, Erik
    Umea Univ, Dept Med Biosci, Umea, Sweden..
    Pastinen, Tomi
    McGill Univ, Dept Human Genet, Montreal, PQ, Canada.;Genome Quebec Innovat Ctr, Montreal, PQ, Canada..
    Lönnerholm, Gudmar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    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.
    DNA methylome analysis of acute lymphoblastic leukemia cells reveals stochastic de novo DNA methylation in CpG islands2016In: Epigenomics, ISSN 1750-1911, Vol. 8, no 10, p. 1367-1387Article in journal (Refereed)
    Abstract [en]

    Aim: To identify regions of aberrant DNA methylation in acute lymphoblastic leukemia (ALL) cells of different subtypes on a genome-wide scale. Materials & methods: Whole-genome bisulfite sequencing (WGBS) was used to determine the DNA methylation levels in cells from four pediatric ALL patients of different subtypes. The findings were confirmed by 450k DNA methylation arrays in a large patient set. Results: Compared with mature B or T cells WGBS detected on average 82,000 differentially methylated regions per patient. Differentially methylated regions are enriched to CpG poor regions, active enhancers and transcriptional start sites. We also identified approximately 8000 CpG islands with variable intermediate DNA methylation that seems to occur as a result of stochastic de novo methylation. Conclusion: WGBS provides an unbiased view and novel insights into the DNA methylome of ALL cells.

  • 276.
    Wang, Chuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    DNA Sequence Variants in Human Autoimmune Diseases2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Human autoimmune diseases are hallmarked by inappropriate loss-of-tolerance and self-attacking response of the immune system. Studies included in this thesis are focusing on the implication and functional impact of genetic factors in three autoimmune diseases rheumatoid arthritis (RA), asthma, and systemic lupus erythematosus (SLE).

    Using genetic association studies, we found in study I and II that sequence variants of the interferon regulatory factor 5 (IRF5) gene were associated with RA and asthma, and the associations were more pronounced in certain disease subtypes. Distinct association patterns or risk alleles of the IRF5 gene variants were revealed in different diseases, indicating that IRF5 contributes to disease manifestations in a dose-dependent manner. In study III, we found that seven out of eight genetic risk loci for SLE, which were originally identified in East Asian populations, also conferred disease risk with the same risk alleles and comparable magnitudes of effect sizes in Caucasians. Remarkable differences in risk allele frequencies were observed for all associated loci across ethnicities, which seems to be the major source of genetic heterogeneity for SLE. In study IV we explored an exhaustive spectrum of sequence variants in the genes inhibitor of kappa light polypeptide gene enhancer in B-cells kinase epsilon (IKBKE) and interferon induced with helicase C domain 1 (IFIH1) by gene resequencing, and identified nine variants in IKBKE and three variants in IFIH1 as genetic risk factors for SLE. One of the associated variants may influence splicing of IKBKE mRNA. In study V we provided genome-wide transcriptional regulatory profiles for IRF5 and signal transducer and activator of transcription 4 (STAT4) using chromatin immunoprecipitation-sequencing (ChIP-seq). The target genes of IRF5 and STAT4 were found to play active roles in pathways related with inflammatory response, and their expression patterns were characteristic for SLE patients. We also identified potential cooperative transcription factors for IRF5 and STAT4, and disease-associated sequence variants which may affect the regulatory function of IRF5 and STAT4.

    In conclusion, this thesis illuminates the contribution of several genetic risk factors to susceptibility of human autoimmune diseases, which facilitates our understanding of the genetic basis of their pathogenesis.

    List of papers
    1. Preferential Association of Interferon Regulatory Factor 5 Gene Variants with Seronegative Rheumatoid Arthritis in 2 Swedish Case-Control Studies
    Open this publication in new window or tab >>Preferential Association of Interferon Regulatory Factor 5 Gene Variants with Seronegative Rheumatoid Arthritis in 2 Swedish Case-Control Studies
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    2011 (English)In: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 38, no 10, p. 2130-2132Article in journal (Refereed) Published
    Abstract [en]

    Objective.

    Two interferon regulatory factor 5 (IRF5) gene variants were examined for association with rheumatoid arthritis (RA).

    Methods.

    A total of 2300 patients with RA and 1836 controls were recruited from 2 independent RA studies in Sweden. One insertion-deletion polymorphism (CGGGG indel) and one single-nucleotide polymorphism (rs10488631) in the IRF5 gene were genotyped and analyzed within RA subgroups stratified by rheumatoid factor (RF) and anticitrullinated peptide antibodies (ACPA).

    Results.

    The CGGGG indel was preferentially associated with the RF-negative (OR 1.29, p = 7.9 × 10−5) and ACPA-negative (OR 1.27, p = 7.3 × 10−5) RA subgroups compared to the seropositive counterparts. rs10488631 was exclusively associated within the seronegative RA subgroups (RF-negative: OR 1.24, p = 0.016; ACPA-negative: OR 1.27, p = 4.1 × 10−3).

    Conclusion.

    Both the CGGGG indel and rs10488631 are relevant for RA susceptibility, especially for seronegative RA.

    Keywords
    rheumatoid arthritis, interferon regulatory factor 5, genetic association study, seronegative
    National Category
    Medical Genetics
    Identifiers
    urn:nbn:se:uu:diva-162381 (URN)10.3899/jrheum.110322 (DOI)000296545400008 ()21807777 (PubMedID)
    Available from: 2011-11-30 Created: 2011-11-30 Last updated: 2018-01-12Bibliographically approved
    2. Evidence of association between interferon regulatory factor 5 gene polymorphisms and asthma
    Open this publication in new window or tab >>Evidence of association between interferon regulatory factor 5 gene polymorphisms and asthma
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    2012 (English)In: Gene, ISSN 0378-1119, E-ISSN 1879-0038, Vol. 504, no 2, p. 220-225Article in journal (Refereed) Published
    Abstract [en]

    Asthma is a heterogeneous disorder hallmarked by chronic inflammation in the respiratory system. Exacerbations of asthma are correlated with respiratory infections. Considering the implication of interferon regulatory factor 5 (IRF5) in innate and adaptive immunity, we investigated the preferential transmission patterns of ten IRF5 gene polymorphisms in two asthmatic family cohorts. A common IRF5 haplotype was found to be associated with asthma and the severity of asthmatic symptoms. Stratified analysis of subgroups of asthmatic individuals revealed that the associations were more pronounced in nonatopic asthmatic individuals. In addition, the risk alleles of IRF5 polymorphisms for asthma were almost completely opposite to those for autoimmune disorders. Our study provides the first evidence of association between IRF5 and asthma, and sheds light on the related but potentially distinct roles of IRF5 alleles in the pathogenesis of asthma and autoimmune disorders.

    Keywords
    interferon regulatory factor 5, asthma, autoimmune disorder, genetic association study
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-179119 (URN)10.1016/j.gene.2012.05.021 (DOI)000306775100010 ()22613848 (PubMedID)
    Available from: 2012-08-08 Created: 2012-08-08 Last updated: 2017-12-07Bibliographically approved
    3. Genes identified in Asian SLE GWASs are also associated with SLE in Caucasian populations
    Open this publication in new window or tab >>Genes identified in Asian SLE GWASs are also associated with SLE in Caucasian populations
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    2013 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 21, no 9, p. 994-999Article in journal (Refereed) Published
    Abstract [en]

    Recent genome-wide association studies (GWASs) conducted in Asian populations have identified novel risk loci for systemic lupus erythematosus (SLE). Here, we genotyped 10 single-nucleotide polymorphisms (SNPs) in eight such loci and investigated their disease associations in three independent Caucasian SLE case-control cohorts recruited from Sweden, Finland and the United States. The disease associations of the SNPs in ETS1, IKZF1, LRRC18-WDFY4, RASGRP3, SLC15A4, TNIP1 and 16p11.2 were replicated, whereas no solid evidence of association was observed for the 7q11.23 locus in the Caucasian cohorts. SLC15A4 was significantly associated with renal involvement in SLE. The association of TNIP1 was more pronounced in SLE patients with renal and immunological disorder, which is corroborated by two previous studies in Asian cohorts. The effects of all the associated SNPs, either conferring risk for or being protective against SLE, were in the same direction in Caucasians and Asians. The magnitudes of the allelic effects for most of the SNPs were also comparable across different ethnic groups. On the contrary, remarkable differences in allele frequencies between Caucasian and Asian populations were observed for all associated SNPs. In conclusion, most of the novel SLE risk loci identified by GWASs in Asian populations were also associated with SLE in Caucasian populations. We observed both similarities and differences with respect to the effect sizes and risk allele frequencies across ethnicities.

    Keywords
    systemic lupus erythematosus, genetic association study, Asian, Caucasian
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-179132 (URN)10.1038/ejhg.2012.277 (DOI)000323281400016 ()
    Available from: 2012-08-08 Created: 2012-08-08 Last updated: 2017-12-07Bibliographically approved
    4. Contribution of IKBKE and IFIH1 gene variants to SLE susceptibility
    Open this publication in new window or tab >>Contribution of IKBKE and IFIH1 gene variants to SLE susceptibility
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    2013 (English)In: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 14, no 4, p. 217-222Article in journal (Refereed) Published
    Abstract [en]

    The type I interferon system genes IKBKE and IFIH1 are associated with the risk of systemic lupus erythematosus (SLE). To identify the sequence variants that are able to account for the disease association, we resequenced the genes IKBKE and IFIH1. Eighty-six single-nucleotide variants (SNVs) with potentially functional effect or differences in allele frequencies between patients and controls determined by sequencing were further genotyped in 1140 SLE patients and 2060 controls. In addition, 108 imputed sequence variants in IKBKE and IFIH1 were included in the association analysis. Ten IKBKE SNVs and three IFIH1 SNVs were associated with SLE. The SNVs rs1539241 and rs12142086 tagged two independent association signals in IKBKE, and the haplotype carrying their risk alleles showed an odds ratio of 1.68 (P-value=1.0 × 10−5). The risk allele of rs12142086 affects the binding of splicing factor 1 in vitro and could thus influence its transcriptional regulatory function. Two independent association signals were also detected in IFIH1, which were tagged by a low-frequency SNV rs78456138 and a missense SNV rs3747517. Their joint effect is protective against SLE (odds ratio=0.56; P-value=6.6 × 10−3). In conclusion, we have identified new SLE-associated sequence variants in IKBKE and IFIH1, and proposed functional hypotheses for the association signals.

    Keywords
    IKBKE, IFIH1, resequencing, association study, systemic lupus erythematosus
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-179133 (URN)10.1038/gene.2013.9 (DOI)000320029300003 ()23535865 (PubMedID)
    Note

    De två första författarna delar förstaförfattarskapet.

    Available from: 2012-08-08 Created: 2012-08-08 Last updated: 2017-12-07Bibliographically approved
    5. Genome-wide profiling of target genes for the systemic lupus erythematosus-associated transcription factors IRF5 and STAT4
    Open this publication in new window or tab >>Genome-wide profiling of target genes for the systemic lupus erythematosus-associated transcription factors IRF5 and STAT4
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    2013 (English)