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  • 101.
    Kaleviste, Epp
    et al.
    Univ Tartu, Inst Biomed & Translat Med, Dept Biomed, Tartu, Estonia.
    Saare, Mario
    Univ Tartu, Inst Biomed & Translat Med, Dept Biomed, Tartu, Estonia.
    Leahy, Timothy Ronan
    Our Ladys Childrens Hosp, Dept Paediat Immunol & Infect Dis, Dublin, Ireland.
    Bondet, Vincent
    Inst Pasteur, INSERM, U1223, Immunobiol Dendrit Cells Unit, Paris, France.
    Duffy, Darragh
    Inst Pasteur, INSERM, U1223, Immunobiol Dendrit Cells Unit, Paris, France.
    Mogensen, Trine H.
    Aarhus Univ Hosp, Dept Infect Dis, Aarhus, Denmark;Aarhus Univ, Dept Biomed, Aarhus, Denmark;Aarhus Univ, Dept Clin Med, Aarhus, Denmark.
    Jörgensen, Sofie E.
    Aarhus Univ, Dept Biomed, Aarhus, Denmark.
    Nurm, Helke
    Tallinn Childrens Hosp, Dept Emergency Care & Acute Infect, Tallinn, Estonia.
    Ip, Winnie
    Great Ormond St Hosp Sick Children, London, England;UCL Great Ormond St Inst Child Hlth, London, England.
    Davies, E. Graham
    Great Ormond St Hosp Sick Children, London, England;UCL Great Ormond St Inst Child Hlth, London, England.
    Sauer, Sascha
    Max Planck Inst Mol Genet, Otto Warburg Lab, Berlin, Germany;Max Delbruck Ctr Mol Med, BIMSB, BIH, Lab Funct Genom Nutrigen & Syst Biol, Berlin, Germany.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Milani, Lili
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.
    Peterson, Pärt
    Univ Tartu, Inst Biomed & Translat Med, Dept Biomed, Tartu, Estonia.
    Kisand, Kai
    Univ Tartu, Inst Biomed & Translat Med, Dept Biomed, Tartu, Estonia.
    Interferon signature in patients with STAT1 gain-of-function mutation is epigenetically determined2019Inngår i: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 49, nr 5, s. 790-800Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    STAT1 gain-of-function (GOF) variants lead to defective Th17 cell development and chronic mucocutaneous candidiasis (CMC), but frequently also to autoimmunity. Stimulation of cells with STAT1 inducing cytokines like interferons (IFN) result in hyperphosphorylation and delayed dephosphorylation of GOF STAT1. However, the mechanism how the delayed dephosphorylation exactly causes the increased expression of STAT1-dependent genes, and how the intracellular signal transduction from cytokine receptors is affected, remains unknown. In this study we show that the circulating levels of IFN-alpha were not persistently elevated in STAT1 GOF patients. Nevertheless, the expression of interferon signature genes was evident even in the patient with low or undetectable serum IFN-alpha levels. Chromatin immunoprecipitation (ChIP) experiments revealed that the active chromatin mark trimethylation of lysine 4 of histone 3 (H3K4me3), was significantly enriched in areas associated with interferon-stimulated genes in STAT1 GOF cells in comparison to cells from healthy donors. This suggests that the chromatin binding of GOF STAT1 variant promotes epigenetic changes compatible with higher gene expression and elevated reactivity to type I interferons, and possibly predisposes for interferon-related autoimmunity. The results also suggest that epigenetic rewiring may be responsible for treatment failure of Janus kinase 1/2 (JAK1/2) inhibitors in certain patients.

  • 102. Kanoni, Stavroula
    et al.
    Nettleton, Jennifer A.
    Hivert, Marie-France
    Ye, Zheng
    van Rooij, Frank J. A.
    Shungin, Dmitry
    Sonestedt, Emily
    Ngwa, Julius S.
    Wojczynski, Mary K.
    Lemaitre, Rozenn N.
    Gustafsson, Stefan
    Anderson, Jennifer S.
    Tanaka, Toshiko
    Hindy, George
    Saylor, Georgia
    Renstrom, Frida
    Bennett, Amanda J.
    van Duijn, Cornelia M.
    Florez, Jose C.
    Fox, Caroline S.
    Hofman, Albert
    Hoogeveen, Ron C.
    Houston, Denise K.
    Hu, Frank B.
    Jacques, Paul F.
    Johansson, Ingegerd
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Liu, Yongmei
    McKeown, Nicola
    Ordovas, Jose
    Pankow, James S.
    Sijbrands, Eric J. G.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Uitterlinden, Andre G.
    Yannakoulia, Mary
    Zillikens, M. Carola
    Wareham, Nick J.
    Prokopenko, Inga
    Bandinelli, Stefania
    Forouhi, Nita G.
    Cupples, L. Adrienne
    Loos, Ruth J.
    Hallmans, Goran
    Dupuis, Josee
    Langenberg, Claudia
    Ferrucci, Luigi
    Kritchevsky, Stephen B.
    McCarthy, Mark I.
    Ingelsson, Erik
    Borecki, Ingrid B.
    Witteman, Jacqueline C. M.
    Orho-Melander, Marju
    Siscovick, David S.
    Meigs, James B.
    Franks, Paul W.
    Dedoussis, George V.
    Total zinc intake may modify the glucose-raising effect of a zinc transporter (SLC30A8) variant: a 14-cohort meta-analysis2011Inngår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 60, nr 9, s. 2407-2416Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE

    Many genetic variants have been associated with glucose homeostasis and type 2 diabetes in genome-wide association studies. Zinc is an essential micronutrient that is important for beta-cell function and glucose homeostasis. We tested the hypothesis that zinc intake could influence the glucose-raising effect of specific variants.

    RESEARCH DESIGN AND METHODS

    We conducted a 14-cohort meta-analysis to assess the interaction of 20 genetic variants known to be related to glycemic traits and zinc metabolism with dietary zinc intake (food sources) and a 5-cohort meta-analysis to assess the interaction with total zinc intake (food sources and supplements) on fasting glucose levels among individuals of European ancestry without diabetes.

    RESULTS

    We observed a significant association of total zinc intake with lower fasting glucose levels (beta-coefficient +/- SE per 1 mg/day of zinc intake: -0.0012 +/- 0.0003 mmol/L, summary P value = 0.0003), while the association of dietary zinc intake was not significant. We identified a nominally significant interaction between total zinc intake and the SLC30A8 rs11558471 variant on fasting glucose levels (beta-coefficient +/- SE per A allele for 1 mg/day of greater total zinc intake: -0.0017 +/- 0.0006 mmol/L, summary interaction P value = 0.005); this result suggests a stronger inverse association between total zinc intake and fasting glucose in individuals carrying the glucose-raising A allele compared with individuals who do not carry it. None of the other interaction tests were statistically significant.

    CONCLUSIONS

    Our results suggest that higher total zinc intake may attenuate the glucose-raising effect of the rs11558471 SLC30A8 (zinc transporter) variant. Our findings also support evidence for the association of higher total zinc intake with lower fasting glucose levels.

  • 103. Karttunen, L
    et al.
    Lönnqvist, L
    Godfrey, M
    Peltonen, L
    Syvänen, Ann-Christine
    An accurate method for comparing transcript levels of two alleles or highly homologous genes: application to fibrillin transcripts in Marfan patients' fibroblasts1996Inngår i: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 6, nr 5, s. 392-403Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We introduce here a novel and generally applicable, solid-phase minisequencing-based approach for rapid estimation of relative levels of transcripts with high sequence homology. This study was undertaken to screen for the consequences of different fibrillin-1 mutations on the transcript levels in patients with the Marfan syndrome (MFS). This dominantly inherited, connective tissue disorder is characterized by pleiotrophic symptoms in cardiovascular, skeletal, and ocular systems. A spectrum of disease mutations in the gene encoding fibrillin-1 (FBN1), a glycoprotein component of extracellular matrix microfibrils, has been identified in MFS patients, but the mechanisms by which mutations result in different phenotypic manifestations are still unknown to a large extent. Our data from the quantitation of FBN1 transcripts provide support for the hypothesis that mutations causing premature stop codons result in a milder phenotype than classical MFS by reducing the stability of the mutant transcript and, consequently, decreasing the interference of mutant polypeptide in the formation of fibrillin fibers. We also applied this mRNA quantitation method to determine the relative ratio between transcripts from the genes coding for two highly homologous microfibrillar components, FBN1 and FBN2, in control fibroblast cultures as well as in fibroblasts from MFS patients. Interestingly, these data show large variations between the levels of the two transcripts in fibroblast cultures, but these variations do not correlate either with the nature of the disease mutation or to the clinical MFS phenotype.

  • 104. Kilpelainen, Tuomas O.
    et al.
    Zillikens, M. Carola
    Stancakova, Alena
    Finucane, Francis M.
    Ried, Janina S.
    Langenberg, Claudia
    Zhang, Weihua
    Beckmann, Jacques S.
    Luan, Jian'an
    Vandenput, Liesbeth
    Styrkarsdottir, Unnur
    Zhou, Yanhua
    Smith, Albert Vernon
    Zhao, Jing-Hua
    Amin, Najaf
    Vedantam, Sailaja
    Shin, So-Youn
    Haritunians, Talin
    Fu, Mao
    Feitosa, Mary F.
    Kumari, Meena
    Halldorsson, Bjarni V.
    Tikkanen, Emmi
    Mangino, Massimo
    Hayward, Caroline
    Song, Ci
    Arnold, Alice M.
    Aulchenko, Yurii S.
    Oostra, Ben A.
    Campbell, Harry
    Cupples, L. Adrienne
    Davis, Kathryn E.
    Doering, Angela
    Eiriksdottir, Gudny
    Estrada, Karol
    Manuel Fernandez-Real, Jose
    Garcia, Melissa
    Gieger, Christian
    Glazer, Nicole L.
    Guiducci, Candace
    Hofman, Albert
    Humphries, Steve E.
    Isomaa, Bo
    Jacobs, Leonie C.
    Jula, Antti
    Karasik, David
    Karlsson, Magnus K.
    Khaw, Kay-Tee
    Kim, Lauren J.
    Kivimaeki, Mika
    Klopp, Norman
    Kuehnel, Brigitte
    Kuusisto, Johanna
    Liu, Yongmei
    Ljunggren, Östen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lorentzon, Mattias
    Luben, Robert N.
    McKnight, Barbara
    Mellstrom, Dan
    Mitchell, Braxton D.
    Mooser, Vincent
    Maria Moreno, Jose
    Mannisto, Satu
    O'Connell, Jeffery R.
    Pascoe, Laura
    Peltonen, Leena
    Peral, Belen
    Perola, Markus
    Psaty, Bruce M.
    Salomaa, Veikko
    Savage, David B.
    Semple, Robert K.
    Skaric-Juric, Tatjana
    Sigurdsson, Gunnar
    Song, Kijoung S.
    Spector, Timothy D.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Talmud, Philippa J.
    Thorleifsson, Gudmar
    Thorsteinsdottir, Unnur
    Uitterlinden, Andre G.
    van Duijn, Cornelia M.
    Vidal-Puig, Antonio
    Wild, Sarah H.
    Wright, Alan F.
    Clegg, Deborah J.
    Schadt, Eric
    Wilson, James F.
    Rudan, Igor
    Ripatti, Samuli
    Borecki, Ingrid B.
    Shuldiner, Alan R.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Jansson, John-Olov
    Kaplan, Robert C.
    Gudnason, Vilmundur
    Harris, Tamara B.
    Groop, Leif
    Kiel, Douglas P.
    Rivadeneira, Fernando
    Walker, Mark
    Barroso, Ines
    Vollenweider, Peter
    Waeber, Gerard
    Chambers, John C.
    Kooner, Jaspal S.
    Soranzo, Nicole
    Hirschhorn, Joel N.
    Stefansson, Kari
    Wichmann, H-Erich
    Ohlsson, Claes
    O'Rahilly, Stephen
    Wareham, Nicholas J.
    Speliotes, Elizabeth K.
    Fox, Caroline S.
    Laakso, Markku
    Loos, Ruth J. F.
    Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile2011Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 43, nr 8, s. 753-U58Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between similar to 2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 x 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 x 10(-11)) and one near SPRY2 (P = 3 x 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.

  • 105. Koivisto, U M
    et al.
    Turtola, H
    Aalto-Setälä, K
    Top, B
    Frants, R R
    Kovanen, P T
    Syvänen, Ann-Christine
    Kontula, K
    The familial hypercholesterolemia (FH)-North Karelia mutation of the low density lipoprotein receptor gene deletes seven nucleotides of exon 6 and is a common cause of FH in Finland1992Inngår i: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 90, nr 1, s. 219-228Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A mutation of the LDL receptor gene very common among Finnish patients with heterozygous familial hypercholesterolemia (FH) was identified. This mutation, designated as FH-North Karelia, deletes seven nucleotides from exon 6 of the LDL receptor gene, causes a translational frameshift, and is predicted to result in a truncated receptor protein. Only minute quantities of mRNA corresponding to the deleted gene were detected. Functional studies using cultured fibroblasts from the patients revealed that the FH-North Karelia gene is associated with a receptor-negative (or binding-defective) phenotype of FH. Carriers of the FH-North Karelia gene showed a typical xanthomatous form of FH, with mean serum total and LDL cholesterol levels of 12 and 10 mmol/liter, respectively. This mutation was found in 69 (34%) out of 201 nonrelated Finnish FH patients and was especially abundant (prevalence 79%) in patients from the eastern Finland. These results, combined with our earlier data on another LDL receptor gene deletion (FH-Helsinki), demonstrate that two "Finnish-type" mutant LDL receptor genes make up about two thirds of FH mutations in this country, reflecting a founder gene effect. This background provides good possibilities to examine whether genetic heterogeneity affects the clinical presentation or responsiveness to therapeutic interventions in FH.

  • 106. Kontula, K
    et al.
    Aalto-Setälä, K
    Kuusi, T
    Hämäläinen, L
    Syvänen, Ann-Christine
    Apolipoprotein E polymorphism determined by restriction enzyme analysis of DNA amplified by polymerase chain reaction: convenient alternative to phenotyping by isoelectric focusing1990Inngår i: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 36, nr 12, s. 2087-2092Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Three common alleles determine six apolipoprotein E (apo E) phenotypes that are associated with variations in serum cholesterol in the population. This genetic variation results from single nucleotide alterations at two DNA loci encoding the amino acid residues 112 and 158 of apo E. We compared results of apo E phenotyping carried out by isoelectric focusing with those of apo E genotyping accomplished by direct DNA analysis. In the latter, the target DNA was amplified by the polymerase chain reaction (PCR) and subsequently analyzed by digestion with the restriction enzyme Hha I, followed by polyacrylamide gel electrophoresis of the cleavage products. With one exception, these two techniques yielded similar results from all 40 samples tested. In addition, a rare variant form of apo E (phenotype E1) was analyzed separately and incorrectly diagnosed as E2 by the Hha I digestion method; the anticipated mutation in the codon 127 was, however, confirmed by demonstration of a new Taq I restriction site in this variant gene. These data confirm that the common isoforms of apo E usually arise from genetic variation of the codons 112 and 158 and demonstrate the feasibility of the PCR technique in apo E genotyping.

  • 107. Kristensen, Vessela N
    et al.
    Edvardsen, Hege
    Tsalenko, Anya
    Nordgard, Silje H
    Sörlie, Therese
    Sharan, Roded
    Vailaya, Aditya
    Ben-Dor, Amir
    Lønning, Per Eystein
    Lien, Sigbjørn
    Omholt, Stig
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Yakhini, Zohar
    Børresen-Dale, Anne-Lise
    Genetic variation in putative regulatory loci controlling gene expression in breast cancer2006Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 103, nr 20, s. 7735-7740Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    Candidate single-nucleotide polymorphisms (SNPs) were analyzed for associations to an unselected whole genome pool of tumor mRNA transcripts in 50 unrelated patients with breast cancer. SNPs were selected from 203 candidate genes of the reactive oxygen species pathway. We describe a general statistical framework for the simultaneous analysis of gene expression data and SNP genotype data measured for the same cohort, which revealed significant associations between subsets of SNPs and transcripts, shedding light on the underlying biology. We identified SNPs in EGF, IL1A, MAPK8, XPC, SOD2, and ALOX12 that are associated with the expression patterns of a significant number of transcripts, indicating the presence of regulatory SNPs in these genes. SNPs were found to act in trans in a total of 115 genes. SNPs in 43 of these 115 genes were found to act both in cis and in trans. Finally, subsets of SNPs that share significantly many common associations with a set of transcripts (biclusters) were identified. The subsets of transcripts that are significantly associated with the same set of SNPs or to a single SNP were shown to be functionally coherent in Gene Ontology and pathway analyses and coexpressed in other independent data sets, suggesting that many of the observed associations are within the same functional pathways. To our knowledge, this article is the first study to correlate SNP genotype data in the germ line with somatic gene expression data in breast tumors. It provides the statistical framework for further genotype expression correlation studies in cancer data sets.

  • 108.
    Kurland, Lisa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Hallberg, Pär
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Liljedahl, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Hashemi, Nashmil
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Kahan, Thomas
    The relationship between the plasma concentration of irbesartan and the antihypertensive response is disclosed by an angiotensin II type 1 receptor polymorphism: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs. Atenolol (SILVHIA) Trial2008Inngår i: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 21, nr 7, s. 836-839Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background 

    The aim of this study was to investigate the effect of the plasma concentration of irbesartan, a specific angiotensin II type 1 receptor (AT1R) antagonist, and the blood pressure response in relation to AT1R gene polymorphisms.

    Methods 

    Plasma irbesartan was analyzed in 42 patients with mild-to-moderate hypertension and left ventricular hypertrophy from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs. Atenolol (SILVHIA) trial, who were treated with irbesartan as monotherapy for 12 weeks. Blood pressure and irbesartan concentration were measured at trough, i.e., 24 ± 3 h after the last dose. Five AT1R gene polymorphisms were analyzed by minisequencing.

    Results 

    Neither the plasma concentration of irbesartan, nor any of the AT1R polymorphisms were associated with the blood pressure response to irbesartan treatment. However, the interaction term between the plasma concentration of irbesartan and the AT1R C5245T polymorphism was related to the reduction in systolic blood pressure after 12 weeks of treatment (P = 0.025). Furthermore, the plasma concentration of irbesartan was related to the change in systolic blood pressure in individuals homozygous for the AT1R 5245 T allele (r = -0.56, P = 0.030), but not for other genotypes.

    Conclusions 

    There was an association between plasma concentrations of irbesartan and the blood pressure response for hypertensive patients with AT1R 5245 TT. Because of the small sample size, this study needs to be viewed as hypothesis generating. This is the first study, to our knowledge, indicating that the concentration–response relationship of an antihypertensive drug may be genotype dependent.

  • 109.
    Kurland, Lisa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Liljedahl, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Karlsson, Julia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Kahan, Thomas
    Malmqvist, Karin
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Angiotensinogen gene polymorphisms: relationship to blood pressure response to antihypertensive treatment. Results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs Atenolol (SILVHIA) trial2004Inngår i: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 17, nr 1, s. 8-13Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: The renin-angiotensin-aldosterone system (RAAS) is important for the development of hypertension, and several antihypertensive drugs target this system. Our aim was to determine whether specific single nucleotide polymorphisms (SNPs) in RAAS genes were related to the blood pressure (BP) lowering effect of antihypertensive treatment. METHODS: Patients with mild to moderate primary hypertension and left ventricular hypertrophy were randomized in a double-blind fashion to treatment with either the angiotensin II type 1 receptor antagonist irbesartan (n = 48) or the beta(1)-adrenergic receptor blocker atenolol (n = 49) as monotherapy. A microarray-based minisequencing system was used to genotype 30 SNPs in seven genes in the RAAS. These polymorphisms were related to the antihypertensive response after 12 weeks treatment. RESULTS: The BP reductions were similar in the atenolol and the irbesartan groups. Presence of the angiotensinogen (AGT) -6A allele or the AGT 235T allele were both associated with the most pronounced systolic BP response to atenolol treatment (P =.001 when -6 AA+AG was compared with GG and P =.008 for presence of the 235T variant compared with 235 MM). CONCLUSIONS: We found that SNPs in the angiotensinogen gene were associated with the BP lowering response to atenolol. This study is limited by a relatively small sample size, and the results should therefore be viewed as preliminary. Despite this limitation, these results illustrate the potential of using SNP genotyping as a pharmacogenetic tool in antihypertensive treatment.

  • 110.
    Kurland, Lisa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lithell, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Farmakogenetik: genvägen till skräddarsydd antihypertensiv terapi2003Inngår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 100, nr 8, s. 600-603Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    The variations in response to pharmacotherapy can in part be explained by genetic factors. Pharmacogenetics, a term coined in the 1950's, describes these relationships. Great technological advances in molecular biology and computational sciences, crowned by the sequencing of the human genome, have brought forth the current interest in pharmacogenetics. Continued technological developments may lead to the understanding of the molecular mechanisms behind complex diseases like cardiovascular disease, and holds the promise of individualized pharmacotherapy. The article gives a background to the field, with emphasis on antihypertensive therapy, and prospects for the future.

  • 111. Kärkkäinen, T
    et al.
    Syvänen, Ann-Christine
    Turpeinen, U
    Hamberg, U
    Isolation and immunologic properties of a heterogeneous antigen with the characteristics of the heavy chain of human plasma kininogen1982Inngår i: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 19, nr 1, s. 179-189Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Kininogen antigen was purified from human plasma fraction IV by ion exchange chromatography, gel filtration and affinity chromatography with antibody specific immunoadsorbents. The immunologically pure glycoprotein had a mol. wt of approximately 60,000 and only one polypeptide chain by SDS-PAGE. An extensive charge heterogeneity by isoelectric focusing and gel filtration on polyacrylamide agarose could only in part depend on a comparatively high sialic acid content, but may be caused by differences in the carbohydrate structures sustained by lectin-binding heterogeneity on Con A-Sepharose. This antigen shares a dominating determinant with native plasma kininogens shown by complete patterns of identity in immunochemical analyses and with the monospecific antisera developed in rabbits against the heterogeneous components. The similar size, amino acid composition, low histidine content, lack of N-terminal amino acid and antigenic homogeneity fit all the so far known characteristics of the human kininogen heavy chain. Notably the antigenic determinant is resistant to degradation by activated kallikrein. This antigen with unimpaired immunologic activity may be a useful tool for preparation of antiserum for immunochemical determination of human plasma kininogen.

  • 112. Laan, M
    et al.
    Grön-Virta, K
    Salo, A
    Aula, P
    Peltonen, L
    Palotie, A
    Syvänen, Ann-Christine
    Solid-phase minisequencing confirmed by FISH analysis in determination of gene copy number1995Inngår i: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 96, nr 3, s. 275-280Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The solid-phase minisequencing method (Syvnen et al. 1990) allows accurate quantative determination of the ratio between two DNA or RNA sequences that are present as a mixture in a sample and differ from each other only by a single nucleotide. Here, we present another application of the minisequencing method, the determination of the gene copy number in a genome. The copy number of a marker gene aspartyl glucosaminidase (AGA) located at 4qter, was determined in three patients with a chromosomal alteration involving the distal region of 4q. For the minisequencing assay an equal amount of DNA from a patient homozygous for a mutation in the AGA gene was added to the DNA samples concerned. The relative amount of the normal sequence determined in each combined sample gives the copy number of the AGA gene. Fluorescence in situ hybridization (FISH), applied in parallel as a control, produced concordant results with solid-phase minisequencing in each case. As the potential of the minisequencing lies in automation, it could be a useful tool in the screening of monosomies, trisomies or loss of heterozygosity in diagnostics.

  • 113. Lahermo, P
    et al.
    Liljedahl, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Alnaes, Grethe
    Axelsson, Tomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Brookes, Anthony J
    Ellonen, Pekka
    Groop, Per-Henrik
    Halldén, Christer
    Holmberg, Dan
    Holmberg, Kristina
    Keinänen, Mauri
    Kepp, Katrin
    Kere, Juha
    Kiviluoma, P
    Kristensen, Vessela
    Lindgren, Cecilia
    Odeberg, Jacob
    Osterman, Pia
    Parkkonen, Maija
    Saarela, Janna
    Sterner, Maria
    Strömqvist, Linda
    Talas, Ulvi
    Wessman, Maija
    Palotie, Aarno
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    A quality assessment survey of SNP genotyping laboratories2006Inngår i: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 27, nr 7, s. 711-714Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    To survey the quality of SNP genotyping, a joint Nordic quality assessment (QA) round was organized between 11 laboratories in the Nordic and Baltic countries. The QA round involved blinded genotyping of 47 DNA samples for 18 or six randomly selected SNPs. The methods used by the participating laboratories included all major platforms for small- to medium-size SNP genotyping. The laboratories used their standard procedures for SNP assay design, genotyping, and quality control. Based on the joint results from all laboratories, a consensus genotype for each DNA sample and SNP was determined by the coordinator of the survey, and the results from each laboratory were compared to this genotype. The overall genotyping accuracy achieved in the survey was excellent. Six laboratories delivered genotype data that were in full agreement with the consensus genotype. The average accuracy per SNP varied from 99.1 to 100% between the laboratories, and it was frequently 100% for the majority of the assays for which SNP genotypes were reported. Lessons from the survey are that special attention should be given to the quality of the DNA samples prior to genotyping, and that a conservative approach for calling the genotypes should be used to achieve a high accuracy.

  • 114.
    Langefeld, Carl D.
    et al.
    Wake Forest Sch Med, Ctr Publ Hlth Genom, Winston Salem, NC 27101 USA.;Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC 27101 USA..
    Ainsworth, Hannah C.
    Wake Forest Sch Med, Ctr Publ Hlth Genom, Winston Salem, NC 27101 USA.;Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC 27101 USA..
    Graham, Deborah S. Cunninghame
    Kings Coll London, Guys Hosp, Div Genet & Mol Med & Immunol Infect & Inflammato, London SE1 9RT, England..
    Kelly, Jennifer A.
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, Oklahoma City, OK 73104 USA..
    Comeau, Mary E.
    Wake Forest Sch Med, Ctr Publ Hlth Genom, Winston Salem, NC 27101 USA.;Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC 27101 USA..
    Marion, Miranda C.
    Wake Forest Sch Med, Ctr Publ Hlth Genom, Winston Salem, NC 27101 USA.;Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC 27101 USA..
    Howard, Timothy D.
    Wake Forest Sch Med, Ctr Publ Hlth Genom, Winston Salem, NC 27101 USA.;Wake Forest Sch Med, Ctr Human Genom & Personalized Med Res, Winston Salem, NC 27101 USA..
    Ramos, Paula S.
    Med Univ S Carolina, Dept Publ Hlth Sci, Charleston, SC 29425 USA.;Med Univ South Carolina, Dept Med, Charleston, SC 29425 USA..
    Croker, Jennifer A.
    UAB Sch Med, Div Clin Immunol & Rheumatol, Birmingham, AL 35294 USA..
    Morris, David L.
    Kings Coll London, Guys Hosp, Div Genet & Mol Med & Immunol Infect & Inflammato, London SE1 9RT, England..
    Sandling, Johanna K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Carlsson Almlöf, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Acevedo-Vasquez, Eduardo M.
    Univ Nacl Mayor San Marcos, Fac Med, Dept Reumatol, Lima 15081, Peru..
    Alarcon, Graciela S.
    Babini, Alejandra M.
    Hosp Italiano Cordoba, Cordoba, Argentina..
    Baca, Vicente
    Hosp Pediat Mexico City, Ctr Med Nacl Siglo XXI, Inst Mexicano Seguro Social, Mexico City 06720, DF, Mexico..
    Bengtsson, Anders A.
    Lund Univ, Dept Clin Sci, Rheumatol, S-22362 Lund, Sweden..
    Berbotto, Guillermo A.
    Hosp Eva Peron, Granadero Baigorria, Argentina..
    Bijl, Marc
    Martini Hosp, Dept Internal Med & Rheumatol, NL-9728 NT Groningen, Netherlands..
    Brown, Elizabeth E.
    Brunner, Hermine I.
    Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Div Rheumatol, Cincinnati, OH 45229 USA.;Univ Cincinnati, Cincinnati, OH 45229 USA..
    Cardiel, Mario H.
    Ctr Invest Clin Morelia, Morelia, Michoacan, Mexico..
    Catoggio, Luis
    Hosp Italiano Buenos Aires, RA-1181 Buenos Aires, DF, Argentina..
    Cervera, Ricard
    Univ Barcelona, Hosp Clin, Dept Autoimmune Dis, Barcelona 08007, Catalonia, Spain..
    Cucho-Venegas, Jorge M.
    Univ Nacl Mayor San Marcos, Fac Med, Dept Reumatol, Lima 15081, Peru..
    Dahlqvist, Solbritt Rantapaa
    Umea Univ, Dept Publ Hlth & Clin Med, Div Rheumatol, S-90187 Umea, Sweden..
    D'Alfonso, Sandra
    Univ Piemonte Orientale, Dept Hlth Sci & Inst Res Autoimmune Dis IRCAD, I-28100 Novara, Italy..
    Da Silva, Berta Martins
    Univ Porto, Inst Ciencias Biomed Abel Salaza, Unidade Multidisciplinar Invest Biomed, P-4099003 Oporto, Portugal..
    de la Rua Figueroa, Inigo
    Hosp Univ Gran Canaria Dr Negrin, Dept Rheumatol, Las Palmas Gran Canaria 35010, Spain..
    Doria, Andrea
    Univ Padua, Dept Med DIMED, Div Rheumatol, I-35122 Padua, Italy..
    Edberg, Jeffrey C.
    UAB Sch Med, Div Clin Immunol & Rheumatol, Birmingham, AL 35294 USA..
    Endreffy, Emoke
    Univ Szeged, Fac Med, Albert Szent Gyorgyi Med Ctr, Dept Pediat, H-6720 Szeged, Hungary.;Univ Szeged, Fac Med, Albert Szent Gyorgyi Med Ctr, Child Hlth Ctr, H-6720 Szeged, Hungary..
    Esquivel-Valerio, Jorge A.
    Hosp Univ Dr Jose Eleuterio Gonzalez Univ Autonom, Monterrey 64020, Mexico..
    Fortin, Paul R.
    Univ Laval, CHU Quebec, Quebec City, PQ G1R 2JG, Canada..
    Freedman, Barry I.
    Wake Forest Sch Med, Ctr Publ Hlth Genom, Winston Salem, NC 27101 USA.;Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC 27101 USA.;Wake Forest Sch Med, Sect Nephrol, Winston Salem, NC 27101 USA..
    Frostegard, Johan
    Karolinska Inst, Inst Environm Med, Unit Immunol & Chron Dis, S-17177 Stockholm, Sweden..
    Garcia, Mercedes A.
    Hosp Interzonal Gen Agudos Gen San Martin, Div Rheumatol, RA-1900 La Plata, Buenos Aires, Argentina..
    Garcia de la Torre, Ignacio
    Univ Guadalajara, Dept Fisiol, Guadalajara, Jalisco 44100, Mexico..
    Gilkeson, Gary S.
    Med Univ South Carolina, Dept Med, Charleston, SC 29425 USA..
    Gladman, Dafna D.
    Toronto Western Hosp, Krembil Res Inst, Ctr Prognosis Studies Rheumat Dis, Toronto, ON M5T 2S8, Canada..
    Gunnarsson, Iva
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Rheumatol Unit, S-17176 Stockholm, Sweden..
    Guthridge, Joel M.
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, Oklahoma City, OK 73104 USA..
    Huggins, Jennifer L.
    Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Div Rheumatol, Cincinnati, OH 45229 USA.;Univ Cincinnati, Cincinnati, OH 45229 USA..
    James, Judith A.
    Hosp Eva Peron, Granadero Baigorria, Argentina.;Univ Oklahoma, Hlth Sci Ctr, Dept Med, Oklahoma City, OK 73104 USA.;Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK 73104 USA..
    Kallenberg, Cees G. M.
    Univ Med Ctr Groningen, Univ Groningen, Dept Rheumatol & Clin Immunol, NL-9713 GZ Groningen, Netherlands..
    Kamen, Diane L.
    Karp, David R.
    Univ Texas Southwestern Med Ctr Dallas, Dept Immunol, Dallas, TX 75235 USA..
    Kaufman, Kenneth M.
    Cincinnati Childrens Hosp Med Ctr, CAGE, Dept Pediat, Cincinnati, OH 45229 USA..
    Kottyan, Leah C.
    Cincinnati Childrens Hosp Med Ctr, CAGE, Dept Pediat, Cincinnati, OH 45229 USA..
    Kovacs, Laszlo
    Univ Szeged, Albert Szent Gyorgyi Med Ctr, Dept Rheumatol, H-6720 Szeged, Hungary..
    Laustrup, Helle
    Odense Univ Hosp, Dept Rheumatol, DK-5000 Odense, Denmark..
    Lauwerys, Bernard R.
    Catholic Univ Louvain, Clin Univ St Luc, Rheumatol, B-1348 Louvain La Neuve, Belgium.;Catholic Univ Louvain, Inst Rech Expt & Clin, B-1348 Louvain La Neuve, Belgium..
    Li, Quan-Zhen
    Univ Texas Southwestern Med Ctr Dallas, Dept Immunol, Dallas, TX 75235 USA..
    Maradiaga-Cecena, Marco A.
    Hosp Gen Culiacan, Sinaloa 80220, Mexico..
    Martin, Javier
    CSIC, Inst Parasitol & Biomed Lopez Neyra, Granada 18100, Spain..
    McCune, Joseph M.
    Univ Michigan, Med Ctr, Ann Arbor, MI 48103 USA..
    McWilliams, David R.
    Wake Forest Sch Med, Ctr Publ Hlth Genom, Winston Salem, NC 27101 USA.;Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC 27101 USA..
    Merrill, Joan T.
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, Oklahoma City, OK 73104 USA..
    Miranda, Pedro
    Ctr Estudios Reumatol, Santiago 7500000, Chile..
    Moctezuma, Jose F.
    Hosp Gen Mexico City, Dept Reumatol, Mexico City 06726, DF, Mexico..
    Nath, Swapan K.
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, Oklahoma City, OK 73104 USA..
    Niewold, Timothy B.
    Mayo Clin, Dept Rheumatol, Rochester, MN 94158 USA..
    Orozco, Lorena
    Inst Nacl Med Genom INMEGEN, Mexico City 14610, DF, Mexico..
    Ortego-Centeno, Norberto
    Hosp Univ San Cecilio, UGC Med Interna, Unidad Enfermedades Autoimmunes Sistem, Granada 18007, Spain..
    Petri, Michelle
    Johns Hopkins Univ, Sch Med, Dept Med, Div Rheumatol, Baltimore, MD 21218 USA..
    Pineau, Christian A.
    McGill Univ, Div Rheumatol, Montreal, PQ H3A 0G4, Canada..
    Pons-Estel, Bernardo A.
    Sanatorio Parque, Dept Rheumatol, Rosario, Santa Fe, Argentina..
    Pope, Janet
    Univ Western Ontario, London, ON M5T 2S8, Canada..
    Raj, Prithvi
    Univ Texas Southwestern Med Ctr Dallas, Dept Immunol, Dallas, TX 75235 USA..
    Ramsey-Goldman, Rosalind
    Northwestern Univ, Feinberg Sch Med, Div Rheumatol, Chicago, IL 60611 USA..
    Reveille, John D.
    Univ Texas Hlth Sci Ctr Houston UTHealth, Med Sch, Houston, TX 77030 USA..
    Russell, Laurie P.
    Wake Forest Sch Med, Ctr Publ Hlth Genom, Winston Salem, NC 27101 USA.;Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC 27101 USA..
    Sabio, Jose M.
    Hosp Univ Virgen de las Nieves, Granada 18014, Spain..
    Aguilar-Salinas, Carlos A.
    Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Dept Endocrinol & Metab, Vasco Quiroga 15, Mexico City 14080, DF, Mexico..
    Scherbarth, Hugo R.
    Autoinmunes HIGA Dr Alende Mar Plata, Unidad Reumatol & Enfermedades, Buenos Aires, DF, Argentina..
    Scorza, Raffaella
    Fdn IRCCS CaGranda Osped Ma Repiore Policlin, Referral Ctr Syst Autoimmune Dis, I-20122 Milan, Italy.;Univ Milan, I-20122 Milan, Italy..
    Seldin, Michael F.
    UC Davis Sch Med, Dept Biochem & Mol Med, Sacramento, CA 95616 USA..
    Sjowall, Christopher
    Linkoping Univ, Dept Clin & Expt Med, Rheumatol Div Neuro & Inflammat Sci, S-58183 Linkoping, Sweden..
    Svenungsson, Elisabet
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Rheumatol Unit, S-17176 Stockholm, Sweden..
    Thompson, Susan D.
    Cincinnati Childrens Hosp Med Ctr, CAGE, Dept Pediat, Cincinnati, OH 45229 USA..
    Toloza, Sergio M. A.
    Minist Hlth, Catamarca, Argentina..
    Truedsson, Lennart
    Lund Univ, Dept Lab Med, Sect Microbiol Immunol & Glycobiol, S-22100 Lund, Sweden..
    Tusie-Luna, Teresa
    UNAM Inst Nacl Ciencias Med & Nutr Salvador Zubir, Inst Invest Biomed, Unidad Biol Mol & Med Genom, Mexico City 14080, DF, Mexico..
    Vasconcelos, Carlos
    Univ Porto, Hosp Santo Antonio, P-4099003 Oporto, Portugal..
    Vila, Luis M.
    Univ Puerto Rico, Sch Med, San Juan, PR 00936 USA..
    Wallace, Daniel J.
    Cedars Sinai Med Ctr, Dept Med, Los Angeles, CA 90048 USA..
    Weisman, Michael H.
    Cedars Sinai Med Ctr, Dept Med, Los Angeles, CA 90048 USA..
    Wither, Joan E.
    Toronto Western Hosp, Krembil Res Inst, Ctr Prognosis Studies Rheumat Dis, Toronto, ON M5T 2S8, Canada..
    Bhangale, Tushar
    Genentech Inc, Human Genet, South San Francisco, CA 94080 USA..
    Oksenberg, Jorge R.
    Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA.;Univ Calif San Francisco, Inst Human Genet, San Francisco, CA 94158 USA..
    Rioux, John D.
    Univ Montreal, Montreal, PQ H1T 1C8, Canada.;Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada..
    Gregersen, Peter K.
    Feinstein Inst Med Res, Ctr Genom Human Genet, Manhasset, NY 11030 USA..
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Criswell, Lindsey A.
    UCSF Sch Med, Rosalind Russell Ephraim P Engleman Rheumatol Res, Div Rheumatol, San Francisco, CA 94158 USA..
    Jacob, Chaim O.
    Keck Sch Med USC, Los Angeles, CA 90033 USA..
    Sivils, Kathy L.
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, Oklahoma City, OK 73104 USA..
    Tsao, Betty P.
    Med Univ South Carolina, Dept Med, Charleston, SC 29425 USA..
    Schanberg, Laura E.
    Duke Univ, Dept Pediat, Durham, NC 27708 USA..
    Behrens, Timothy W.
    Genentech Inc, Human Genet, South San Francisco, CA 94080 USA..
    Silverman, Earl D.
    Hosp Sick Children, Res Inst, Dept Pediat, Toronto, ON M5G 1X8, Canada.;Hosp Sick Children, Res Inst, Inst Med Sci, Toronto, ON M5G 1X8, Canada.;Univ Toronto, Toronto, ON M5G 1X8, Canada..
    Alarcon-Riquelme, Marta E.
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, Oklahoma City, OK 73104 USA.;Univ Granada, Pfizer, Junta De Andalucia Ctr Genom & Oncol Res GENYO, Granada 18007, Spain.;Karolinska Inst, Unit Inst Environm Med, S-17177 Solnavagen, Sweden..
    Kimberly, Robert P.
    UAB Sch Med, Div Clin Immunol & Rheumatol, Birmingham, AL 35294 USA..
    Harley, John B.
    Cincinnati Childrens Hosp Med Ctr, CAGE, Dept Pediat, Cincinnati, OH 45229 USA..
    Wakeland, Edward K.
    Univ Texas Southwestern Med Ctr Dallas, Dept Immunol, Dallas, TX 75235 USA..
    Graham, Robert R.
    Genentech Inc, Human Genet, South San Francisco, CA 94080 USA..
    Gaffney, Patrick M.
    Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, Oklahoma City, OK 73104 USA..
    Vyse, Timothy J.
    Kings Coll London, Guys Hosp, Div Genet & Mol Med & Immunol Infect & Inflammato, London SE1 9RT, England..
    Transancestral mapping and genetic load in systemic lupus erythematosus2017Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, artikkel-id 16021Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (similar to 50% of these regions have multiple independent associations); these include 24 novel SLE regions (P < 5 x 10(-8)), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.

  • 115. Lappalainen, Tuuli
    et al.
    Sammeth, Michael
    Friedländer, Marc R
    't Hoen, Peter A C
    Monlong, Jean
    Rivas, Manuel A
    Gonzàlez-Porta, Mar
    Kurbatova, Natalja
    Griebel, Thasso
    Ferreira, Pedro G
    Barann, Matthias
    Wieland, Thomas
    Greger, Liliana
    van Iterson, Maarten
    Almlöf, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ribeca, Paolo
    Pulyakhina, Irina
    Esser, Daniela
    Giger, Thomas
    Tikhonov, Andrew
    Sultan, Marc
    Bertier, Gabrielle
    Macarthur, Daniel G
    Lek, Monkol
    Lizano, Esther
    Buermans, Henk P J
    Padioleau, Ismael
    Schwarzmayr, Thomas
    Karlberg, Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ongen, Halit
    Kilpinen, Helena
    Beltran, Sergi
    Gut, Marta
    Kahlem, Katja
    Amstislavskiy, Vyacheslav
    Stegle, Oliver
    Pirinen, Matti
    Montgomery, Stephen B
    Donnelly, Peter
    McCarthy, Mark I
    Flicek, Paul
    Strom, Tim M
    Lehrach, Hans
    Schreiber, Stefan
    Sudbrak, Ralf
    Carracedo, Angel
    Antonarakis, Stylianos E
    Häsler, Robert
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    van Ommen, Gert-Jan
    Brazma, Alvis
    Meitinger, Thomas
    Rosenstiel, Philip
    Guigó, Roderic
    Gut, Ivo G
    Estivill, Xavier
    Dermitzakis, Emmanouil T
    Transcriptome and genome sequencing uncovers functional variation in humans2013Inngår i: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 501, nr 7468, s. 506-511Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Genome sequencing projects are discovering millions of genetic variants in humans, and interpretation of their functional effects is essential for understanding the genetic basis of variation in human traits. Here we report sequencing and deep analysis of messenger RNA and microRNA from lymphoblastoid cell lines of 462 individuals from the 1000 Genomes Project-the first uniformly processed high-throughput RNA-sequencing data from multiple human populations with high-quality genome sequences. We discover extremely widespread genetic variation affecting the regulation of most genes, with transcript structure and expression level variation being equally common but genetically largely independent. Our characterization of causal regulatory variation sheds light on the cellular mechanisms of regulatory and loss-of-function variation, and allows us to infer putative causal variants for dozens of disease-associated loci. Altogether, this study provides a deep understanding of the cellular mechanisms of transcriptome variation and of the landscape of functional variants in the human genome.

  • 116.
    Leonard, Dag
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Svenungsson, E.
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.
    Dahlqvist, Johanna
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Alexsson, Andrei
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ärlestig, L.
    Umea Univ, Dept Publ Hlth & Clin Med Rheumatol, Umea, Sweden.
    Taylor, K. E.
    Univ Calif San Francisco, Rosalind Russell Ephraim P Engleman Rheumatol Res, San Francisco, CA 94143 USA.
    Sandling, Johanna K.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Bengtsson, C.
    Umea Univ, Dept Publ Hlth & Clin Med Rheumatol, Umea, Sweden.
    Frodlund, M.
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    Jönsen, A.
    Skane Univ Hosp, Dept Rheumatol, Lund, Sweden.
    Eketjäll, S.
    Karolinska Inst, Cardiovasc & Metab Dis, Innovat Med & Early Dev Biotech Unit, AstraZeneca,ICMC, Huddinge, Sweden.
    Jensen-Urstad, K.
    Karolinska Inst, Dept Clin Physiol, Stockholm, Sweden.
    Gunnarsson, I.
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.
    Sjöwall, C.
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    Bengtsson, A. A.
    Skane Univ Hosp, Dept Rheumatol, Lund, Sweden.
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Rantapää-Dahlqvist, S.
    Umea Univ, Dept Publ Hlth & Clin Med Rheumatol, Umea, Sweden.
    Criswell, L. A.
    Univ Calif San Francisco, Rosalind Russell Ephraim P Engleman Rheumatol Res, San Francisco, CA 94143 USA.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Novel gene variants associated with cardiovascular disease in systemic lupus erythematosus and rheumatoid arthritis2018Inngår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, s. 1063-1069Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives Patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) have increased risk of cardiovascular disease (CVD). We investigated whether single nucleotide polymorphisms (SNPs) at autoimmunity risk loci were associated with CVD in SLE and RA. Methods Patients with SLE (n=1045) were genotyped using the 200K Immunochip SNP array (Illumina). The allele frequency was compared between patients with and without different manifestations of CVD. Results were replicated in a second SLE cohort (n=1043) and in an RA cohort (n=824). We analysed publicly available genetic data from general population, performed electrophoretic mobility shift assays and measured cytokine levels and occurrence of antiphospholipid antibodies (aPLs). Results We identified two new putative risk loci associated with increased risk for CVD in two SLE populations, which remained after adjustment for traditional CVD risk factors. An IL19 risk allele, rs17581834(T) was associated with stroke/myocardial infarction (MI) in SLE (OR 2.3 (1.5 to 3.4), P=8.5×10−5) and RA (OR 2.8 (1.4 to 5.6), P=3.8×10−3), meta-analysis (OR 2.5 (2.0 to 2.9), P=3.5×10−7), but not in population controls. The IL19 risk allele affected protein binding, and SLE patients with the risk allele had increased levels of plasma-IL10 (P=0.004) and aPL (P=0.01). An SRP54-AS1 risk allele, rs799454(G) was associated with stroke/transient ischaemic attack in SLE (OR 1.7 (1.3 to 2.2), P=2.5×10−5) but not in RA. The SRP54-AS1 risk allele is an expression quantitative trait locus for four genes. Conclusions The IL19 risk allele was associated with stroke/MI in SLE and RA, but not in the general population, indicating that shared immune pathways may be involved in the CVD pathogenesis in inflammatory rheumatic diseases.

  • 117.
    Leonard, Dag
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Svenungsson, Elisabet
    Sandling, Johanna K
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Berggren, Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Jönsen, Andreas
    Bengtsson, Christine
    Wang, Chuan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Jensen-Urstad, Kerstin
    Granstam, Sven-Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk fysiologi.
    Bengtsson, Anders A
    Gustafsson, Johanna T
    Gunnarsson, Iva
    Rantapää-Dahlqvist, Solbritt
    Nordmark, Gunnel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Syvänen, Ann-Christine
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Coronary heart disease in systemic lupus erythematosus is associated with interferon regulatory factor-8 gene variants2013Inngår i: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 6, nr 3, s. 255-263Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background- Patients with systemic lupus erythematosus have increased morbidity and mortality in coronary heart disease (CHD). We asked whether there was a genetic influence on CHD in systemic lupus erythematosus. Methods and Results- The association between single-nucleotide polymorphisms (SNPs) and CHD in 2 populations of patients with systemic lupus erythematosus was assessed. Patients were genotyped on a custom 12k Illumina Array. The allele frequencies were compared between patients with (n=66) and without (n=509) CHD. We found 61 SNPs with an association (P<0.01) to CHD, with the strongest association for 3 SNPs located in the interferon regulatory factor-8 (IRF8) gene. Comparison of the allele frequencies of these 61 SNPs in patients with (n=27) and without (n=212) CHD in the second study population revealed that 2 SNPs, rs925994 and rs10514610 in IRF8 (linkage disequilibrium, r(2)=0.84), were associated with CHD in both study populations. Meta-analysis of the SNP rs925994 gave an odds ratio of 3.6 (2.1-6.3), P value 1.9×10(-6). The identified IRF8 allele remained as a risk factor for CHD after adjustment for traditional CHD risk factors. The IRF8 risk allele was associated with the presence of carotid plaques (P<0.001) and increased intima-media thickness (P=0.01). By electrophoretic mobility shift assays, we show weaker binding of protein to the risk allele of the highly linked SNP rs11117415, and by flow cytometry, a reduced frequency of circulating B cells was detected in patients with the IRF8 risk allele. Conclusions- There is a considerable genetic component for CHD in systemic lupus erythematosus, with IRF8 as a strong susceptibility locus.

  • 118.
    Liljedahl, Ulrika
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Fredriksson, Mona
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Dahlgren, Andreas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Detecting imbalanced expression of SNP alleles by minisequencing on microarrays2004Inngår i: BMC Biotechnology, ISSN 1472-6750, E-ISSN 1472-6750, Vol. 4, nr 24, s. 1-10Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND:

    Each of the human genes or transcriptional units is likely to contain single nucleotide polymorphisms that may give rise to sequence variation between individuals and tissues on the level of RNA. Based on recent studies, differential expression of the two alleles of heterozygous coding single nucleotide polymorphisms (SNPs) may be frequent for human genes. Methods with high accuracy to be used in a high throughput setting are needed for systematic surveys of expressed sequence variation. In this study we evaluated two formats of multiplexed, microarray based minisequencing for quantitative detection of imbalanced expression of SNP alleles. We used a panel of ten SNPs located in five genes known to be expressed in two endothelial cell lines as our model system.

    RESULTS:

    The accuracy and sensitivity of quantitative detection of allelic imbalance was assessed for each SNP by constructing regression lines using a dilution series of mixed samples from individuals of different genotype. Accurate quantification of SNP alleles by both assay formats was evidenced for by R2 values > 0.95 for the majority of the regression lines. According to a two sample t-test, we were able to distinguish 1-9% of a minority SNP allele from a homozygous genotype, with larger variation between SNPs than between assay formats. Six of the SNPs, heterozygous in either of the two cell lines, were genotyped in RNA extracted from the endothelial cells. The coefficient of variation between the fluorescent signals from five parallel reactions was similar for cDNA and genomic DNA. The fluorescence signal intensity ratios measured in the cDNA samples were compared to those in genomic DNA to determine the relative expression levels of the two alleles of each SNP. Four of the six SNPs tested displayed a higher than 1.4-fold difference in allelic ratios between cDNA and genomic DNA. The results were verified by allele-specific oligonucleotide hybridisation and minisequencing in a microtiter plate format.

    CONCLUSIONS:

    We conclude that microarray based minisequencing is an accurate and accessible tool for multiplexed screening for imbalanced allelic expression in multiple samples and tissues in parallel.

  • 119.
    Liljedahl, Ulrika
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Fredriksson, Mona
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Analysis of DNA sequence variation in the microarray format2005Inngår i: Microarray Technology and Its Applications / [ed] U R Müller & Dan V Nicolau, Berlin: Springer, 2005, s. 211-227Kapittel i bok, del av antologi (Annet (populærvitenskap, debatt, mm))
  • 120.
    Liljedahl, Ulrika
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Kahan, Thomas
    Malmqvist, Karin
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Kurland, Lisa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Single nucleotide polymorphisms predict the change in left ventricular mass in response to antihypertensive treatment2004Inngår i: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 22, nr 12, s. 2321-8Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Our aim was to determine whether the change in left ventricular (LV) mass in response to antihypertensive treatment could be predicted by multivariate analysis of single nucleotide polymorphisms (SNPs) in candidate genes reflecting pathways likely to be involved in blood pressure control. METHODS: Patients with mild to moderate primary hypertension and LV hypertrophy were randomized in a double-blind fashion to treatment with either the angiotensin II type 1 receptor antagonist irbesartan (n = 48) or the beta1 adrenoreceptor blocker atenolol (n = 49). A microarray-based minisequencing system was used for genotyping 74 SNPs in 25 genes. These genotypes were related to the change in LV mass index by echocardiography, after 12 weeks treatment as monotherapy, using stepwise multiple regression analysis. RESULTS: The blood pressure reductions were similar and significant in both treatment groups. Two SNPs in two separate genes (the angiotensinogen T1198C polymorphism, corresponding to the M235T variant and the apolipoprotein B G10108A polymorphism) for those treated with irbesartan, and the adrenoreceptor alpha2A A1817G for those treated with atenolol, significantly predicted the change in LV mass. The predictive power of these SNPs was independent of the degree of blood pressure reduction. CONCLUSION: SNPs in the angiotensinogen, apolipoprotein B, and the alpha2 adrenoreceptor gene predicted the change in LV mass during antihypertensive therapy. These results illustrate the potential of using microarray-based technology for SNP genotyping in predicting individual drug responses.

  • 121.
    Liljedahl, Ulrika
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Karlsson, Julia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Kurland, Lisa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lindersson, Marie
    Kahan, Thomas
    Nyström, Fredrik
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    A microarray minisequencing system for pharmacogenetic profiling of antihypertensive drug response2003Inngår i: Pharmacogenetics, ISSN 0960-314X, E-ISSN 1473-561X, Vol. 13, nr 1, s. 7-17Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We aimed to develop a microarray genotyping system for multiplex analysis of a panel of single nucleotide polymorphisms (SNPs) in genes encoding proteins involved in blood pressure regulation, and to apply this system in a pilot study demonstrating its feasibility in the pharmacogenetics of hypertension. A panel of 74 SNPs in 25 genes involved in blood pressure regulation was selected from the SNP databases, and genotyped in DNA samples of 97 hypertensive patients. The patients had been randomized to double-blind treatment with either the angiotensin II type 1 receptor blocker irbesartan or the beta 1-adrenergic receptor blocker atenolol. Genotyping was performed using a microarray based DNA polymerase assisted 'minisequencing' single nucleotide primer extension assay with fluorescence detection. The observed genotypes were related to the blood pressure reduction using stepwise multiple regression analysis. The allele frequencies of the selected SNPs were determined in the Swedish population. The established microarray-based genotyping system was validated and allowed unequivocal multiplex genotyping of the panel of 74 SNPs in every patient. Almost 7200 SNP genotypes were generated in the study. Profiles of four or five SNP-genotypes that may be useful as predictors of blood pressure reduction after antihypertensive treatment were identified. Our results highlight the potential of microarray-based technology for SNP genotyping in pharmacogenetics.

  • 122. Liljedahl, Ulrika
    et al.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Kurland, Lisa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Berglund, Lars
    Kahan, Thomas
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Single nucleotide polymorphisms in the apolipoprotein B and low density lipoprotein receptor genes affect response to antihypertensive treatment2004Inngår i: BMC Cardiovascular Disorders, ISSN 1471-2261, E-ISSN 1471-2261, Vol. 4, nr 1, s. 16-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Dyslipidemia has been associated with hypertension. The present study explored if polymorphisms in genes encoding proteins in lipid metabolism could be used as predictors for the individual response to antihypertensive treatment. METHODS: Ten single nucleotide polymorphisms (SNP) in genes related to lipid metabolism were analysed by a microarray based minisequencing system in DNA samples from ninety-seven hypertensive subjects randomised to treatment with either 150 mg of the angiotensin II type 1 receptor blocker irbesartan or 50 mg of the beta1-adrenergic receptor blocker atenolol for twelve weeks. RESULTS: The reduction in blood pressure was similar in both treatment groups. The SNP C711T in the apolipoprotein B gene was associated with the blood pressure response to irbesartan with an average reduction of 19 mmHg in the individuals carrying the C-allele, but not to atenolol. The C16730T polymorphism in the low density lipoprotein receptor gene predicted the change in systolic blood pressure in the atenolol group with an average reduction of 14 mmHg in the individuals carrying the C-allele. CONCLUSIONS: Polymorphisms in genes encoding proteins in the lipid metabolism are associated with the response to antihypertensive treatment in a drug specific pattern. These results highlight the potential use of pharmacogenetics as a guide for individualised antihypertensive treatment, and also the role of lipids in blood pressure control.

  • 123.
    Liljedahl, Ulrika
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Multiplex minisequencing on microarrays: Applications to pharmacogenetics of antihypertensive drug response2005Inngår i: Pharmacogenomics / [ed] Werner Kalow, Urs A Meyer, Rachel Tyndale, New York: Taylor & Francis, 2005, 2nd ed, s. 341-351Kapittel i bok, del av antologi (Annet (populærvitenskap, debatt, mm))
  • 124.
    Limbach, Maia
    et al.
    Inst Biomed & Translat Med, Mol Pathol, Tartu, Estonia..
    Saare, Mario
    Inst Biomed & Translat Med, Mol Pathol, Tartu, Estonia..
    Tserel, Liina
    Inst Biomed & Translat Med, Mol Pathol, Tartu, Estonia..
    Kisand, Kai
    Inst Biomed & Translat Med, Mol Pathol, Tartu, Estonia..
    Eglit, Trim
    Univ Tartu, Dept Internal Med, Ulikooli 18, EE-50090 Tartu, Estonia.;Tartu Univ Hosp, Internal Med Clin, Tartu, Estonia..
    Sauer, Sascha
    Max Planck Inst Mol Genet, Ihnestr 73, D-14195 Berlin, Germany..
    Axelsson, Tomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Metspalu, Andres
    Univ Tartu, Inst Mol & Cell Biol, Estonian Genome Ctr, Ulikooli 18, EE-50090 Tartu, Estonia..
    Milani, Lili
    Univ Tartu, Inst Mol & Cell Biol, Estonian Genome Ctr, Ulikooli 18, EE-50090 Tartu, Estonia..
    Peterson, Paert
    Inst Biomed & Translat Med, Mol Pathol, Tartu, Estonia..
    Epigenetic profiling in CD4+and CD8+T cells from Graves' disease patients reveals changes in genes associated with T cell receptor signaling2016Inngår i: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 67, s. 46-56Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In Graves' disease (GD), a combination of genetic, epigenetic and environmental factors causes an autoimmune response to the thyroid gland, characterized by lymphocytic infiltrations and autoantibodies targeting the thyroid stimulating hormone receptor (TSHR) and other thyroid antigens. To identify the epigenetic changes involved in GD, we performed a genome-wide analysis of DNA methylation and enrichment of H3K4me3 and H3K27ac histone marks in sorted CD4+ and CD8+ T cells. We found 365 and 3322 differentially methylated CpG sites in CD4+ and CD8+ T cells, respectively. Among the hypermethylated CpG sites, we specifically found enrichment of genes involved in T cell signaling (CD247, LCK, ZAP70, CD3D, CD3E, CD3G, CTLA4 and CD8A) and decreased expression of CD3 gene family members. The hypermethylation was accompanied with decreased levels of H3K4me3 and H3K27ac marks at several T cell signaling genes in ChIP-seq analysis. In addition, we found hypermethylation of the TSHR gene first intron, where several GD-associated polymorphisms are located. Our results demonstrate an involvement of dysregulated DNA methylation and histone modifications at T cell signaling genes in GD patients.

  • 125.
    Lind, Lars
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Ingelsson, Erik
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Kumar, Jitender
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden .
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Axelsson, Tomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Teerlink, Tom
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Genetic variation in the dimethylarginine dimethylaminohydrolase 1 gene (DDAH1) is related to asymmetric dimethylarginine (ADMA) levels, but not to endothelium-dependent vasodilation2013Inngår i: Vascular Medicine, ISSN 1358-863X, E-ISSN 1477-0377, Vol. 18, nr 4, s. 192-199Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives:

    Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. The breakdown of ADMA is mainly governed by the activity of dimethylarginine dimethylaminohydrolases (DDAHs). We investigated if genetic variation in the DDAH1 and DDAH2 genes were related to ADMA and l-arginine levels, as well as measures of endothelium-dependent vasodilation.

    Methods:

    In 1016 70-year-old participants of the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (50% women), we measured endothelium-dependent vasodilation (EDV) using the invasive forearm technique with acetylcholine given in the brachial artery and the brachial artery ultrasound technique with measurement of flow-mediated dilatation (FMD). Plasma l-arginine and ADMA levels were measured by high-performance liquid chromatography and 55 single nucleotide polymorphisms (SNPs) in the DDAH1 and DDAH2 genes were genotyped.

    Results:

    Several of the genotypes in the DDAH1 gene were highly significantly related to ADMA levels (p = 10−7 at best), but not to the l-arginine levels. No relationships between the genotypes in the DDAH2 gene and ADMA or l-arginine levels were found. None of the DDAH1 genotypes being closely related to ADMA levels were significantly related to EDV or FMD. Neither were any of the DDAH2 genotypes closely related to any of the measurements of vasoreactivity.

    Conclusion:

    A close relationship was seen between SNPs in the DDAH1, but not DDAH2, gene and ADMA levels. However, variation in those genes was not related to measures of EDV in this elderly population.

  • 126.
    Lind, Lars
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Penell, Johanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Luttropp, Karin
    Nordfors, Louise
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Axelsson, Tomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Salihovic, Samira
    van Bavel, Bert
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lind, P Monica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Global DNA hypermethylation is associated with high serum levels of persistent organic pollutants in an elderly population2013Inngår i: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 59, s. 456-461Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Dioxin exposure has experimentally been associated with changes in DNA methylation, an epigenetic change that is associated with disease. The present study aims to investigate if serum levels of dioxin and other persistent environmental pollutants are related to global DNA methylation in a human sample. In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (all aged 70), global DNA methylation was measured by the Luminometric Methylation Assay in 524 subjects. Twenty-three different POPs, including 16 PCBs, five pesticides, one dioxin (OCDD) and one brominated flame retardant (BDE47) were analysed by HRGC/HRMS. Ten single nucleotide polymorphisms (SNPs) in the Aryl hydrocarbon (Ah)-receptor were analysed by mini-sequencing. High levels of toxic equivalency (TEQ) for PCBs and dioxin were associated with DNA hypermethylation (p=0.030). This was mainly attributed to coplanar non-ortho PCBs. While no significant associations were found between DNA methylation and SNPs in the Ah-receptor, an interaction was found between the SNP rs2237297 and TEQ so that TEQ was associated with hypermethylation (p=0.009) only in subjects with one G-allele (n=103). Also high levels of the PCB126 congener, the OCDD, and the pesticide metabolite p,p'-DDE were related to DNA hypermethylation (p=0.01, 0.03 and 0.003, respectively). In conclusion, in a sample of elderly subjects, high TEQ including PCBs and the dioxin OCDD and high serum levels of PCB126, OCDD, and p,p'-DDE were related to global DNA hypermethylation in a cross-sectional analysis.

  • 127.
    Lind, Lars
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Penell, Johanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Axelsson, Tomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Morris, Andrew P
    Lindgren, Cecilia
    Salihovic, Samira
    van Bavel, Bert
    Lind, P Monica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Genetic variation in the CYP1A1 gene is related to circulating PCB118 levels in a population-based sample2014Inngår i: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 133, s. 135-140Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Several of the polychlorinated biphenyls (PCBs), i.e. the dioxin-like PCBs, are known to induce the P450 enzymes CYP1A1, CYP1A2 and CYP1B1 by activating the aryl hydrocarbon receptor (Ah)-receptor. We evaluated if circulating levels of PCBs in a population sample were related to genetic variation in the genes encoding these CYPs. In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (1016 subjects all aged 70), 21 SNPs in the CYP1A1, CYP1A2 and CYP1B1 genes were genotyped. Sixteen PCB congeners were analysed by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/ HRMS). Of the investigated relationships between SNPs in the CYP1A1, CYP1A2 and CYP1B1 and six PCBs (congeners 118, 126, 156, 169, 170 and 206) that captures >80% of the variation of all PCBs measured, only the relationship between CYP1A1 rs2470893 was significantly related to PCB118 levels following strict adjustment for multiple testing (p=0.00011). However, there were several additional SNPs in the CYP1A2 and CYP1B1 that showed nominally significant associations with PCB118 levels (p-values in the 0.003-0.05 range). Further, several SNPs in the CYP1B1 gene were related to both PCB156 and PCB206 with p-values in the 0.005-0.05 range. Very few associations with p<0.05 were seen for PCB126, PCB169 or PCB170. Genetic variation in the CYP1A1 was related to circulating PCB118 levels in the general elderly population. Genetic variation in CYP1A2 and CYP1B1 might also be associated with other PCBs.

  • 128.
    Lind, Lars
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Axelsson, Tomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Lundmark, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Hagg, S.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Variation in genes in the endothelin pathway and endothelium-dependent and endothelium-independent vasodilation in an elderly population2013Inngår i: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 208, nr 1, s. 88-94Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aim Indirect evidences by blockade of the endothelin receptors have suggested a role of endothelin in endothelium-dependent vasodilation. This study aimed to investigate whether circulating levels of endotehlin-1 or genetic variations in genes in the endothelin pathway were related to endothelium-dependent vasodilation. Methods In 1016 seventy-year-old participants of the population-based Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study (52% women), we measured endothelium-dependent vasodilation using the invasive forearm technique with acetylcholine given in the brachial artery (EDV) and the brachial artery ultrasound technique with measurement of flow-mediated dilatation (FMD). Plasma endothelin-1 levels were measured and 60 SNPs in genes in the endothelin pathway (ECE1, EDN1, EDNRA, EDNRB) were genotyped. Results No significant associations were found between circulating endothelin levels and EDV or FMD. No single genotype was related to EDV or FMD following adjustment for multiple testing, but a genotype score for 3 SNPs (rs11618266 in EDNRB, rs17675063 in EDNRA, rs3026868 in ECE1) was significantly related to EDV (beta coefficient 0.070, 95% CI 0.0250.12, P=0.002) when adjusting for gender, systolic blood pressure, HDL and LDL cholesterol, serum triglycerides, BMI, diabetes, smoking, antihypertensive medication or statins and CRP. This score was also related to nitroprusside-induced vasodilation in the forearm. Conclusion A combination of genotypes in the endothelin pathway was related to both endothelium-dependent and endothelium-independent vasodilation in forearm resistance vessels, but not in the brachial artery in an elderly population, giving evidence for a role of the endothelin system in resistance vessel reactivity independent of major cardiovascular risk factors.

  • 129.
    Lindqvist, C. Mårten
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lundmark, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Nordlund, Jessica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Freyhult, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Centrum för bioinformatik.
    Ekman, Diana
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Almlöf, Jonas Carlsson
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Raine, Amanda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Övernäs, Elin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Abrahamsson, Jonas
    Queen Silvia Childrens Hosp, Dept Pediat, Gothenburg, Sweden..
    Frost, Britt-Marie
    Univ Childrens Hosp, Dept Womens & Childrens Hlth, Uppsala, Sweden..
    Grander, Dan
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Heyman, Mats
    Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Dept Women & Child Hlth, Childhood Canc Res Unit, Stockholm, Sweden..
    Palle, Josefine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik. Uppsala Univ, Dept Med Sci, Mol Med & Sci Life Lab, Uppsala, Sweden.;Univ Childrens Hosp, Dept Womens & Childrens Hlth, Uppsala, Sweden..
    Forestier, Erik
    Umea Univ, Dept Med Biosci, Umea, Sweden..
    Lönnerholm, Gudmar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    Berglund, Eva C.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Deep targeted sequencing in pediatric acute lymphoblastic leukemia unveils distinct mutational patterns between genetic subtypes and novel relapse-associated genes2016Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, nr 39, s. 64071-64088Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To characterize the mutational patterns of acute lymphoblastic leukemia (ALL) we performed deep next generation sequencing of 872 cancer genes in 172 diagnostic and 24 relapse samples from 172 pediatric ALL patients. We found an overall greater mutational burden and more driver mutations in T-cell ALL (T-ALL) patients compared to B-cell precursor ALL (BCP-ALL) patients. In addition, the majority of the mutations in T-ALL had occurred in the original leukemic clone, while most of the mutations in BCP-ALL were subclonal. BCP-ALL patients carrying any of the recurrent translocations ETV6-RUNX1, BCR-ABL or TCF3-PBX1 harbored few mutations in driver genes compared to other BCP-ALL patients. Specifically in BCP-ALL, we identified ATRX as a novel putative driver gene and uncovered an association between somatic mutations in the Notch signaling pathway at ALL diagnosis and increased risk of relapse. Furthermore, we identified EP300, ARID1A and SH2B3 as relapse-associated genes. The genes highlighted in our study were frequently involved in epigenetic regulation, associated with germline susceptibility to ALL, and present in minor subclones at diagnosis that became dominant at relapse. We observed a high degree of clonal heterogeneity and evolution between diagnosis and relapse in both BCP-ALL and T-ALL, which could have implications for the treatment efficiency.

  • 130.
    Lindqvist, C Mårten
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Nordlund, Jessica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ekman, Diana
    Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Sweden.
    Johansson, Anna
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär evolution.
    Moghadam, Behrooz Torabi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Raine, Amanda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Övernäs, Elin
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Dahlberg, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Wahlberg, Per
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Henriksson, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Abrahamsson, Jonas
    Department of Pediatrics, Queen Silvia Children's Hospital, Gothenburg, Sweden.
    Frost, Britt-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Grandér, Dan
    Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
    Heyman, Mats
    Childhood Cancer Research Unit, Department of Women and Child Health, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Palle, Josefine
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Söderhäll, Stefan
    Childhood Cancer Research Unit, Department of Women and Child Health, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Forestier, Erik
    Lönnerholm, Gudmar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Berglund, Eva C
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    The Mutational Landscape in Pediatric Acute Lymphoblastic Leukemia Deciphered by Whole Genome Sequencing2015Inngår i: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 36, nr 1, s. 118-128Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Genomic characterization of pediatric acute lymphoblastic leukemia (ALL) has identified distinct patterns of genes and pathways altered in patients with well-defined genetic aberrations. To extend the spectrum of known somatic variants in ALL, we performed whole genome and transcriptome sequencing of three B-cell precursor patients, of which one carried the t(12;21)ETV6-RUNX1 translocation and two lacked a known primary genetic aberration, and one T-ALL patient. We found that each patient had a unique genome, with a combination of well-known and previously undetected genomic aberrations. By targeted sequencing in 168 patients, we identified KMT2D and KIF1B as novel putative driver genes. We also identified a putative regulatory non-coding variant that coincided with overexpression of the growth factor MDK. Our results contribute to an increased understanding of the biological mechanisms that lead to ALL and suggest that regulatory variants may be more important for cancer development than recognized to date. The heterogeneity of the genetic aberrations in ALL renders whole genome sequencing particularly well suited for analysis of somatic variants in both research and diagnostic applications.

  • 131.
    Lindqvist, Carl Mårten
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Dahlberg, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Raine, Amanda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Övernäs, Elin
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Ekman, Diana
    Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
    Nordlund, Jessica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Frost, B M
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Grandér, Dan
    Karolinska Institutet, Dept. Oncology and Pathology, Stockholm, Sweden.
    Forestier, Erik
    Dept. of Medical Biosciences, University of Umeå, Umeå, Sweden.
    Lönnerholm, G
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Barnneurologi/Barnonkologi.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Berglund, Eva Caroline
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär evolution. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Identification of somatic single nucleotide variants inleukemia by targeted sequencing of non-indexed overlapping poolsManuskript (preprint) (Annet vitenskapelig)
  • 132. Lindroos, Katarina
    et al.
    Liljedahl, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Raitio, Mirja
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Minisequencing on oligonucleotide microarrays: comparison of immobilisation chemistries2001Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 29, nr 13, s. e69-e69Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In the microarray format of the minisequencing method multiple oligonucleotide primers immobilised on a glass surface are extended with fluorescent ddNTPs using a DNA polymerase. The method is a promising tool for large-scale single nucleotide polymorphism (SNP) detection. We have compared eight chemical methods for covalent immobilisation of the oligonucleotide primers on glass surfaces. We included both commercially available, activated slides and slides that were modified by ourselves. In the comparison the differently derivatised glass slides were evaluated with respect to background fluorescence, efficiency of attaching oligonucleotides and performance of the primer arrays in minisequencing reactions. We found that there are significant differences in background fluorescence levels among the different coatings, and that the attachment efficiency, which was measured indirectly using extension by terminal transferase, varied largely depending on which immobilisation strategy was used. We also found that the attachment chemistry affects the genotyping accuracy, when minisequencing on microarrays is used as the genotyping method. The best genotyping results were observed using mercaptosilane-coated slides attaching disulfide-modified oligonucleotides.

  • 133.
    Lindroos, Katarina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Liljedahl, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Raitio, Mirja
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Minisequencing on oligonucleotide microarrays: comparison of immobilisation chemistries2001Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 29, nr 13, s. e69-e69Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In the microarray format of the minisequencing method multiple oligonucleotide primers immobilised on a glass surface are extended with fluorescent ddNTPs using a DNA polymerase. The method is a promising tool for large-scale single nucleotide polymorphism (SNP) detection. We have compared eight chemical methods for covalent immobilisation of the oligonucleotide primers on glass surfaces. We included both commercially available, activated slides and slides that were modified by ourselves. In the comparison the differently derivatised glass slides were evaluated with respect to background fluorescence, efficiency of attaching oligonucleotides and performance of the primer arrays in minisequencing reactions. We found that there are significant differences in background fluorescence levels among the different coatings, and that the attachment efficiency, which was measured indirectly using extension by terminal transferase, varied largely depending on which immobilisation strategy was used. We also found that the attachment chemistry affects the genotyping accuracy, when minisequencing on microarrays is used as the genotyping method. The best genotyping results were observed using mercaptosilane-coated slides attaching disulfide-modified oligonucleotides.

  • 134.
    Lindroos, Katarina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Liljedahl, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Genotyping SNPs by minisequencing primer extension using oligonucleotide microarrays2003Inngår i: Methods in Molecular Biology, ISSN 1064-3745, E-ISSN 1940-6029, Vol. 212, s. 149-165Artikkel i tidsskrift (Annet vitenskapelig)
  • 135.
    Lindroos, Katarina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Sigurdsson, Snaevar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Johansson, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Multiplex SNP genotyping in pooled DNA samples by a four-colour microarray system2002Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 30, nr 14, s. e70-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We selected 125 candidate single nucleotide polymorphisms (SNPs) in genes belonging to the human type 1 interferon (IFN) gene family and the genes coding for proteins in the main type 1 IFN signalling pathway by screening databases and by in silico comparison of DNA sequences. Using quantitative analysis of pooled DNA samples by solid-phase mini-sequencing, we found that only 20% of the candidate SNPs were polymorphic in the Finnish and Swedish populations. To allow more effective validation of candidate SNPs, we developed a four-colour microarray-based mini-sequencing assay for multiplex, quantitative allele frequency determination in pooled DNA samples. We used cyclic mini-sequencing reactions with primers carrying 5'-tag sequences, followed by capture of the products on microarrays by hybridisation to complementary tag oligonucleotides. Standard curves prepared from mixtures of known amounts of SNP alleles demonstrate the applicability of the system to quantitative analysis, and showed that for about half of the tested SNPs the limit of detection for the minority allele was below 5%. The microarray-based genotyping system established here is universally applicable for genotyping and quantification of any SNP, and the validated system for SNPs in type 1 IFN-related genes should find many applications in genetic studies of this important immunoregulatory pathway.

  • 136. Locke, Adam E
    et al.
    Kahali, Bratati
    Berndt, Sonja I
    Justice, Anne E
    Pers, Tune H
    Day, Felix R
    Powell, Corey
    Vedantam, Sailaja
    Buchkovich, Martin L
    Yang, Jian
    Croteau-Chonka, Damien C
    Esko, Tonu
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ferreira, Teresa
    Gustafsson, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Kutalik, Zoltán
    Luan, Jian'an
    Mägi, Reedik
    Randall, Joshua C
    Winkler, Thomas W
    Wood, Andrew R
    Workalemahu, Tsegaselassie
    Faul, Jessica D
    Smith, Jennifer A
    Hua Zhao, Jing
    Zhao, Wei
    Chen, Jin
    Fehrmann, Rudolf
    Hedman, Åsa K
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Karjalainen, Juha
    Schmidt, Ellen M
    Absher, Devin
    Amin, Najaf
    Anderson, Denise
    Beekman, Marian
    Bolton, Jennifer L
    Bragg-Gresham, Jennifer L
    Buyske, Steven
    Demirkan, Ayse
    Deng, Guohong
    Ehret, Georg B
    Feenstra, Bjarke
    Feitosa, Mary F
    Fischer, Krista
    Goel, Anuj
    Gong, Jian
    Jackson, Anne U
    Kanoni, Stavroula
    Kleber, Marcus E
    Kristiansson, Kati
    Lim, Unhee
    Lotay, Vaneet
    Mangino, Massimo
    Mateo Leach, Irene
    Medina-Gomez, Carolina
    Medland, Sarah E
    Nalls, Michael A
    Palmer, Cameron D
    Pasko, Dorota
    Pechlivanis, Sonali
    Peters, Marjolein J
    Prokopenko, Inga
    Shungin, Dmitry
    Stančáková, Alena
    Strawbridge, Rona J
    Ju Sung, Yun
    Tanaka, Toshiko
    Teumer, Alexander
    Trompet, Stella
    van der Laan, Sander W
    van Setten, Jessica
    Van Vliet-Ostaptchouk, Jana V
    Wang, Zhaoming
    Yengo, Loïc
    Zhang, Weihua
    Isaacs, Aaron
    Albrecht, Eva
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Arscott, Gillian M
    Attwood, Antony P
    Bandinelli, Stefania
    Barrett, Amy
    Bas, Isabelita N
    Bellis, Claire
    Bennett, Amanda J
    Berne, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Blagieva, Roza
    Blüher, Matthias
    Böhringer, Stefan
    Bonnycastle, Lori L
    Böttcher, Yvonne
    Boyd, Heather A
    Bruinenberg, Marcel
    Caspersen, Ida H
    Ida Chen, Yii-Der
    Clarke, Robert
    Warwick Daw, E
    de Craen, Anton J M
    Delgado, Graciela
    Dimitriou, Maria
    Doney, Alex S F
    Eklund, Niina
    Estrada, Karol
    Eury, Elodie
    Folkersen, Lasse
    Fraser, Ross M
    Garcia, Melissa E
    Geller, Frank
    Giedraitis, Vilmantas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Gigante, Bruna
    Go, Alan S
    Golay, Alain
    Goodall, Alison H
    Gordon, Scott D
    Gorski, Mathias
    Grabe, Hans-Jörgen
    Grallert, Harald
    Grammer, Tanja B
    Gräßler, Jürgen
    Grönberg, Henrik
    Groves, Christopher J
    Gusto, Gaëlle
    Haessler, Jeffrey
    Hall, Per
    Haller, Toomas
    Hallmans, Goran
    Hartman, Catharina A
    Hassinen, Maija
    Hayward, Caroline
    Heard-Costa, Nancy L
    Helmer, Quinta
    Hengstenberg, Christian
    Holmen, Oddgeir
    Hottenga, Jouke-Jan
    James, Alan L
    Jeff, Janina M
    Johansson, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Jolley, Jennifer
    Juliusdottir, Thorhildur
    Kinnunen, Leena
    Koenig, Wolfgang
    Koskenvuo, Markku
    Kratzer, Wolfgang
    Laitinen, Jaana
    Lamina, Claudia
    Leander, Karin
    Lee, Nanette R
    Lichtner, Peter
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Lindström, Jaana
    Sin Lo, Ken
    Lobbens, Stéphane
    Lorbeer, Roberto
    Lu, Yingchang
    Mach, François
    Magnusson, Patrik K E
    Mahajan, Anubha
    McArdle, Wendy L
    McLachlan, Stela
    Menni, Cristina
    Merger, Sigrun
    Mihailov, Evelin
    Milani, Lili
    Moayyeri, Alireza
    Monda, Keri L
    Morken, Mario A
    Mulas, Antonella
    Müller, Gabriele
    Müller-Nurasyid, Martina
    Musk, Arthur W
    Nagaraja, Ramaiah
    Nöthen, Markus M
    Nolte, Ilja M
    Pilz, Stefan
    Rayner, Nigel W
    Renstrom, Frida
    Rettig, Rainer
    Ried, Janina S
    Ripke, Stephan
    Robertson, Neil R
    Rose, Lynda M
    Sanna, Serena
    Scharnagl, Hubert
    Scholtens, Salome
    Schumacher, Fredrick R
    Scott, William R
    Seufferlein, Thomas
    Shi, Jianxin
    Vernon Smith, Albert
    Smolonska, Joanna
    Stanton, Alice V
    Steinthorsdottir, Valgerdur
    Stirrups, Kathleen
    Stringham, Heather M
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Swertz, Morris A
    Swift, Amy J
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Tan, Sian-Tsung
    Tayo, Bamidele O
    Thorand, Barbara
    Thorleifsson, Gudmar
    Tyrer, Jonathan P
    Uh, Hae-Won
    Vandenput, Liesbeth
    Verhulst, Frank C
    Vermeulen, Sita H
    Verweij, Niek
    Vonk, Judith M
    Waite, Lindsay L
    Warren, Helen R
    Waterworth, Dawn
    Weedon, Michael N
    Wilkens, Lynne R
    Willenborg, Christina
    Wilsgaard, Tom
    Wojczynski, Mary K
    Wong, Andrew
    Wright, Alan F
    Zhang, Qunyuan
    Brennan, Eoin P
    Choi, Murim
    Dastani, Zari
    Drong, Alexander W
    Eriksson, Per
    Franco-Cereceda, Anders
    Gådin, Jesper R
    Gharavi, Ali G
    Goddard, Michael E
    Handsaker, Robert E
    Huang, Jinyan
    Karpe, Fredrik
    Kathiresan, Sekar
    Keildson, Sarah
    Kiryluk, Krzysztof
    Kubo, Michiaki
    Lee, Jong-Young
    Liang, Liming
    Lifton, Richard P
    Ma, Baoshan
    McCarroll, Steven A
    McKnight, Amy J
    Min, Josine L
    Moffatt, Miriam F
    Montgomery, Grant W
    Murabito, Joanne M
    Nicholson, George
    Nyholt, Dale R
    Okada, Yukinori
    Perry, John R B
    Dorajoo, Rajkumar
    Reinmaa, Eva
    Salem, Rany M
    Sandholm, Niina
    Scott, Robert A
    Stolk, Lisette
    Takahashi, Atsushi
    Tanaka, Toshihiro
    Van't Hooft, Ferdinand M
    Vinkhuyzen, Anna A E
    Westra, Harm-Jan
    Zheng, Wei
    Zondervan, Krina T
    Heath, Andrew C
    Arveiler, Dominique
    Bakker, Stephan J L
    Beilby, John
    Bergman, Richard N
    Blangero, John
    Bovet, Pascal
    Campbell, Harry
    Caulfield, Mark J
    Cesana, Giancarlo
    Chakravarti, Aravinda
    Chasman, Daniel I
    Chines, Peter S
    Collins, Francis S
    Crawford, Dana C
    Adrienne Cupples, L
    Cusi, Daniele
    Danesh, John
    de Faire, Ulf
    den Ruijter, Hester M
    Dominiczak, Anna F
    Erbel, Raimund
    Erdmann, Jeanette
    Eriksson, Johan G
    Farrall, Martin
    Felix, Stephan B
    Ferrannini, Ele
    Ferrières, Jean
    Ford, Ian
    Forouhi, Nita G
    Forrester, Terrence
    Franco, Oscar H
    Gansevoort, Ron T
    Gejman, Pablo V
    Gieger, Christian
    Gottesman, Omri
    Gudnason, Vilmundur
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hall, Alistair S
    Harris, Tamara B
    Hattersley, Andrew T
    Hicks, Andrew A
    Hindorff, Lucia A
    Hingorani, Aroon D
    Hofman, Albert
    Homuth, Georg
    Kees Hovingh, G
    Humphries, Steve E
    Hunt, Steven C
    Hyppönen, Elina
    Illig, Thomas
    Jacobs, Kevin B
    Jarvelin, Marjo-Riitta
    Jöckel, Karl-Heinz
    Johansen, Berit
    Jousilahti, Pekka
    Wouter Jukema, J
    Jula, Antti M
    Kaprio, Jaakko
    Kastelein, John J P
    Keinanen-Kiukaanniemi, Sirkka M
    Kiemeney, Lambertus A
    Knekt, Paul
    Kooner, Jaspal S
    Kooperberg, Charles
    Kovacs, Peter
    Kraja, Aldi T
    Kumari, Meena
    Kuusisto, Johanna
    Lakka, Timo A
    Langenberg, Claudia
    Le Marchand, Loic
    Lehtimäki, Terho
    Lyssenko, Valeriya
    Männistö, Satu
    Marette, André
    Matise, Tara C
    McKenzie, Colin A
    McKnight, Barbara
    Moll, Frans L
    Morris, Andrew D
    Morris, Andrew P
    Murray, Jeffrey C
    Nelis, Mari
    Ohlsson, Claes
    Oldehinkel, Albertine J
    Ong, Ken K
    Madden, Pamela A F
    Pasterkamp, Gerard
    Peden, John F
    Peters, Annette
    Postma, Dirkje S
    Pramstaller, Peter P
    Price, Jackie F
    Qi, Lu
    Raitakari, Olli T
    Rankinen, Tuomo
    Rao, D C
    Rice, Treva K
    Ridker, Paul M
    Rioux, John D
    Ritchie, Marylyn D
    Rudan, Igor
    Salomaa, Veikko
    Samani, Nilesh J
    Saramies, Jouko
    Sarzynski, Mark A
    Schunkert, Heribert
    Schwarz, Peter E H
    Sever, Peter
    Shuldiner, Alan R
    Sinisalo, Juha
    Stolk, Ronald P
    Strauch, Konstantin
    Tönjes, Anke
    Trégouët, David-Alexandre
    Tremblay, Angelo
    Tremoli, Elena
    Virtamo, Jarmo
    Vohl, Marie-Claude
    Völker, Uwe
    Waeber, Gérard
    Willemsen, Gonneke
    Witteman, Jacqueline C
    Zillikens, M Carola
    Adair, Linda S
    Amouyel, Philippe
    Asselbergs, Folkert W
    Assimes, Themistocles L
    Bochud, Murielle
    Boehm, Bernhard O
    Boerwinkle, Eric
    Bornstein, Stefan R
    Bottinger, Erwin P
    Bouchard, Claude
    Cauchi, Stéphane
    Chambers, John C
    Chanock, Stephen J
    Cooper, Richard S
    de Bakker, Paul I W
    Dedoussis, George
    Ferrucci, Luigi
    Franks, Paul W
    Froguel, Philippe
    Groop, Leif C
    Haiman, Christopher A
    Hamsten, Anders
    Hui, Jennie
    Hunter, David J
    Hveem, Kristian
    Kaplan, Robert C
    Kivimaki, Mika
    Kuh, Diana
    Laakso, Markku
    Liu, Yongmei
    Martin, Nicholas G
    März, Winfried
    Melbye, Mads
    Metspalu, Andres
    Moebus, Susanne
    Munroe, Patricia B
    Njølstad, Inger
    Oostra, Ben A
    Palmer, Colin N A
    Pedersen, Nancy L
    Perola, Markus
    Pérusse, Louis
    Peters, Ulrike
    Power, Chris
    Quertermous, Thomas
    Rauramaa, Rainer
    Rivadeneira, Fernando
    Saaristo, Timo E
    Saleheen, Danish
    Sattar, Naveed
    Schadt, Eric E
    Schlessinger, David
    Eline Slagboom, P
    Snieder, Harold
    Spector, Tim D
    Thorsteinsdottir, Unnur
    Stumvoll, Michael
    Tuomilehto, Jaakko
    Uitterlinden, André G
    Uusitupa, Matti
    van der Harst, Pim
    Walker, Mark
    Wallaschofski, Henri
    Wareham, Nicholas J
    Watkins, Hugh
    Weir, David R
    Wichmann, H-Erich
    Wilson, James F
    Zanen, Pieter
    Borecki, Ingrid B
    Deloukas, Panos
    Fox, Caroline S
    Heid, Iris M
    O'Connell, Jeffrey R
    Strachan, David P
    Stefansson, Kari
    van Duijn, Cornelia M
    Abecasis, Gonçalo R
    Franke, Lude
    Frayling, Timothy M
    McCarthy, Mark I
    Visscher, Peter M
    Scherag, André
    Willer, Cristen J
    Boehnke, Michael
    Mohlke, Karen L
    Lindgren, Cecilia M
    Beckmann, Jacques S
    Barroso, Inês
    North, Kari E
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hirschhorn, Joel N
    Loos, Ruth J F
    Speliotes, Elizabeth K
    Genetic studies of body mass index yield new insights for obesity biology2015Inngår i: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 518, nr 7538, s. 197-206Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10−8), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ~2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

  • 137.
    Lopes, Fatima
    et al.
    Univ Minho, Life & Hlth Sci Res Inst ICVS, Sch Hlth Sci, P-4710057 Braga, Portugal.;ICVS 3Bs PT Govt Associate Lab, Braga, Portugal..
    Barbosa, Mafalda
    Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, Mindich Child Hlth & Dev Inst, Seaver Autism Ctr Res & Treatment, New York, NY 10029 USA.;Inst Gulbenkian Ciencias, Oeiras, Portugal..
    Ameur, Adam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Soares, Gabriela
    Ctr Hosp Porto, Ctr Med Genet Dr Jacinto Magalhaes, Oporto, Portugal..
    de Sa, Joaquim
    Ctr Hosp & Univ Coimbra, Hosp Pediat, Serv Genet Med, Coimbra, Portugal..
    Dias, Ana Isabel
    Ctr Hosp Lisboa Cent, Hosp D Estefania, Serv Neurol Pediat, Lisbon, Portugal..
    Oliveira, Guiomar
    Ctr Hosp & Univ Coimbra, Hosp Pediat, Unidade Neurodesenvolvimento & Autismo, Ctr Desenvolvimento Crianca, Coimbra, Portugal.;Ctr Hosp & Univ Coimbra, Hosp Pediat, Ctr Invest & Formacao Clin, Coimbra, Portugal.;Univ Coimbra, Univ Clin Pediat, Fac Med, Coimbra, Portugal.;Univ Coimbra, Inst Biomed Imaging & Life Sci, Coimbra, Portugal..
    Cabral, Pedro
    Egas Moniz Hosp, Dept Neurol, Lisbon, Portugal..
    Temudo, Teresa
    Ctr Hosp Porto, Dept Neuropediat, Oporto, Portugal..
    Calado, Eulalia
    Ctr Hosp Lisboa Cent, Hosp D Estefania, Serv Neurol Pediat, Lisbon, Portugal..
    Cruz, Isabel Fineza
    Ctr Hosp Univ Coimbra, Ctr Desenvolvimento Luis Borges, Hosp Pediat, Coimbra, Portugal..
    Vieira, Jose Pedro
    Ctr Hosp Lisboa Cent, Hosp D Estefania, Serv Neurol Pediat, Lisbon, Portugal..
    Oliveira, Renata
    Ctr Hosp & Univ Coimbra, Hosp Pediat, Serv Genet Med, Coimbra, Portugal..
    Esteves, Sofia
    Univ Minho, Life & Hlth Sci Res Inst ICVS, Sch Hlth Sci, P-4710057 Braga, Portugal.;ICVS 3Bs PT Govt Associate Lab, Braga, Portugal..
    Sauer, Sascha
    Max Planck Inst Mol Genet, Otto Warburg Lab, Ihnestr 73, D-14195 Berlin, Germany.;Univ Wurzburg, CU Syst Med, D-97070 Wurzburg, Germany..
    Jonasson, Inger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala Univ, Mol Med & Sci Life Lab, Dept Med Sci, Uppsala, Sweden..
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Pinto, Dalila
    Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, Mindich Child Hlth & Dev Inst, Seaver Autism Ctr Res & Treatment, New York, NY 10029 USA..
    Maciel, Patricia
    Univ Minho, Life & Hlth Sci Res Inst ICVS, Sch Hlth Sci, P-4710057 Braga, Portugal.;ICVS 3Bs PT Govt Associate Lab, Braga, Portugal..
    Identification of novel genetic causes of Rett syndrome-like phenotypes2016Inngår i: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 53, nr 3, s. 190-199Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background The aim of this work was to identify new genetic causes of Rett-like phenotypes using array comparative genomic hybridisation and a whole exome sequencing approach. Methods and results We studied a cohort of 19 Portuguese patients (16 girls, 3 boys) with a clinical presentation significantly overlapping Rett syndrome (RTT). Genetic analysis included filtering of the single nucleotide variants and indels with preference for de novo, homozygous/compound heterozygous, or maternally inherited X linked variants. Examination by MRI and muscle biopsies was also performed. Pathogenic genomic imbalances were found in two patients (10.5%): an 18q21.2 deletion encompassing four exons of the TCF4 gene and a mosaic UPD of chromosome 3. Variants in genes previously implicated in neurodevelopmental disorders (NDD) were identified in six patients (32%): de novo variants in EEF1A2, STXBP1 and ZNF238 were found in three patients, maternally inherited X linked variants in SLC35A2, ZFX and SHROOM4 were detected in two male patients and one homozygous variant in EIF2B2 was detected in one patient. Variants were also detected in five novel NDD candidate genes (26%): we identified de novo variants in the RHOBTB2, SMARCA1 and GABBR2 genes; a homozygous variant in EIF4G1; compound heterozygous variant in HTT. Conclusions Network analysis reveals that these genes interact by means of protein interactions with each other and with the known RTT genes. These findings expand the phenotypical spectrum of previously known NDD genes to encompass RTT-like clinical presentations and identify new candidate genes for RTT-like phenotypes.

  • 138.
    Lovmar, Lovisa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Ahlford, Annika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Jonsson, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Silhouette scores for assessment of SNP genotype clusters2005Inngår i: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 6, artikkel-id 35Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: High-throughput genotyping of single nucleotide polymorphisms ( SNPs) generates large amounts of data. In many SNP genotyping assays, the genotype assignment is based on scatter plots of signals corresponding to the two SNP alleles. In a robust assay the three clusters that define the genotypes are well separated and the distances between the data points within a cluster are short. "Silhouettes" is a graphical aid for interpretation and validation of data clusters that provides a measure of how well a data point was classified when it was assigned to a cluster. Thus "Silhouettes" can potentially be used as a quality measure for SNP genotyping results and for objective comparison of the performance of SNP assays at different circumstances. Results: We created a program (ClusterA) for calculating "Silhouette scores", and applied it to assess the quality of SNP genotype clusters obtained by single nucleotide primer extension ("minisequencing") in the Tag-microarray format. A Silhouette score condenses the quality of the genotype assignment for each SNP assay into a single numeric value, which ranges from 1.0, when the genotype assignment is unequivocal, down to -1.0, when the genotype assignment has been arbitrary. In the present study we applied Silhouette scores to compare the performance of four DNA polymerases in our minisequencing system by analyzing 26 SNPs in both DNA polarities in 16 DNA samples. We found Silhouettes to provide a relevant measure for the quality of SNP assays at different reaction conditions, illustrated by the four DNA polymerases here. According to our result, the genotypes can be unequivocally assigned without manual inspection when the Silhouette score for a SNP assay is > 0.65. All four DNA polymerases performed satisfactorily in our Tag-array minisequencing system. Conclusion: "Silhouette scores" for assessing the quality of SNP genotyping clusters is convenient for evaluating the quality of SNP genotype assignment, and provides an objective, numeric measure for comparing the performance of SNP assays. The program we created for calculating Silhouette scores is freely available, and can be used for quality assessment of the results from all genotyping systems, where the genotypes are assigned by cluster analysis using scatter plots.

  • 139.
    Lovmar, Lovisa
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Fock, Caroline
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Espinoza, Felix
    Bucardo, Filemon
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Bondeson, Kåre
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Microarrays for genotyping human group a rotavirus by multiplex capture and2003Inngår i: J Clin Microbiol, ISSN 0095-1137, Vol. 41, nr 11, s. 5153-8Artikkel i tidsskrift (Fagfellevurdert)
  • 140.
    Lovmar, Lovisa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Fock, Caroline
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk bakteriologi.
    Espinoza, Felix
    Bucardo, Filemon
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Bondeson, Kåre
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk virologi.
    Microarrays for genotyping human group A rotavirus by multiplex capture and type-specific primer extension2003Inngår i: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 41, nr 11, s. 5153-5158Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human group A rotavirus (HRV) is the major cause of severe gastroenteritis in infants worldwide. HRV shares the feature of a high degree of genetic diversity with many other RNA viruses, and therefore, genotyping of this organism is more complicated than genotyping of more stable DNA viruses. We describe a novel microarray-based method that allows high-throughput genotyping of RNA viruses with a high degree of polymorphism by multiplex capture and type-specific extension on microarrays. Denatured reverse transcription (RT)-PCR products derived from two outer capsid genes of clinical isolates of HRV were hybridized to immobilized capture oligonucleotides representing the most commonly occurring P and G genotypes on a microarray. Specific primer extension of the type-specific capture oligonucleotides was applied to incorporate the fluorescent nucleotide analogue cyanine 5-labeled dUTP as a detectable label. Laser scanning and fluorescence detection of the microarrays was followed by visual or computer-assisted interpretation of the fluorescence patterns generated on the microarrays. Initially, the method detected HRV in all 40 samples and correctly determined both the G and the P genotypes of 35 of the 40 strains analyzed. After modification by inclusion of additional capture oligonucleotides specific for the initially unassigned genotypes, all genotypes could be correctly defined. The results of genotyping with the microarray fully agreed with the results obtained by nucleotide sequence analysis and sequence-specific multiplex RT-PCR. Owing to its robustness, simplicity, and general utility, the microarray-based method may gain wide applicability for the genotyping of microorganisms, including highly variable RNA and DNA viruses.

  • 141.
    Lovmar, Lovisa
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Fredriksson, Mona
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Liljedahl, Ulrika
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Sigurdsson, Snaevar
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Quantitative evaluation by minisequencing and microarrays reveals accurate multiplexed SNP genotyping of whole genome amplified DNA.2003Inngår i: Nucleic Acids Res, ISSN 1362-4962, Vol. 31, nr 21, s. e129-Artikkel i tidsskrift (Annet vitenskapelig)
  • 142.
    Lovmar, Lovisa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Fredriksson, Mona
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Liljedahl, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Sigurdsson, Snaevar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Quantitative evaluation by minisequencing and microarrays reveals accurate multiplexed SNP genotyping of whole genome amplified DNA2003Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 31, nr 21, s. e129-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Whole genome amplification (WGA) procedures such as primer extension preamplification (PEP) or multiple displacement amplification (MDA) have the potential to provide an unlimited source of DNA for large-scale genetic studies. We have performed a quantitative evaluation of PEP and MDA for genotyping single nucleotide polymorphisms (SNPs) using multiplex, four-color fluorescent minisequencing in a microarray format. Forty-five SNPs were genotyped and the WGA methods were evaluated with respect to genotyping success, signal-to-noise ratios, power of genotype discrimination, yield and imbalanced amplification of alleles in the MDA product. Both PEP and MDA products provided genotyping results with a high concordance to genomic DNA. For PEP products the power of genotype discrimination was lower than for MDA due to a 2-fold lower signal-to-noise ratio. MDA products were indistinguishable from genomic DNA in all aspects studied. To obtain faithful representation of the SNP alleles at least 0.3 ng DNA should be used per MDA reaction. We conclude that the use of WGA, and MDA in particular, is a highly promising procedure for producing DNA in sufficient amounts even for genome wide SNP mapping studies.

  • 143.
    Lovmar, Lovisa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Genotyping single-nucleotide polymorphisms by minisequencing using tag arrays2005Inngår i: Microarrays in Clinical Diagnostics / [ed] Thomas O. Joos & Paolo Fortina, Totowa, N.J.: Humana Press, 2005, Vol. 114, s. 79-92Kapittel i bok, del av antologi (Annet vitenskapelig)
    Abstract [en]

    The need for large-scale and high-throughput methods for SNP genotyping has rapidly increased during the last decade. Our system, presented here, combines the highly specific genotyping principle of minisequencing with the advantages of a microarray format that allows highly multiplexed and parallel analysis. Cyclic minisequencing reactions with fluorescently labeled dideoxynucleotides (ddNTPs) are performed in solution using multiplex PCR product as template and detection primers, designed to anneal immediately adjacent and upstream of the SNP site. The detection primers carry unique 5' tag sequences and oligonucleotides complementary to the tag sequence, cTags, are immobilized on a microarray. After extension, the tagged detection primers are allowed to hybridize to the cTags; then the fluorescent signals from the array are measured, and the genotypes are deduced according to the label incorporated. The "array of arrays" format of the system, accomplished by a silicon rubber grid giving separate reaction chambers, allows either 80 or 14 samples to be analyzed for up to 200 or 600 SNPs, respectively, on a single microscope slide.

  • 144. Lovmar, Lovisa
    et al.
    Syvänen, Ann-Christine
    Multiple displacement amplification to create a long-lasting source of DNA for genetic studies.2006Inngår i: Hum Mutat, ISSN 1098-1004, Vol. 27, nr 7, s. 603-14Artikkel i tidsskrift (Annet vitenskapelig)
  • 145.
    Lundmark, Per E
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Liljedahl, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Boomsma, Dorret I
    Mannila, Heikki
    Martin, Nicholas G
    Palotie, Aarno
    Peltonen, Leena
    Perola, Markus
    Spector, Tim D
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Evaluation of HapMap data in six populations of European descent2008Inngår i: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 16, nr 9, s. 1142-1150Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We studied how well the European CEU samples used in the Haplotype Mapping Project (HapMap) represent five European populations by analyzing nuclear family samples from the Swedish, Finnish, Dutch, British and Australian (European ancestry) populations. The number of samples from each population (about 30 parent-offspring trios) was similar to that in the HapMap sample sets. A panel of 186 single nucleotide polymorphisms (SNPs) distributed over the 1.5 Mb region of the GRID2 gene on chromosome 4 was genotyped. The genotype data were compared pair-wise between the HapMap sample and the other population samples. Principal component analysis (PCA) was used to cluster the data from different populations with respect to allele frequencies and to define the markers responsible for observed variance. The only sample with detectable differences in allele frequencies was that from Kuusamo, Finland. This sample also separated from the others, including the other Finnish sample, in the PCA analysis. A set of tagSNPs was defined based on the HapMap data and applied to the samples. The tagSNPs were found to capture the genetic variation in the analyzed region at r(2)>0.8 at levels ranging from 95% in the Kuusamo sample to 87% in the Australian sample. To capture the maximal genetic variation in the region, the Kuusamo, HapMap and Australian samples required 58, 63 and 73 native tagSNPs, respectively. The HapMap CEU sample represents the European samples well for tagSNP selection, with some caution regarding estimation of allele frequencies in the Finnish Kuusamo sample, and a slight reduction in tagging efficiency in the Australian sample.

  • 146.
    Lundmark, Per
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Lundmark, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Liljedahl, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Enström, Camilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Pastinen, Tomi
    Deloukas, Panos
    Cambien, François
    Goodall, Alison H
    Ouwehand, Willem H
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Identification of trait-associated single nucleotide polymorphisms with cis-regulatory effects on long non-coding RNAsManuskript (preprint) (Annet vitenskapelig)
  • 147. Lundström, Emeli
    et al.
    Gustafsson, Johanna T
    Jönsen, Andreas
    Leonard, Dag
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Zickert, Agneta
    Elvin, Kerstin
    Sturfelt, Gunnar
    Nordmark, Gunnel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Bengtsson, Anders A
    Sundin, Ulf
    Källberg, Henrik
    Sandling, Johanna K
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Klareskog, Lars
    Gunnarsson, Iva
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Padyukov, Leonid
    Svenungsson, Elisabet
    HLA-DRB1*04/*13 alleles are associated with vascular disease and antiphospholipid antibodies in systemic lupus erythematosus2013Inngår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 72, nr 6, s. 1018-1025Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND AND OBJECTIVES:

    Vascular disease is common in systemic lupus erythematosus (SLE) and patients with antiphospholipid antibodies (aPL) are at high risk to develop arterial and venous thrombosis. Since HLA class II genotypes have been linked to the presence of pro-thrombotic aPL, we investigated the relationship between HLA-DRB1 alleles, aPL and vascular events in SLE patients.

    METHODS:

    665 SLE patients of Caucasian origin and 1403 controls were included. Previous manifestations of ischaemic heart disease, ischaemic cerebrovascular disease (ICVD) and venous thromboembolism (together referred to as any vascular events (AVE)) were tabulated. aPL were measured with ELISA. Two-digit HLA-DRB1 typing was performed by sequence-specific primer-PCR.

    RESULTS:

    HLA-DRB1*04 was more frequent among SLE patients with ICVD compared to unaffected patients. This association remained after adjustment for known traditional cardiovascular risk factors. HLA-DRB1*13 was associated with AVE. All measured specificities of aPL—cardiolipin IgG and IgM, β2-glycoprotein-1 IgG, prothrombin (PT) IgG and a positive lupus anticoagulant test were associated with HLA-DRB1*04—while HLA-DRB1*13 was associated with IgG antibodies (β2-glycoprotein-1, cardiolipin and PT). In patients with the combined risk alleles, HLA-DRB1*04/*13, there was a significant additive interaction for the outcomes AVE and ICVD.

    CONCLUSIONS:

    The HLA-DRB1*04 and HLA-DRB1*13 alleles are associated with vascular events and an aPL positive immune-phenotype in SLE. Results demonstrate that a subset of SLE patients is genetically disposed to vascular vulnerability.

  • 148. Madrigal, Irene
    et al.
    Alvarez-Mora, Maria Isabel
    Rosell, Jordi
    Rodríguez-Revenga, Laia
    Karlberg, Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sauer, Sascha
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Mila, Montserrat
    A novel splicing mutation in the IQSEC2 gene that modulates the phenotype severity in a family with intellectual disability.2016Inngår i: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 24, nr 8, s. 1117-1123Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The IQSEC2 gene is located on chromosome Xp11.22 and encodes a guanine nucleotide exchange factor for the ADP-ribosylation factor family of small GTPases. This gene is known to have a significant role in cytoskeletal organization, dendritic spine morphology and synaptic organization. Variants in IQSEC2 cause moderate to severe intellectual disability in males and a variable phenotype in females because this gene escapes from X-chromosome inactivation. Here we report on the first splicing variant in IQSEC2 (g.88032_88033del; NG_021296.1) that co-segregates in a family diagnosed with an X-linked form of ID. In a percentage of the cells, the variant activates an intraexonic splice acceptor site that abolishes 26 amino acids from the highly conserved PH domain of IQSEC2 and creates a premature stop codon 36 amino acids later in exon 13. Interestingly, the percentage of aberrant splicing seems to correlate with the severity of the disease in each patient. The impact of this variant in the target tissue is unknown, but we can hypothesize that these differences may be related to the amount of abnormal IQSEC2 transcript. To our knowledge, we are reporting a novel mechanism of IQSEC2 involvement in ID. Variants that affect splicing are related to many genetic diseases and the understanding of their role in disease expands potential opportunities for gene therapy. Modulation of aberrant splicing transcripts can become a potent therapeutic approach for many of these diseases.

  • 149. Madrigal, Irene
    et al.
    Isabel Alvarez-Mora, Maria
    Karlberg, Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Rodriguez-Revenga, Laia
    Elurbe, Dei M.
    Rabionet, Raquel
    Mur, Antonio
    Pie, Juan
    Ballesta, Francisca
    Sauer, Sascha
    Syvänen, Ann-Christine
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Mila, Montserrat
    Efficient application of next-generation sequencing for the diagnosis of rare genetic syndromes2014Inngår i: Journal of Clinical Pathology, ISSN 0021-9746, E-ISSN 1472-4146, Vol. 67, nr 12, s. 1099-1103Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims The causes of intellectual disability, which affects 1%-3% of the general population, are highly heterogeneous and the genetic defect remains unknown in around 40% of patients. The application of next-generation sequencing is changing the nature of biomedical diagnosis. This technology has quickly become the method of choice for searching for pathogenic mutations in rare uncharacterised genetic diseases. Methods Whole-exome sequencing was applied to a series of families affected with intellectual disability in order to identify variants underlying disease phenotypes. Results We present data of three families in which we identified the disease-causing mutations and which benefited from receiving a clinical diagnosis: Cornelia de Lange, Cohen syndrome and Dent-2 disease. The genetic heterogeneity and the variability in clinical presentation of these disorders could explain why these patients are difficult to diagnose. Conclusions The accessibility to next-generation sequencing allows clinicians to save much time and cost in identifying the aetiology of rare diseases. The presented cases are excellent examples that demonstrate the efficacy of next-generation sequencing in rare disease diagnosis.

  • 150. Mahajan, Anubha
    et al.
    Go, Min Jin
    Zhang, Weihua
    Below, Jennifer E
    Gaulton, Kyle J
    Ferreira, Teresa
    Horikoshi, Momoko
    Johnson, Andrew D
    Ng, Maggie C Y
    Prokopenko, Inga
    Saleheen, Danish
    Wang, Xu
    Zeggini, Eleftheria
    Abecasis, Goncalo R
    Adair, Linda S
    Almgren, Peter
    Atalay, Mustafa
    Aung, Tin
    Baldassarre, Damiano
    Balkau, Beverley
    Bao, Yuqian
    Barnett, Anthony H
    Barroso, Ines
    Basit, Abdul
    Been, Latonya F
    Beilby, John
    Bell, Graeme I
    Benediktsson, Rafn
    Bergman, Richard N
    Boehm, Bernhard O
    Boerwinkle, Eric
    Bonnycastle, Lori L
    Burtt, Noel
    Cai, Qiuyin
    Campbell, Harry
    Carey, Jason
    Cauchi, Stephane
    Caulfield, Mark
    Chan, Juliana C N
    Chang, Li-Ching
    Chang, Tien-Jyun
    Chang, Yi-Cheng
    Charpentier, Guillaume
    Chen, Chien-Hsiun
    Chen, Han
    Chen, Yuan-Tsong
    Chia, Kee-Seng
    Chidambaram, Manickam
    Chines, Peter S
    Cho, Nam H
    Cho, Young Min
    Chuang, Lee-Ming
    Collins, Francis S
    Cornelis, Marilyn C
    Couper, David J
    Crenshaw, Andrew T
    van Dam, Rob M
    Danesh, John
    Das, Debashish
    de Faire, Ulf
    Dedoussis, George
    Deloukas, Panos
    Dimas, Antigone S
    Dina, Christian
    Doney, Alex S F
    Donnelly, Peter J
    Dorkhan, Mozhgan
    van Duijn, Cornelia
    Dupuis, Josee
    Edkins, Sarah
    Elliott, Paul
    Emilsson, Valur
    Erbel, Raimund
    Eriksson, Johan G
    Escobedo, Jorge
    Esko, Tonu
    Eury, Elodie
    Florez, Jose C
    Fontanillas, Pierre
    Forouhi, Nita G
    Forsen, Tom
    Fox, Caroline
    Fraser, Ross M
    Frayling, Timothy M
    Froguel, Philippe
    Frossard, Philippe
    Gao, Yutang
    Gertow, Karl
    Gieger, Christian
    Gigante, Bruna
    Grallert, Harald
    Grant, George B
    Groop, Leif C
    Groves, Christopher J
    Grundberg, Elin
    Guiducci, Candace
    Hamsten, Anders
    Han, Bok-Ghee
    Hara, Kazuo
    Hassanali, Neelam
    Hattersley, Andrew T
    Hayward, Caroline
    Hedman, Asa K
    Herder, Christian
    Hofman, Albert
    Holmen, Oddgeir L
    Hovingh, Kees
    Hreidarsson, Astradur B
    Hu, Cheng
    Hu, Frank B
    Hui, Jennie
    Humphries, Steve E
    Hunt, Sarah E
    Hunter, David J
    Hveem, Kristian
    Hydrie, Zafar I
    Ikegami, Hiroshi
    Illig, Thomas
    Ingelsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Islam, Muhammed
    Isomaa, Bo
    Jackson, Anne U
    Jafar, Tazeen
    James, Alan
    Jia, Weiping
    Jockel, Karl-Heinz
    Jonsson, Anna
    Jowett, Jeremy B M
    Kadowaki, Takashi
    Kang, Hyun Min
    Kanoni, Stavroula
    Kao, Wen Hong L
    Kathiresan, Sekar
    Kato, Norihiro
    Katulanda, Prasad
    Keinanen-Kiukaanniemi, Sirkka M
    Kelly, Ann M
    Khan, Hassan
    Khaw, Kay-Tee
    Khor, Chiea-Chuen
    Kim, Hyung-Lae
    Kim, Sangsoo
    Kim, Young Jin
    Kinnunen, Leena
    Klopp, Norman
    Kong, Augustine
    Korpi-Hyovalti, Eeva
    Kowlessur, Sudhir
    Kraft, Peter
    Kravic, Jasmina
    Kristensen, Malene M
    Krithika, S
    Kumar, Ashish
    Kumate, Jesus
    Kuusisto, Johanna
    Kwak, Soo Heon
    Laakso, Markku
    Lagou, Vasiliki
    Lakka, Timo A
    Langenberg, Claudia
    Langford, Cordelia
    Lawrence, Robert
    Leander, Karin
    Lee, Jen-Mai
    Lee, Nanette R
    Li, Man
    Li, Xinzhong
    Li, Yun
    Liang, Junbin
    Liju, Samuel
    Lim, Wei-Yen
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Lindgren, Cecilia M
    Lindholm, Eero
    Liu, Ching-Ti
    Liu, Jian Jun
    Lobbens, Stephane
    Long, Jirong
    Loos, Ruth J F
    Lu, Wei
    Luan, Jian'an
    Lyssenko, Valeriya
    Ma, Ronald C W
    Maeda, Shiro
    Magi, Reedik
    Mannisto, Satu
    Matthews, David R
    Meigs, James B
    Melander, Olle
    Metspalu, Andres
    Meyer, Julia
    Mirza, Ghazala
    Mihailov, Evelin
    Moebus, Susanne
    Mohan, Viswanathan
    Mohlke, Karen L
    Morris, Andrew D
    Muhleisen, Thomas W
    Muller-Nurasyid, Martina
    Musk, Bill
    Nakamura, Jiro
    Nakashima, Eitaro
    Navarro, Pau
    Ng, Peng-Keat
    Nica, Alexandra C
    Nilsson, Peter M
    Njolstad, Inger
    Nothen, Markus M
    Ohnaka, Keizo
    Ong, Twee Hee
    Owen, Katharine R
    Palmer, Colin N A
    Pankow, James S
    Park, Kyong Soo
    Parkin, Melissa
    Pechlivanis, Sonali
    Pedersen, Nancy L
    Peltonen, Leena
    Perry, John R B
    Peters, Annette
    Pinidiyapathirage, Janani M
    Platou, Carl G P
    Potter, Simon
    Price, Jackie F
    Qi, Lu
    Radha, Venkatesan
    Rallidis, Loukianos
    Rasheed, Asif
    Rathmann, Wolfgang
    Rauramaa, Rainer
    Raychaudhuri, Soumya
    Rayner, N William
    Rees, Simon D
    Rehnberg, Emil
    Ripatti, Samuli
    Robertson, Neil
    Roden, Michael
    Rossin, Elizabeth J
    Rudan, Igor
    Rybin, Denis
    Saaristo, Timo E
    Salomaa, Veikko
    Saltevo, Juha
    Samuel, Maria
    Sanghera, Dharambir K
    Saramies, Jouko
    Scott, James
    Scott, Laura J
    Scott, Robert A
    Segre, Ayellet V
    Sehmi, Joban
    Sennblad, Bengt
    Shah, Nabi
    Shah, Sonia
    Shera, A Samad
    Shu, Xiao Ou
    Shuldiner, Alan R
    Sigurðsson, Gunnar
    Sijbrands, Eric
    Silveira, Angela
    Sim, Xueling
    Sivapalaratnam, Suthesh
    Small, Kerrin S
    So, Wing Yee
    Stancakova, Alena
    Stefansson, Kari
    Steinbach, Gerald
    Steinthorsdottir, Valgerdur
    Stirrups, Kathleen
    Strawbridge, Rona J
    Stringham, Heather M
    Sun, Qi
    Suo, Chen
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Takayanagi, Ryoichi
    Takeuchi, Fumihiko
    Tay, Wan Ting
    Teslovich, Tanya M
    Thorand, Barbara
    Thorleifsson, Gudmar
    Thorsteinsdottir, Unnur
    Tikkanen, Emmi
    Trakalo, Joseph
    Tremoli, Elena
    Trip, Mieke D
    Tsai, Fuu Jen
    Tuomi, Tiinamaija
    Tuomilehto, Jaakko
    Uitterlinden, Andre G
    Valladares-Salgado, Adan
    Vedantam, Sailaja
    Veglia, Fabrizio
    Voight, Benjamin F
    Wang, Congrong
    Wareham, Nicholas J
    Wennauer, Roman
    Wickremasinghe, Ananda R
    Wilsgaard, Tom
    Wilson, James F
    Wiltshire, Steven
    Winckler, Wendy
    Wong, Tien Yin
    Wood, Andrew R
    Wu, Jer-Yuarn
    Wu, Ying
    Yamamoto, Ken
    Yamauchi, Toshimasa
    Yang, Mingyu
    Yengo, Loic
    Yokota, Mitsuhiro
    Young, Robin
    Zabaneh, Delilah
    Zhang, Fan
    Zhang, Rong
    Zheng, Wei
    Zimmet, Paul Z
    Altshuler, David
    Bowden, Donald W
    Cho, Yoon Shin
    Cox, Nancy J
    Cruz, Miguel
    Hanis, Craig L
    Kooner, Jaspal
    Lee, Jong-Young
    Seielstad, Mark
    Teo, Yik Ying
    Boehnke, Michael
    Parra, Esteban J
    Chambers, John C
    Tai, E Shyong
    McCarthy, Mark I
    Morris, Andrew P
    Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility2014Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 46, nr 3, s. 234-244Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.

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