Genome-Wide Association Analysis in Primary Sclerosing Cholangitis and Ulcerative Colitis Identifies Risk Loci at GPR35 and TCF4

被引：119

作者：

Ellinghaus, David ^{[1
]}

Folseraas, Trine ^{[2
,3
,4
]}

Holm, Kristian ^{[2
,3
]}

Ellinghaus, Eva ^{[1
]}

Melum, Espen ^{[2
,3
,4
]}

Balschun, Tobias ^{[1
]}

Laerdahl, Jon K. ^{[5
,6
,7
]}

Shiryaev, Alexey ^{[2
,3
,4
]}

Gotthardt, Daniel N. ^{[8
]}

Weismueller, Tobias J. ^{[9
,10
]}

Schramm, Christoph ^{[11
]}

Wittig, Michael ^{[1
]}

Bergquist, Annika ^{[12
]}

Bjornsson, Einar ^{[13
]}

Marschall, Hanns-Ulrich ^{[13
]}

Vatn, Morten ^{[4
,14
,15
,16
,17
]}

Teufel, Andreas ^{[18
]}

Rust, Christian ^{[19
]}

Gieger, Christian ^{[20
]}

Wichmann, H-Erich ^{[21
,22
,23
]}

Runz, Heiko ^{[24
]}

Sterneck, Martina ^{[25
]}

Rupp, Christian ^{[26
]}

Braun, Felix ^{[27
]}

Weersma, Rinse K. ^{[28
,29
]}

Wijmenga, Cisca ^{[30
,31
]}

Ponsioen, Cyriel Y. ^{[32
]}

Mathew, Christopher G. ^{[33
]}

Rutgeerts, Paul ^{[34
]}

Vermeire, Severine ^{[34
]}

Schrumpf, Erik ^{[2
,4
,14
]}

Hov, Johannes R. ^{[2
,3
,4
,14
]}

Manns, Michael P. ^{[9
,10
]}

Boberg, Kirsten M. ^{[2
,14
]}

Schreiber, Stefan ^{[1
,35
]}

Franke, Andre ^{[1
,35
]}

Karlsen, Tom H. ^{[2
,3
,14
,36
]}

机构：

[1] Univ Kiel, Inst Clin Mol Biol, Kiel, Germany

[2] Natl Hosp Norway, Oslo Univ Hosp, Norwegian PSC Res Ctr, Div Canc Surg & Transplantat, N-0424 Oslo, Norway

[3] Natl Hosp Norway, Oslo Univ Hosp, Internal Med Res Inst, N-0424 Oslo, Norway

[4] Univ Oslo, Inst Clin Med, Oslo, Norway

[5] Natl Hosp Norway, Oslo Univ Hosp, Ctr Mol Biol & Neurosci, N-0424 Oslo, Norway

[6] Natl Hosp Norway, Oslo Univ Hosp, Dept Microbiol, N-0424 Oslo, Norway

[7] Univ Oslo, Dept Informat, Bioinformat Core Facil, N-0316 Oslo, Norway

[8] Univ Heidelberg Hosp, Dept Med, Heidelberg, Germany

[9] Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, Hannover, Germany

[10] Hannover Med Sch, Integrated Res & Treatment Ctr Transplantat, Hannover, Germany

[11] Univ Med Ctr Hamburg Eppendorf, Dept Med 1, Hamburg, Germany

[12] Karolinska Univ Hosp Huddinge, Dept Gastroenterol & Hepatol, Stockholm, Sweden

[13] Sahlgrens Univ Hosp, Dept Internal Med, Sect Gastroenterol & Hepatol, Gothenburg, Sweden

[14] Natl Hosp Norway, Oslo Univ Hosp, Div Canc Surg & Transplantat, Sect Gastroenterol,Dept Transplantat Med, N-0424 Oslo, Norway

[15] Akershus Univ Hosp, EpiGen Inst, Oslo, Norway

[16] Oslo Univ Hosp, Dept Gastroenterol, Oslo, Norway

[17] Univ Oslo, Inst Clin Med, Oslo, Norway

[18] Johannes Gutenberg Univ Mainz, Dept Med 1, Mainz, Germany

[19] Univ Munich, Dept Med 2, Munich, Germany

[20] Ctr Environm Hlth, Helmholtz Ctr Munich, Inst Genet Epidemiol, German Res, Neuherberg, Germany

[21] German Res Ctr Environm Hlth, Helmholtz Ctr Munich, Inst Epidemiol 1, Neuherberg, Germany

[22] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany

[23] Univ Munich, Klinikum Grosshadern, D-80539 Munich, Germany

[24] Univ Heidelberg Hosp, Dept Human Genet, Heidelberg, Germany

[25] Univ Med Ctr Hamburg Eppendorf, Dept Hepatobiliary Surg & Transplantat, Hamburg, Germany

[26] Univ Heidelberg Hosp, Dept Internal Med 4, Heidelberg, Germany

[27] Univ Hosp, Dept Gen Thorac & Transplantat Surg, Kiel, Germany

[28] Univ Groningen, Univ Med Ctr Groningen, Dept Gastroenterol & Hepatol, NL-9713 AV Groningen, Netherlands

[29] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands

[30] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands

[31] Univ Groningen, Univ Med Ctr Groningen, Groningen, Netherlands

[32] Univ Amsterdam, Acad Med Ctr, Dept Gastroenterol & Hepatol, NL-1105 AZ Amsterdam, Netherlands

[33] Kings Coll London, Div Genet & Mol Med, London WC2R 2LS, England

[34] Univ Hosp Gasthuisberg, Dept Gastroenterol, B-3000 Louvain, Belgium

[35] Univ Kiel, Dept Gen Internal Med, Kiel, Germany

[36] Univ Bergen, Inst Med, Div Gastroenterol, Bergen, Norway

来源：

HEPATOLOGY | 2013年 / 58卷 / 03期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

TRANSCRIPTION FACTOR E2-2;

D O I：

10.1002/hep.25977

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Approximately 60%-80% of patients with primary sclerosing cholangitis (PSC) have concurrent ulcerative colitis (UC). Previous genome-wide association studies (GWAS) in PSC have detected a number of susceptibility loci that also show associations in UC and other immune-mediated diseases. We aimed to systematically compare genetic associations in PSC with genotype data in UC patients with the aim of detecting new susceptibility loci for PSC. We performed combined analyses of GWAS for PSC and UC comprising 392 PSC cases, 987 UC cases, and 2,977 controls and followed up top association signals in an additional 1,012 PSC cases, 4,444 UC cases, and 11,659 controls. We discovered novel genome-wide significant associations with PSC at 2q37 [rs3749171 at G-protein-coupled receptor 35 (GPR35); P = 3.0 x 10(-9) in the overall study population, combined odds ratio [OR] and 95% confidence interval [CI] of 1.39 (1.24-1.55)] and at 18q21 [rs1452787 at transcription factor 4 (TCF4); P = 2.61 x 10(-8), OR (95% CI) = 0.75 (0.68-0.83)]. In addition, several suggestive PSC associations were detected. The GPR35 rs3749171 is a missense single nucleotide polymorphism resulting in a shift from threonine to methionine. Structural modeling showed that rs3749171 is located in the third transmembrane helix of GPR35 and could possibly alter efficiency of signaling through the GPR35 receptor. Conclusion: By refining the analysis of a PSC GWAS by parallel assessments in a UC GWAS, we were able to detect two novel risk loci at genome-wide significance levels. GPR35 shows associations in both UC and PSC, whereas TCF4 represents a PSC risk locus not associated with UC. Both loci may represent previously unexplored aspects of PSC pathogenesis. (HEPATOLOGY 2013;58:1074-1083)

引用

页码：1074 / 1083

页数：10

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