Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility

被引：476

作者：

Franke, Andre ^{[1
]}

Balschun, Tobias ^{[1
]}

Karlsen, Tom H. ^{[2
]}

Sventoraityte, Jurgita ^{[1
]}

Nikolaus, Susanna ^{[3
,4
]}

Mayr, Gabriele ^{[5
]}

Domingues, Francisco S. ^{[5
]}

Albrecht, Mario ^{[5
]}

Nothnagel, Michael ^{[6
]}

Ellinghaus, David ^{[1
]}

Sina, Christian ^{[3
,4
]}

Onnie, Clive M. ^{[7
]}

Weersma, Rinse K. ^{[8
,9
]}

Stokkers, Pieter C. F. ^{[10
]}

Wijmenga, Cisca ^{[9
,11
]}

Gazouli, Maria ^{[12
]}

Strachan, David ^{[13
]}

McArdle, Wendy L. ^{[14
]}

Vermeire, Severine ^{[15
]}

Rutgeerts, Paul ^{[15
]}

Rosenstiel, Philip ^{[1
]}

Krawczak, Michael ^{[6
]}

Vatn, Morten H. ^{[2
,16
]}

Mathew, Christopher G. ^{[7
]}

Schreiber, Stefan ^{[1
,4
]}

机构：

[1] Univ Kiel, Inst Clin Mol Biol, D-24105 Kiel, Germany

[2] Rikshosp Univ Hosp, Dept Med, N-0027 Oslo, Norway

[3] Univ Kiel, Poppgen Biobank, D-24105 Kiel, Germany

[4] Univ Kiel, Univ Hosp Schleswig Holstein, Dept Gen Internal Med, D-24105 Kiel, Germany

[5] Max Planck Inst Informat, D-66123 Saarbrucken, Germany

[6] Univ Kiel, Inst Med Informat & Stat, D-24105 Kiel, Germany

[7] Kings Coll London, Sch Med, Dept Med & Mol Genet, London SE1 9RT, England

[8] Univ Med Ctr Groningen, Dept Gastroenterol & Hepatol, NL-9700 RB Groningen, Netherlands

[9] Univ Groningen, NL-9700 RB Groningen, Netherlands

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

[11] Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands

[12] Univ Athens, Sch Med, Dept Biol, GR-11527 Athens, Greece

[13] St Georgess Univ, Div Community Hlth Sci, London SW17 0RE, England

[14] Univ Bristol, Dept Social Med, ALSPAC, Bristol BS8 1TQ, Avon, England

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

[16] Akershus Univ Hosp, Fac Med, N-1474 Oslo, Norway

来源：

NATURE GENETICS | 2008年 / 40卷 / 11期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

D O I：

10.1038/ng.221

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Inflammatory bowel disease (IBD) typically manifests as either ulcerative colitis (UC) or Crohn's disease (CD). Systematic identification of susceptibility genes for IBD has thus far focused mainly on CD, and little is known about the genetic architecture of UC. Here we report a genome-wide association study with 440,794 SNPs genotyped in 1,167 individuals with UC and 777 healthy controls. Twenty of the most significantly associated SNPs were tested for replication in three independent European case-control panels comprising a total of 1,855 individuals with UC and 3,091 controls. Among the four consistently replicated markers, SNP rs3024505 immediately flanking the IL10 (interleukin 10) gene on chromosome 1q32.1 showed the most significant association in the combined verification samples (P = 1.35 x 10(-12); OR = 1.46 (1.31-1.62)). The other markers were located in ARPC2 and in the HLA-BTNL2 region. Association between rs3024505 and CD (1,848 cases, 1,804 controls) was weak (P = 0.013; OR = 1.17 (1.01-1.34)). IL10 is an immunosuppressive cytokine that has long been proposed to influence IBD pathophysiology. Our findings strongly suggest that defective IL10 function is central to the pathogenesis of the UC subtype of IBD.

引用

页码：1319 / 1323

页数：5

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