TY - JOUR
T1 - Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility
AU - Franke, Andre
AU - Balschun, Tobias
AU - Karlsen, Tom H.
AU - Sventoraityte, Jurgita
AU - Nikolaus, Susanna
AU - Mayr, Gabriele
AU - Domingues, Francisco S.
AU - Albrecht, Mario
AU - Nothnagel, Michael
AU - Ellinghaus, David
AU - Sina, Christian
AU - Onnie, Clive M.
AU - Weersma, Rinse K.
AU - Stokkers, Pieter C. F.
AU - Wijmenga, Cisca
AU - Gazouli, Maria
AU - Strachan, David
AU - McArdle, Wendy L.
AU - Vermeire, Severine
AU - Rutgeerts, Paul
AU - Rosenstiel, Philip
AU - Krawczak, Michael
AU - Vatn, Morten H.
AU - Mathew, Christopher G.
AU - Schreiber, Stefan
PY - 2008/11
Y1 - 2008/11
N2 - 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.
AB - 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.
U2 - 10.1038/ng.221
DO - 10.1038/ng.221
M3 - Article
SN - 1546-1718
VL - 40
SP - 1319
EP - 1323
JO - Nature Genetics
JF - Nature Genetics
IS - 11
ER -