Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility.
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.
Institute for Clinical Molecular Biology, Christian-Albrechts-University, Kiel 24105, Germany.
Andre
A
Franke
Tobias
T
Balschun
Tom H
TH
Karlsen
Jurgita
J
Sventoraityte
Susanna
S
Nikolaus
Gabriele
G
Mayr
Francisco S
FS
Domingues
Mario
M
Albrecht
Michael
M
Nothnagel
David
D
Ellinghaus
Christian
C
Sina
Clive M
CM
Onnie
Rinse K
RK
Weersma
Pieter C F
PC
Stokkers
Cisca
C
Wijmenga
Maria
M
Gazouli
David
D
Strachan
Wendy L
WL
McArdle
Séverine
S
Vermeire
Paul
P
Rutgeerts
Philip
P
Rosenstiel
Michael
M
Krawczak
Morten H
MH
Vatn
Christopher G
CG
Mathew
Stefan
S
Schreiber
D051376:Actin-Related Protein 2-3 Complex / Q000235:genetics*; D001483:Base Sequence; D016022:Case-Control Studies; D003093:Colitis, Ulcerative / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics*; D009154:Mutation / Q000235:genetics*
D051376:Actin-Related Protein 2-3 Complex; D016753:Interleukin-10