Identification of a common variant with potential pleiotropic effect on risk of inflammatory bowel disease and colorectal cancer
Creators: name: Casey, Graham
name: Taverna, Darin
name: Gala, Manish
name: Wactawski-Wende, Jean
name: Hopper, John L.
name: Chan, Andrew T.
name: Haiman, Chris
name: Hsu, Li
name: Hutter, Carolyn M.
name: Henderson, Brian
name: Lindor, Noralane M.
name: Nan, Hongmei
name: Hudson, Thomas J.
name: Gallinger, Steven
name: Le Marchand, Loic
name: Khalili, Hamed
name: Austin, Thomas R.
name: Bézieau, Stéphane
name: Nishihara, Reiko
name: White, Emily
name: Ogino, Shuji
name: Haile, Robert W.
name: Kraft, Peter
name: Chanock, Stephen J.
name: Conti, David V.
name: LaCroix, Andrea
name: Newcomb, Polly A.
name: Caan, Bette
name: Baron, John A.
name: Qu, Conghui
name: Harrison, Tabitha A.
name: Wu, Kana
name: Baba, Yoshifumi
name: Küry, Sébastien
name: Morikawa, Teppei
name: Campbell, Peter T.
name: Jiao, Shuo
name: Chang-Claude, Jenny
name: Zanke, Brent W.
name: Ng, Kimmie
name: Slattery, Martha L.
name: Berndt, Sonja I.
name: Duggan, David
name: Manson, Jo Ann E.
name: Schumacher, Fredrick R.
name: Hayes, Richard
name: Chen, Constance
name: Seminara, Daniela
name: Kolonel, Laurence N.
name: Hoffmeister, Michael
name: Schoen, Robert E.
name: Jenkins, Mark A.
name: Gong, Jian
name: Fuchs, Charles S.
name: Lemire, Mathieu
name: Hazra, Aditi
name: Potter, John D.
name: Ma, Jing
name: Brenner, Hermann
name: Peters, Ulrike
name: Thibodeau, Stephen
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2015

description: Although genome-wide association studies (GWAS) have separately identified many genetic susceptibility loci for ulcerative colitis (UC), Crohn’s disease (CD) and colorectal cancer (CRC), there has been no large-scale examination for pleiotropy, or shared genetic susceptibility, for these conditions. We used logistic regression modeling to examine the associations of 181 UC and CD susceptibility variants previously identified by GWAS with risk of CRC using data from the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. We also examined associations of significant variants with clinical and molecular characteristics in a subset of the studies. Among 11794 CRC cases and 14190 controls, rs11676348, the susceptibility single nucleotide polymorphism (SNP) for UC, was significantly associated with reduced risk of CRC (P = 7E−05). The multivariate-adjusted odds ratio of CRC with each copy of the T allele was 0.93 (95% CI 0.89–0.96). The association of the SNP with risk of CRC differed according to mucinous histological features (P heterogeneity = 0.008). In addition, the (T) allele was associated with lower risk of tumors with Crohn’s-like reaction but not tumors without such immune infiltrate (P heterogeneity = 0.02) and microsatellite instability-high (MSI-high) but not microsatellite stable or MSI-low tumors (P heterogeneity = 0.03). The minor allele (T) in SNP rs11676348, located downstream from CXCR2 that has been implicated in CRC progression, is associated with a lower risk of CRC, particularly tumors with a mucinous component, Crohn’s-like reaction and MSI-high. Our findings offer the promise of risk stratification of inflammatory bowel disease patients for complications such as CRC.