Identification of a common variant with potential pleiotropic effect on risk of inflammatory bowel disease and colorectal cancer

GECCO, CCFR

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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 (Pheterogeneity = 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 (Pheterogeneity = 0.02) and microsatellite instability-high (MSI-high) but not microsatellite stable or MSI-low tumors (Pheterogeneity = 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.

Original languageEnglish (US)
Pages (from-to)999-1007
Number of pages9
JournalCarcinogenesis
Volume36
Issue number9
DOIs
StatePublished - Mar 24 2015

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Inflammatory Bowel Diseases
Colorectal Neoplasms
Ulcerative Colitis
Single Nucleotide Polymorphism
Microsatellite Instability
Genome-Wide Association Study
Alleles
Genetic Predisposition to Disease
Crohn Disease
Colonic Neoplasms
Neoplasms
Genetic Loci
Molecular Epidemiology
Disease Susceptibility
Microsatellite Repeats
Registries
Logistic Models
Odds Ratio

ASJC Scopus subject areas

  • Cancer Research

Cite this

Identification of a common variant with potential pleiotropic effect on risk of inflammatory bowel disease and colorectal cancer. / GECCO; CCFR.

In: Carcinogenesis, Vol. 36, No. 9, 24.03.2015, p. 999-1007.

Research output: Contribution to journalArticle

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abstract = "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 (Pheterogeneity = 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 (Pheterogeneity = 0.02) and microsatellite instability-high (MSI-high) but not microsatellite stable or MSI-low tumors (Pheterogeneity = 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.",
author = "GECCO and CCFR and Hamed Khalili and Jian Gong and Hermann Brenner and Austin, {Thomas R.} and Hutter, {Carolyn M.} and Yoshifumi Baba and Baron, {John A.} and Berndt, {Sonja I.} and St{\'e}phane B{\'e}zieau and Bette Caan and Campbell, {Peter T.} and Jenny Chang-Claude and Chanock, {Stephen J.} and Constance Chen and Li Hsu and Shuo Jiao and Conti, {David V.} and David Duggan and Fuchs, {Charles S.} and Manish Gala and Steven Gallinger and Haile, {Robert W.} and Harrison, {Tabitha A.} and Richard Hayes and Aditi Hazra and Brian Henderson and Chris Haiman and Michael Hoffmeister and Hopper, {John L.} and Jenkins, {Mark A.} and Kolonel, {Laurence N.} and S{\'e}bastien K{\"u}ry and Andrea LaCroix and {Le Marchand}, Loic and Mathieu Lemire and Lindor, {Noralane Morey} and Jing Ma and Manson, {JoAnn E.} and Teppei Morikawa and Hongmei Nan and Kimmie Ng and Newcomb, {Polly A.} and Reiko Nishihara and Potter, {John D.} and Conghui Qu and Schoen, {Robert E.} and Schumacher, {Fredrick R.} and Daniela Seminara and Darin Taverna and Thibodeau, {Stephen N}",
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AU - GECCO

AU - CCFR

AU - Khalili, Hamed

AU - Gong, Jian

AU - Brenner, Hermann

AU - Austin, Thomas R.

AU - Hutter, Carolyn M.

AU - Baba, Yoshifumi

AU - Baron, John A.

AU - Berndt, Sonja I.

AU - Bézieau, Stéphane

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AU - Campbell, Peter T.

AU - Chang-Claude, Jenny

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AU - Chen, Constance

AU - Hsu, Li

AU - Jiao, Shuo

AU - Conti, David V.

AU - Duggan, David

AU - Fuchs, Charles S.

AU - Gala, Manish

AU - Gallinger, Steven

AU - Haile, Robert W.

AU - Harrison, Tabitha A.

AU - Hayes, Richard

AU - Hazra, Aditi

AU - Henderson, Brian

AU - Haiman, Chris

AU - Hoffmeister, Michael

AU - Hopper, John L.

AU - Jenkins, Mark A.

AU - Kolonel, Laurence N.

AU - Küry, Sébastien

AU - LaCroix, Andrea

AU - Le Marchand, Loic

AU - Lemire, Mathieu

AU - Lindor, Noralane Morey

AU - Ma, Jing

AU - Manson, JoAnn E.

AU - Morikawa, Teppei

AU - Nan, Hongmei

AU - Ng, Kimmie

AU - Newcomb, Polly A.

AU - Nishihara, Reiko

AU - Potter, John D.

AU - Qu, Conghui

AU - Schoen, Robert E.

AU - Schumacher, Fredrick R.

AU - Seminara, Daniela

AU - Taverna, Darin

AU - Thibodeau, Stephen N

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N2 - 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 (Pheterogeneity = 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 (Pheterogeneity = 0.02) and microsatellite instability-high (MSI-high) but not microsatellite stable or MSI-low tumors (Pheterogeneity = 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.

AB - 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 (Pheterogeneity = 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 (Pheterogeneity = 0.02) and microsatellite instability-high (MSI-high) but not microsatellite stable or MSI-low tumors (Pheterogeneity = 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.

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