title: Identification of a common variant with potential pleiotropic effect on risk of inflammatory bowel disease and colorectal cancer.
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 (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.
authors.affiliation: Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA, USA.
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authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
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authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany, German Cancer Cosortium (DKTK), Heidelberg, Germany.
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authors.lastname: Brenner
authors.affiliation: Whitman College, Walla Walla, WA, USA.
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authors.affiliation: Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD, USA.
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authors.affiliation: Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
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authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
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authors.affiliation: CHU Nantes, Service de Génétique Médicale, Nantes, France.
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authors.affiliation: Division of Hematology, Faculty of Medicine, The University of Ottawa, Ottawa, ON, Canada.
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authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
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authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
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authors.affiliation: Program in Molecular and Genetic Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
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authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
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authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA, Department of Epidemiology, Indiana University School of Public Health, Indianapolis, IN, USA.
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authors.initials: CS
authors.lastname: Fuchs
authors.affiliation: Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA, USA.
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authors.affiliation: Department of Surgery, University Health Network Toronto General Hospital, Toronto, ON, Canada.
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authors.affiliation: Division of Epidemiology, New York University School of Medicine, New York, NY, USA.
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authors.affiliation: Department of Epidemiology, Indiana University School of Public Health, Indianapolis, IN, USA.
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authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.
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authors.affiliation: Division of Epidemiology, New York University School of Medicine, New York, NY, USA.
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authors.affiliation: CHU Nantes, Service de Génétique Médicale, Nantes, France.
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authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA, Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA achan@mgh.harvard.edu shuji_ogino@dfci.harvard.edu.
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authors.affiliation: Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA, USA, Department of Epidemiology, Indiana University School of Public Health, Indianapolis, IN, USA, achan@mgh.harvard.edu shuji_ogino@dfci.harvard.edu.
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mesh_terms: D003093:Colitis, Ulcerative / Q000150:complications / Q000453:epidemiology / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D003424:Crohn Disease / Q000150:complications / Q000453:epidemiology / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D053842:Microsatellite Instability; D018895:Microsatellite Repeats / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D044465:White People