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Genotype-environment interactions in microsatellite stable/microsatellite instability-low colorectal cancer: results from a genome-wide association study.


ABSTRACT: Genome-wide association studies (GWAS) have led to the identification of a number of common susceptibility loci for colorectal cancer (CRC); however, none of these GWAS have considered gene-environment (G × E) interactions. Therefore, it is unclear whether current hits are modified by environmental exposures or whether there are additional hits whose effects are dependent on environmental exposures.We conducted a systematic search for G × E interactions using genome wide data from the Colon Cancer Family Registry that included 1,191 cases of microsatellite stable (MSS) or microsatellite instability-low (MSI-L) CRC and 999 controls genotyped using either the Illumina Human1M or Human1M-Duo BeadChip. We tested for interactions between genotypes and 14 environmental factors using 3 methods: a traditional case-control test, a case-only test, and the recently proposed 2-step method by Murcray and colleagues. All potentially significant findings were replicated in the ARCTIC Study.No G × E interactions were identified that reached genome-wide significance by any of the 3 methods. When analyzing previously reported susceptibility loci, 7 significant G × E interactions were found at a 5% significance level. We investigated these 7 interactions in an independent sample and none of the interactions were replicated.Identifying G × E interactions will present challenges in a GWAS setting. Our power calculations illustrate the need for larger sample sizes; however, as CRC is a heterogeneous disease, a tradeoff between increasing sample size and heterogeneity needs to be considered.The results from this first genome-wide analysis of G × E in CRC identify several challenges, which may be addressed by large consortium efforts.

SUBMITTER: Figueiredo JC 

PROVIDER: S-EPMC3089660 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Genotype-environment interactions in microsatellite stable/microsatellite instability-low colorectal cancer: results from a genome-wide association study.

Figueiredo Jane C JC   Lewinger Juan Pablo JP   Song Chi C   Campbell Peter T PT   Conti David V DV   Edlund Christopher K CK   Duggan Dave J DJ   Rangrej Jagadish J   Lemire Mathieu M   Hudson Thomas T   Zanke Brent B   Cotterchio Michelle M   Gallinger Steven S   Jenkins Mark M   Hopper John J   Haile Robert R   Newcomb Polly P   Potter John J   Baron John A JA   Le Marchand Loic L   Casey Graham G  

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20110225 5


<h4>Background</h4>Genome-wide association studies (GWAS) have led to the identification of a number of common susceptibility loci for colorectal cancer (CRC); however, none of these GWAS have considered gene-environment (G × E) interactions. Therefore, it is unclear whether current hits are modified by environmental exposures or whether there are additional hits whose effects are dependent on environmental exposures.<h4>Methods</h4>We conducted a systematic search for G × E interactions using g  ...[more]

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