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Genome-wide investigation of gene–environment interactions in colorectal cancer

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Abstract

Colorectal cancer (CRC), one of the most frequent neoplasias worldwide, has both genetic and environmental causes. As yet, however, gene–environment (G × E) interactions in CRC have been studied mostly for a small number of candidate genes only. Therefore, we investigated the possible interaction, in CRC etiology, between single-nucleotide polymorphisms (SNPs) on the one hand, and overweight, smoking and alcohol consumption on the other, at a genome-wide level. To this end, we adopted a two-tiered approach comprising a case-only screening stage I (314 cases) and a case–control validation stage II (259 cases, 1,002 controls). Interactions with the smallest p value in stage I were verified in stage II using multiple logistic regression analysis adjusted for sex and age. In addition, we specifically studied known CRC-associated SNPs for possible G × E interactions. Upon adjustment for sex and age, and after allowing for multiple testing, however, only a single SNP (rs1944511) was found to be involved in a statistically significant interaction, namely with overweight (multiplicity-corrected p = 0.042 in stage II). Several other G × E interactions were nominally significant but failed correction for multiple testing, including a previously reported interaction between rs9929218 and alcohol consumption that also emerged in our candidate SNP study (nominal p = 0.008). Notably, none of the interactions identified in our genome-wide analysis was with a previously reported CRC-associated SNP. Our study therefore highlights the potential of an “agnostic” genome-wide approach to G × E analysis.

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Acknowledgments

This study was supported by the German Federal Ministry of Education and Research (BMBF) through the National Genome Research Network (NGFNplus 01GS0809 to M.N.) and by the German Research Foundation (DFG) through Excellence Cluster ‘Inflammation at Interfaces’ (EXC 306 to S.Si., M.N. and U.N.). None of the funding organizations had any influence upon the design, conduct, or conclusions of the study. The authors wish to thank all study participants for their commitment, and the PopGen team at Kiel for excellent technical support.

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Correspondence to Michael Krawczak.

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Ute Nöthlings and Michael Krawczak shared the last authorship.

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Siegert, S., Hampe, J., Schafmayer, C. et al. Genome-wide investigation of gene–environment interactions in colorectal cancer. Hum Genet 132, 219–231 (2013). https://doi.org/10.1007/s00439-012-1239-2

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