Gene-environment interactions and colorectal cancer risk: An umbrella review of systematic reviews and meta-analyses of observational studies

Abstract

The cause of colorectal cancer (CRC) is multifactorial, involving both genetic variants and environmental risk factors. We systematically searched the MEDLINE, EMBASE, China National Knowledge Infrastructure (CNKI) and Wanfang databases from inception to December 2016, to identify systematic reviews and meta-analyses of observational studies that investigated gene-environment (G×E) interactions in CRC risk. Then, we critically evaluated the cumulative evidence for the G×E interactions using an extension of the Human Genome Epidemiology Network's Venice criteria. Overall, 15 articles reporting systematic reviews of observational studies on 89 G×E interactions, 20 articles reporting meta-analyses of candidate gene- or single-nucleotide polymorphism-based studies on 521 G×E interactions, and 8 articles reporting 33 genome-wide G×E interaction analyses were identified. On the basis of prior and observed scores, only the interaction between rs6983267 (8q24) and aspirin use was found to have a moderate overall credibility score as well as main genetic and environmental effects. Though 5 other interactions were also found to have moderate evidence, these interaction effects were tenuous due to the lack of main genetic effects and/or environmental effects. We did not find highly convincing evidence for any interactions, but several associations were found to have moderate strength of evidence. Our conclusions are based on application of the Venice criteria which were designed to provide a conservative assessment of G×E interactions and thus do not include an evaluation of biological plausibility of an observed joint effect.

Keywords: colorectal cancer; diet; environment; gene; interaction; risk factor.

Figure 1

Flow chart of the literature search in MEDLINE, EMBASE, CNKI and Wanfang. *For the search in MEDLINE and EMBASE, we used both AND and OR to combine the keywords “G×E interactions” and “((gene* OR genom*) AND specific environmental risk factors)”, considering that there might be some publications that did not include the keyword “G×E interactions”. †For the search in CNKI and Wanfang, both strategies that included and not included specific environmental risk factors were used due to the limit of length of search strategies in these two databases.

Figure 2

Steps in assessing G×E interactions with P for interaction < 0.05 or reached genome‐wide significance thresholds. [Color figure can be viewed at wileyonlinelibrary.com]