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. 2012 Jun;41(3):686-704.
doi: 10.1093/ije/dys010. Epub 2012 May 16.

Recommendations and proposed guidelines for assessing the cumulative evidence on joint effects of genes and environments on cancer occurrence in humans

Paolo Boffetta  1 , Deborah M Winn, John P Ioannidis, Duncan C Thomas, Julian Little, George Davey Smith, Vincent J Cogliano, Stephen S Hecht, Daniela Seminara, Paolo Vineis, Muin J Khoury
Affiliations

Recommendations and proposed guidelines for assessing the cumulative evidence on joint effects of genes and environments on cancer occurrence in humans

Paolo Boffetta et al. Int J Epidemiol. 2012 Jun.

Abstract

We propose guidelines to evaluate the cumulative evidence of gene-environment (G × E) interactions in the causation of human cancer. Our approach has its roots in the HuGENet and IARC Monographs evaluation processes for genetic and environmental risk factors, respectively, and can be applied to common chronic diseases other than cancer. We first review issues of definitions of G × E interactions, discovery and modelling methods for G × E interactions, and issues in systematic reviews of evidence for G × E interactions, since these form the foundation for appraising the credibility of evidence in this contentious field. We then propose guidelines that include four steps: (i) score the strength of the evidence for main effects of the (a) environmental exposure and (b) genetic variant; (ii) establish a prior score category and decide on the pattern of interaction to be expected; (iii) score the strength of the evidence for interaction between the environmental exposure and the genetic variant; and (iv) examine the overall plausibility of interaction by combining the prior score and the strength of the evidence and interpret results. We finally apply the scheme to the interaction between NAT2 polymorphism and tobacco smoking in determining bladder cancer risk.

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Figures

Figure 1
Figure 1
Patterns of G × E interaction
Figure 2
Figure 2
Risk of upper aerodigestive cancer by ADH1B genetic variation, stratified by drinking intensity and smoking status. OR and 95% CI of upper aerodigestive cancer by re1229984 variant in ADH1B. Rare allele (dominant model) carriers vs common allele homozygous genotype. ORs are derived from fixed effects models and are standardized by age, sex, centre, cumulative alcohol consumption and tobacco smoking. Source: ref.
Figure 3
Figure 3
Categories for the credibility of cumulative epidemiological evidence for genetic associations
Figure 4
Figure 4
Steps in assessing G × E interactions
Figure 5
Figure 5
Assessment of NAT2, tobacco smoking and bladder cancer G × E interactions
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Comment in

References

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    1. Ioannidis JP, Boffetta P, Little J, et al. Assessment of cumulative evidence on genetic associations: interim guidelines. Int J Epidemiol. 2008;37:120–32. - PubMed
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