Gene-environment interactions and familial relative risks

Objectives: Parents share genes and environmental exposures with their offspring. Spouses are often unrelated and their excess of genetic sharing is low, but the similar lifestyles of spouses regarding, for example, tobacco consumption may also result in a familial clustering of disease. This study investigates the influence of gene-environment interactions on the relative risks of disease for the offspring and the spouses of affected individuals. Methods: Theoretical models were developed to explore the dependence of familial relative risks on environmental parameters (exposure frequency, relative risk of disease for exposed versus unexposed individuals, extent of environmental sharing), on genetic parameters (allele frequency, genotype relative risk and mode of inheritance), on the number of descendants in exposed versus unexposed individuals, and on the model of gene-environment interaction. Lung cancer was used as an example of a complex disease with smoking as a known risk factor. Results: The parent-offspring and the spouse-spouse relative risks of disease varied widely in the strength of the environmental and genetic components and their degree of interaction. The familial relative risk of lung cancer decreased with increasing smoking prevalence. The relationship between exposure frequency and relative risk was markedly different when genes and environment had similar effects on disease susceptibility. Conclusions: Estimates of the relative risk of disease for varying exposure frequencies may help to assess the relevance of genetic effects in disease etiology. In particular, a positive association between offspring relative risk and exposure frequency may be indicative of genes interacting with environmental factors of similar effect sizes, with the corresponding implications for gene identification studies. Copyright (C) 2008 S. Karger AG, Basel.