Gene-environment interactions in human disease: nuisance or opportunity?

Abstract

Many environmental risk factors for common, complex human diseases have been revealed by epidemiologic studies, but how genotypes at specific loci modulate individual responses to environmental risk factors is largely unknown. Gene-environment interactions will be missed in genome-wide association studies and could account for some of the 'missing heritability' for these diseases. In this review, we focus on asthma as a model disease for studying gene-environment interactions because of relatively large numbers of candidate gene-environment interactions with asthma risk in the literature. Identifying these interactions using genome-wide approaches poses formidable methodological problems, and elucidating molecular mechanisms for these interactions has been challenging. We suggest that studying gene-environment interactions in animal models, although more tractable, might not be sufficient to shed light on the genetic architecture of human diseases. Lastly, we propose avenues for future studies to find gene-environment interactions.

Figure 1

Risk and Protection Factors Influence Asthma Risk Throughout the Lifecycle. Epidemiologic studies of asthma have established numerous risk and protection factors that exert their effects at specific stages of the lifecycle. The relationship of some investigated exposures that have equivocal associations with risk or protection are not shown. These include breastfeeding effects and cat in the home at birth on subsequent risk for asthma in the child, as examples. A. Environmental exposures that have been associated with increased risk for asthma. B. Stages of the lifecycle that are “sensitive” to the epidemiologic risk and protective factors. C. Environmental exposures associated with protection from asthma.

Figure 2

Types of GEIs. The yellow line in each panel corresponds to risk in exposed individuals; the red line corresponds to risk in non-exposed individuals. Examples from this review that illustrate each type of interaction are shown below the panels. It is notable that no clear examples of specific SNPs or genes involved in GEIs limited to non-exposed individuals were reported in the studies reviewed here, including the recent GWIS of farming exposures and asthma. Not all interactions shown have been replicated or substantiated by other reports in the literature.