How to identify gene-environment interactions in a multifactorial disease: CHD as an example

CHD is a multifactorial disease, caused by both genetic and environmental factors. The inherited 'defective' genes will vary from individual to individual, and any single mutation is likely to be making only a small contribution to risk. The context dependency, i.e. the importance of environmental factors in influencing genetic risk, is now becoming evident. Thus, a mutation may have a modest effect on risk in individuals who maintain a low environmental risk, but a major effect in a high-risk environment. Methods of analysing gene-environment interactions on CHD risk will be discussed and illustrated with several examples. APOE has three common alleles, epsilon2, epsilon3 and epsilon4. The epsilon4 allele has consistently been associated with CHD risk, which has been confirmed by meta-analysis. However, when the effect of genotype on risk was considered in smokers and non-smokers separately, risk in non-smokers was similar in all APOE genotypes. By comparison, in the smokers, epsilon3 homozygotes, as expected, had an approximately 2-fold higher risk, while for epsilon4 carriers there was a significantly greater than additive effect of genotype and smoking on risk (P < 0.007). Thus, the impact of the epsilon 4 allele on CHD risk appears to be confined to current smokers, an effect that has been confirmed in several studies. Another example is the interaction between the alcohol dehydrogenase 3 gene variant and alcohol consumption on CHD risk (P < 0.001), showing the context dependency of the effect. Thus, the importance of considering environmental factors as potential genotype-risk modifiers has major public health implications.