Epidemiologic and genetic approaches in the study of gene-environment interaction: an overview of available methods.

The interest in conducting studies to examine geneenvironment interaction is increasing for most chronic and complex diseases such as cancer. This increased interest is mostly due to considerable advances in molecular genetic techniques. Gene-environment studies are motivated by different situations including: 1) The detection of major genes that do not have estimated lifetime risks that reach 100 percent (i.e., incomplete penetrance); the incomplete penetrance may result from the role of other factors in disease etiology, such as environmental factors, that may or may not interact with the genetic factors. In such a situation, the genetic factor would be considered as the major risk factor and the environmental exposure as a modifier. 2) The identification of gene-environment interaction as a common biologic process in pharmacogenetic studies of complex diseases; pharmacogenetics hypothesizes that hereditary factors that control the metabolism of carcinogens or other toxic substances may modulate risk of disease. Indeed, different genotypes (for example, GSTM1 null genotype versus nonnull) seem to respond differently to environmental risk factors. In this situation, the environmental factor would be considered as the major risk factor and the genetic factor as a modifier. 3) Inconsistent associations across studies between a disease and a suspected risk factor; one reason for the inconsistencies is that relevant risk factors may be difficult to detect, possibly due to heterogeneity in the studied populations. One source of heterogeneity could be unknown genetic susceptibility that predisposes to differential