Experimental studies offer unique promise for validating G×E interactions, as both exposure and genotypes can be carefully controlled through randomization. Model organisms are commonly used for evaluating genetic modifiers of drug response; for example, Koch and Britton123 used selective breeding of rats on aerobic capacity to study gene-diet interactions in body weight and various metabolic markers. In human challenge studies, a randomized crossover design is typically used, in which volunteers are exposed to one or more environmental exposures in random order. In one intra-nasal challenge study of allergen alone or with diesel exhaust particles, various immunological responses were measured124. Stratified analyses revealed that those with the GSTM1 null or GSTP1 I/I genotypes had significantly larger increases in IgE and histamine levels after diesel challenge. Subjects were not preselected on the basis of genotype, so results were limited by the relatively small numbers of subjects with the susceptible genotypes. Challenge studies nested within epidemiologic cohorts for which genotypes (and possibly various outcomes) are already available could be more powerful.
