Models of gene-environment interactions

A) In the most simplified example of a dichotomous genotype (for example, carriers versus non-carriers of an allele corresponding to a dominant trait), and dichotomous exposure (for example, exposed versus non-exposed), three categories of joint exposure can be compared with a reference category (for which the relative risk is, by definition, 1.0). Using this simple scheme, graph A shows the different patterns of risk that are observed in some diseases in which inherited susceptibility clearly interacts with environmental exposures to jointly determine disease risk. In the example shown here, the relative risk of developing a disease is much greater in individuals who are both genetically susceptible to the condition and have been exposed to the environmental variable (box d), than in individuals who carry the wild-type genotype and are not exposed to the environmental variable (box a), or who are either only exposed to the environment or genetically susceptible (boxes b and c, respectively). B) In the slightly more complex situation in which there are three categories of exposure, it has been proposed that genetically susceptible individuals could be at risk of disease at lower levels of exposure; in this model, the difference in risk between genotypes among individuals at the medium level of exposure is the only indication of an interaction.