Gene--environment interactions in the application of biomarkers of cancer susceptibility in epidemiology.

Metabolic susceptibility genes are important determinants of individual susceptibility to the effects of environmental carcinogens. These genes follow the form of 'type 2' gene-environment interaction, whereby the polymorphic genetic risk factor functions only in the presence of an environmental exposure. Two different effects of carcinogen dose have been observed for these genes. Sometimes, increasing dose leads to a decreasing interaction, so that cases with the genetic risk factor have lower exposures than those cases without it. Other examples of a direct dose effect, whereby increasing exposure leads to increased interaction, have also been described. We propose a model based on multiple logistic regression to assess the nature of the dose effect in this type of gene-environment interaction. This model allows for distinction between these two dose effects, and other effects such as protective or non-interactive effects of environmental and genetic risk factors.