Gene-environment interactions in the pathogenesis of type 2 diabetes and metabolism.

Gene-environment interaction can be viewed as a departure from an otherwise expected additivity of genetic and environmental factors on a given outcome measure. Important genetic and environmental factors contribute to the pathogenesis of type 2 diabetes and intermediary traits, probably modulated by their complex interaction. This paper provides an update on the current literature investigating gene-environment interactions of type 2 diabetes and metabolic phenotypes, and discusses the future perspectives of this research. Recent advances in gene-environment interaction studies of metabolism have involved LIPC, APOA5 and PPARG variation, and nutrition and physical activity, of which the most consistently replicated observations have been obtained for APOA5. Also, intervention studies of the promising TCF7L2 type 2 diabetes gene and possible future strategies are discussed. Possibly as a result of the complexity of these multifactorial diseases, recent years have seen only limited success in unravelling significant gene-environment interactions, but important insights have been gained and they hold promise for implementation in lifestyle intervention strategies. We need to evolve to more complex, but realistic, scenarios involving several genes and environmental factors. Recent progress in statistical methods allowing for higher-order interactions may make this possible.