Gene-Environment and Gene-Treatment Interactions in Type 2 Diabetes

Type 2 diabetes has rapidly emerged as a global health crisis. Because population-level genetic changes take many generations to occur, this epidemic is almost certainly primarily a consequence of recent environmental changes; nonetheless, diabetes does appear to occur preferentially in genetically predisposed populations, which suggests that the effects of pre-existing susceptibility genes have been triggered by recent shifts in nongenetic factors. Predisposition is influenced by the level of certain environmental exposures, personal factors, access to good-quality primary care, and by genotype. Interactions between genetic and nongenetic risk factors are hypothesized to raise diabetes risk in a synergistic manner; reciprocally, health-enhancing changes in behavior, body composition, or medication may reduce the risk of disease conveyed by genetic factors. Defining the nature of these interactions and identifying ways through which reliable observations of gene-environment interactions (GEIs) can be translated into the public health settingmight help 1) optimize targeting of health interventions to persons most likely to respond well to them, 2) improve costand health-effectiveness of existing preventive and treatment paradigms; 3) reduce unnecessary adverse consequences of interventions; 4) increase patient adherence to health practitioners’ recommendations; and 5) identify novel interventions that are beneficial only in a defined genetic subgroup of the population. In this Perspective, we describe the rationale and evidence relating to the existence of gene-environment and genetreatment interactions in type 2 diabetes. We discuss the tried, tested, and oftenfailed approaches to investigating genelifestyle interactions in type 2 diabetes; we discuss some recent developments in gene-treatment interactions (pharmacogenetics); and we look forward to the strategies that are likely to dominate these fields of research in the future. We conclude with a discussion of the requirements for translating findings from these future studies into a form where they can be used to help predict, prevent, or treat diabetes. Here we describe the rationale and evidence concerning GEIs and gene-treatment interactions in type 2 diabetes, provide an interpretation of current findings and strategies, and offer a view for their future translation.