Previously Associated Type 2 Diabetes Variants May Interact With Physical Activity to Modify the Risk of Impaired Glucose Regulation and Type 2 Diabetes: A Study of 16,003 Swedish Adults

OBJECTIVE

Recent advances in type 2 diabetes genetics have culminated in the discovery and confirmation of multiple risk variants. Two important and largely unanswered questions are whether this information can be used to identify individuals most susceptible to the adverse consequences of sedentary behavior and to predict their response to lifestyle intervention; such evidence would be mechanistically informative and provide a rationale for targeting genetically susceptible subgroups of the population.

RESEARCH DESIGN AND METHODS

Gene × physical activity interactions were assessed for 17 polymorphisms in a prospective population-based cohort of initially nondiabetic middle-aged adults. Outcomes were 1) impaired glucose regulation (IGR) versus normal glucose regulation determined with either fasting or 2-h plasma glucose concentrations (n = 16,003), 2) glucose intolerance (in mmol/l, n = 8,860), or 3) incident type 2 diabetes (n = 2,063 events).

RESULTS

Tests of gene × physical activity interactions on IGR risk for 3 of the 17 polymorphisms were nominally statistically significant:CDKN2A/B rs10811661 (P_interaction = 0.015), HNF1B rs4430796 (P_interaction = 0.026), and PPARG rs1801282 (P_interaction = 0.04). Consistent interactions were observed for the CDKN2A/B (P_interaction = 0.013) and HNF1B (P_interaction = 0.0009) variants on 2-h glucose concentrations. Where type 2 diabetes was the outcome, only one statistically significant interaction effect was observed, and this was for the HNF1B rs4430796 variant (P_interaction = 0.0004). The interaction effects for HNF1B on IGR risk and incident diabetes remained significant after correction for multiple testing (P_interaction = 0.015 and 0.0068, respectively).

CONCLUSIONS

Our observations suggest that the genetic predisposition to hyperglycemia is partially dependent on a person''s lifestyle.Recent advances in high-throughput genotyping methods have facilitated the discovery and confirmation (1–7) of multiple common genetic risk factors for type 2 diabetes. The notion of using genetic information for disease prevention is predicated on the assumption that genetic risk can be offset with drug or lifestyle intervention. Thus, studies that explore this possibility are integral to the process of translating the results of genetic association studies into preventive practice. Furthermore, because interaction effects modify the extent to which genetic risk is conveyed, with the risk varying in magnitude across the spectrum of environmental exposure, information on gene × environment interactions may help improve the sensitivity and specificity of genetic prediction models (8).In a recent report from the Diabetes Prevention Program, 10 of the previously associated type 2 diabetes risk polymorphisms were assessed in the context of a clinical trial of drug or lifestyle intervention for diabetes risk reduction (9). In that study, a single nucleotide polymorphism (SNP) at the cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) locus (rs10811661) was shown to modify the effects of lifestyle intervention on diabetes risk reduction, such that the lifestyle intervention slowed the progression to type 2 diabetes to a greater extent in those carrying the previously reported high-risk genotype at rs10811661 compared with those with the lower-risk genotypes.In the current study, we aimed to determine whether the effects of 17 previously associated type 2 diabetes gene variants on the risk of impaired glucose regulation (IGR) or incident type 2 diabetes are modified by physical activity. The study was undertaken in an ethnically homogeneous prospective population-based cohort study of ∼16,000 initially nondiabetic middle-aged adults from Sweden.