Gene X Environment Interaction in Diabetic Nephropathy: The Look AHEAD Trial
This grant application responds to the Diabetic Complications Consortium’s Annual Pilot and Feasibility Program, addressing the three following areas of interest: 1) testing the role of genes of loci that arise from ongoing human genetics efforts, 2) use of relevant model systems to accelerate gene x environment studies and 3) analysis of human data and cohorts to elucidate epidemiologic/population associations relative to understanding diabetic complications. Roughly 40% of individuals with diabetes experience diabetic nephropathy (DN), substantially increasing risk for end-stage kidney disease, cardiovascular disease events and mortality. Behavioral intervention targeting weight and physical activity appears to be an environmental/behavioral intervention successful in reducing incidence of chronic kidney disease (CKD) in overweight individuals with type 2 diabetes. At the same time, genome-wide association studies (GWAS) have been successful in discovering genetic markers associated with chronic kidney disease (CKD) in the general population and DN in type 1 diabetes. The prognostic value of these genetic markers for DN among individuals with type 2 diabetes and the potential for gene x environment interaction involving weight loss, diet and physical activity remains unclear. This pilot and feasibility study will enable us to begin to determine whether human genetic discoveries in kidney disease predict the course of diabetic nephropathy among overweight or obese individuals with type 2 diabetes. Using gene x environment interaction models, we will also determine whether randomized lifestyle change involving weight loss through calorie restriction and physical activity can diminish these effects. The Look AHEAD (Action for Health and Diabetes) Study is an NIH-funded, multi-center randomized controlled trial with the primary goal of determining the health benefits of weight loss achieved through an intensive lifestyle intervention (ILI), including diet and physical activity, relative to Diabetes Support and Education (DSE) among overweight or obese individuals with type 2 diabetes (N = 4,045 with genetic consent and successful genotyping). Given the successful weight loss and associated reduction in DN over 10 years follow-up, Look AHEAD provides a unique opportunity to determine the prognostic value of single nucleotide polymorphisms (SNPs) associated with CKD in DN and whether weight loss and physical activity can blunt these associations. Support for this work will provide pilot data for a larger application seeking additional genotyping to determine common and distinct SNPs associated with incidence of nephropathy, retinopathy and neuropathy over ten years in this overweight, diabetic cohort and whether these genetic associations are mitigated through environmental intervention (GxE).

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