Assessing gene-treatment interactions at the FTO and INSIG2 loci on obesity-related traits in the Diabetes Prevention Program

The single nucleotide polymorphism (SNP) rs9939609 in the fat mass and obesity associated gene (FTO) and the rs7566605 SNP located 10 kb upstream of the insulin-induced gene 2 gene (INSIG2) have been proposed as risk factors for common obesity. We tested for genotype-treatment interactions on changes in obesity-related traits in the Diabetes Prevention Program (DPP). The DPP is a randomised controlled trial of 3,548 high-risk individuals from 27 participating centres throughout the USA who were originally randomised to receive metformin, troglitazone, intensive lifestyle modification or placebo to prevent the development of type 2 diabetes. Measures of adiposity from computed tomography were available in a subsample (n=908). This report focuses on the baseline and 1 year results. The minor A allele at FTO rs9939609 was positively associated with baseline BMI (p=0.003), but not with baseline adiposity or the change at 1 year in any anthropometric trait. For the INSIG2 rs7566605 genotype, the minor C allele was associated with more subcutaneous adiposity (second and third lumbar vertebrae [L2/3]) at baseline (p=0.04). During follow-up, CC homozygotes lost more weight than G allele carriers (p=0.009). In an additive model, we observed nominally significant gene-lifestyle interactions on weight change (p=0.02) and subcutaneous (L2/3 [p=0.01] and L4/5 [p=0.03]) and visceral (L2/3 [p=0.02]) adipose areas. No statistical evidence of association with physical activity energy expenditure or energy intake was observed for either genotype. Within the DPP study population, common variants in FTO and INSIG2 are nominally associated with quantitative measures of obesity, directly and possibly by interacting with metformin or lifestyle intervention. Trial registration: ClinicalTrials.gov NCT00004992 Funding: The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute on Aging (NIA), the National Institute of Child Health and Human Development (NICHD), the National Center on Minority Health and Health Disparities (NCMHD) and the Office of Research on Women's Health (ORWH).