Pan, QingDelahanty, LindaJablonski, Kathleen A.Knowler, William C.Kahn, Steven E.Florez, JoseFranks, Paul W.2014-07-072013Pan, Qing, Linda M. Delahanty, Kathleen A. Jablonski, William C. Knowler, Steven E. Kahn, Jose C. Florez, and Paul W. Franks. 2013. “Variation at the Melanocortin 4 Receptor gene and response to weight-loss interventions in the Diabetes Prevention Program.” Obesity (Silver Spring, Md.) 21 (9): E520-E526. doi:10.1002/oby.20459. http://dx.doi.org/10.1002/oby.20459.1930-7381http://nrs.harvard.edu/urn-3:HUL.InstRepos:12406958Objective: To assess associations and genotype × treatment interactions for melanocortin 4 receptor (MC4R) locus variants and obesity-related traits. Design and Methods Diabetes Prevention Program (DPP) participants (N=3,819, of whom 3,356 were genotyped for baseline and 3,234 for longitudinal analyses) were randomized into intensive lifestyle modification (diet, exercise, weight loss), metformin or placebo control. Adiposity was assessed in a subgroup (n=909) using computed tomography. All analyses were adjusted for age, sex, ethnicity and treatment. Results: The rs1943218 minor allele was nominally associated with short-term (6 month; P=0.032) and long-term (2 year; P=0.038) weight change. Eight SNPs modified response to treatment on short-term (rs17066856, rs9966412, rs17066859, rs8091237, rs17066866, rs7240064) or long-term (rs12970134, rs17066866) reduction in body weight, or diabetes incidence (rs17066829) (all Pinteraction <0.05). Conclusion: This is the first study to comprehensively assess the role of MC4R variants and weight regulation in a weight loss intervention trial. One MC4R variant was directly associated with obesity-related traits or diabetes; numerous other variants appear to influence body weight and diabetes risk by modifying the protective effects of the DPP interventions.en-USRandomized Controlled TrialLifestyleMetforminGene-Environment InteractionGeneticObesityDiabetes Prevention ProgramAdiposityJournal Article2014-07-0710.1002/oby.20459