*A list of Diabetes Prevention Program Research Group investigators is provided in the Appendix
Variation at the melanocortin 4 receptor gene and response to weight-loss interventions in the diabetes prevention program
Article first published online: 25 JUN 2013
Copyright © 2013 The Obesity Society
Volume 21, Issue 9, pages E520–E526, September 2013
How to Cite
Pan, Q., Delahanty, L. M., Jablonski, K. A., Knowler, W. C., Kahn, S. E., Florez, J. C., Franks, P. W. and Diabetes Prevention Program Research Group (2013), Variation at the melanocortin 4 receptor gene and response to weight-loss interventions in the diabetes prevention program. Obesity, 21: E520–E526. doi: 10.1002/oby.20459
Disclosure: The authors have no competing interests.
Funding agents: The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health provided funding to the clinical centers and the Coordinating Center for the design and conduct of the study; collection, management, analysis, and interpretation of the data (U01 DK048489). The Southwestern American Indian Centers were supported directly by the NIDDK and the Indian Health Service. The General Clinical Research Center Program, National Center for Research Resources supported data collection at many of the clinical centers. Funding for data collection and participant support was also provided by the Office of Research on Minority Health, the National Institute of Child Health and Human Development, the National Institute on Aging, the Centers for Disease Control and Prevention, the Office of Research on Women's Health, the Department of Veterans Affairs, and the American Diabetes Association. This research was also supported, in part, by the intramural research program of the NIDDK. McKesson BioServices Corp., Matthews Media Group, Inc., and the Henry M. Jackson Foundation provided support services under subcontract with the Coordinating Center. This work was funded by R01 DK072041-02 to JCF and KAJ (PWF and WCK are unpaid co-investigators). PWF was supported by grants from Novo Nordisk, the Swedish Research Council, the Swedish Heart-Lung Foundation and the Swedish Diabetes Association. SEK is supported in part by the Department of Veterans Affairs. JCF has received consulting honoraria from Novartis, Lilly and Pfizer. No other potential conflict of interest is declared by any author.
Author contributions: QP, LMD, LCF, and PWF designed the research; WCK and SEK conducted the research; QP and KAJ performed the statistical analysis; QP and PWF wrote the article; QP and PWF have primary responsibility for final content. All authors contributed with critical comments on the article and approved its submission.
- Issue published online: 23 SEP 2013
- Article first published online: 25 JUN 2013
- Accepted manuscript online: 20 MAR 2013 02:17AM EST
- Manuscript Accepted: 5 MAR 2013
- Manuscript Received: 25 SEP 2012
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.
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).
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.