Dataset Information

Variation at the melanocortin 4 receptor gene and response to weight-loss interventions in the diabetes prevention program.

ABSTRACT: To assess associations and genotype × treatment interactions for melanocortin 4 receptor (MC4R) locus variants and obesity-related traits.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.

SUBMITTER: Pan Q

PROVIDER: S-EPMC4023472 | biostudies-other | 2013 Sep

REPOSITORIES: biostudies-other

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Variation at the melanocortin 4 receptor gene and response to weight-loss interventions in the diabetes prevention program.

Pan Qing Q Delahanty Linda M LM Jablonski Kathleen A KA Knowler William C WC Kahn Steven E SE Florez Jose C JC Franks Paul W PW

Obesity (Silver Spring, Md.) 20130625 9

<h4>Objective</h4>To assess associations and genotype × treatment interactions for melanocortin 4 receptor (MC4R) locus variants and obesity-related traits.<h4>Design and methods</h4>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 to ...[more]

PMID: 23512951

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Project description:BackgroundIn the 2.8 years of the Diabetes Prevention Program (DPP) randomised clinical trial, diabetes incidence in high-risk adults was reduced by 58% with intensive lifestyle intervention and by 31% with metformin, compared with placebo. We investigated the persistence of these effects in the long term.MethodsAll active DPP participants were eligible for continued follow-up. 2766 of 3150 (88%) enrolled for a median additional follow-up of 5.7 years (IQR 5.5-5.8). 910 participants were from the lifestyle, 924 from the metformin, and 932 were from the original placebo groups. On the basis of the benefits from the intensive lifestyle intervention in the DPP, all three groups were offered group-implemented lifestyle intervention. Metformin treatment was continued in the original metformin group (850 mg twice daily as tolerated), with participants unmasked to assignment, and the original lifestyle intervention group was offered additional lifestyle support. The primary outcome was development of diabetes according to American Diabetes Association criteria. Analysis was by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT00038727.FindingsDuring the 10.0-year (IQR 9.0-10.5) follow-up since randomisation to DPP, the original lifestyle group lost, then partly regained weight. The modest weight loss with metformin was maintained. Diabetes incidence rates during the DPP were 4.8 cases per 100 person-years (95% CI 4.1-5.7) in the intensive lifestyle intervention group, 7.8 (6.8-8.8) in the metformin group, and 11.0 (9.8-12.3) in the placebo group. Diabetes incidence rates in this follow-up study were similar between treatment groups: 5.9 per 100 person-years (5.1-6.8) for lifestyle, 4.9 (4.2-5.7) for metformin, and 5.6 (4.8-6.5) for placebo. Diabetes incidence in the 10 years since DPP randomisation was reduced by 34% (24-42) in the lifestyle group and 18% (7-28) in the metformin group compared with placebo.InterpretationDuring follow-up after DPP, incidences in the former placebo and metformin groups fell to equal those in the former lifestyle group, but the cumulative incidence of diabetes remained lowest in the lifestyle group. Prevention or delay of diabetes with lifestyle intervention or metformin can persist for at least 10 years.FundingNational Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

Project description:The Diabetes Prevention Program (DPP) lifestyle intervention reduced the incidence of type 2 diabetes mellitus (DM) among high-risk adults by 58%, with weight loss as the dominant predictor. However, it has not been adequately translated into primary care.We evaluated 2 adapted DPP lifestyle interventions among overweight or obese adults who were recruited from 1 primary care clinic and had pre-DM and/or metabolic syndrome. Participants were randomized to (1) a coach-led group intervention (n = 79), (2) a self-directed DVD intervention (n = 81), or (3) usual care (n = 81). During a 3-month intensive intervention phase, the DPP-based behavioral weight-loss curriculum was delivered by lifestyle coach-led small groups or home-based DVD. During the maintenance phase, participants in both interventions received lifestyle change coaching and support remotely-through secure email within an electronic health record system and the American Heart Association Heart360 website for weight and physical activity goal setting and self-monitoring. The primary outcome was change in body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) from baseline to 15 months.At baseline, participants had a mean (SD) age of 52.9 (10.6) years and a mean BMI of 32.0 (5.4); 47% were female; 78%, non-Hispanic white; and 17%, Asian/Pacific Islander. At month 15, the mean ± SE change in BMI from baseline was -2.2 ± 0.3 in the coach-led group vs -0.9 ± 0.3 in the usual care group (P < .001) and -1.6 ± 0.3 in the self-directed group vs usual care (P = .02). The percentages of participants who achieved the 7% DPP-based weight-loss goal were 37.0% (P = .003) and 35.9% (P = .004) in the coach-led and self-directed groups, respectively, vs 14.4% in the usual care group. Both interventions also achieved greater net improvements in waist circumference and fasting plasma glucose level.Proven effective in a primary care setting, the 2 DPP-based lifestyle interventions are readily scalable and exportable with potential for substantial clinical and public health impact.clinicaltrials.gov Identifier: NCT00842426.

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Variation at the melanocortin 4 receptor gene and response to weight-loss interventions in the diabetes prevention program.

Publications

Variation at the melanocortin 4 receptor gene and response to weight-loss interventions in the diabetes prevention program.

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