Variation at the Melanocortin 4 Receptor Gene and Response to Weight-Loss Interventions in the Diabetes Prevention Program

被引:28
作者
Pan, Qing [1 ]
Delahanty, Linda M. [2 ,3 ]
Jablonski, Kathleen A. [1 ]
Knowler, William C. [4 ]
Kahn, Steven E. [5 ,6 ]
Florez, Jose C. [3 ,7 ,8 ,9 ]
Franks, Paul W. [10 ,11 ,12 ]
机构
[1] George Washington Univ, Biostat Ctr, Dept Biostat & Epidemiol, Dept Stat, Rockville, MD USA
[2] Massachusetts Gen Hosp, Diabet Res Ctr, MGH Diabet Ctr, Dept Med, Boston, MA 02114 USA
[3] Harvard Univ, Sch Med, Dept Med, Boston, MA USA
[4] NIDDK, Diabet Epidemiol & Clin Res Sect, Phoenix, AZ USA
[5] VA Puget Sound Hlth Care Syst, Div Metab Endocrinol & Nutr, Seattle, WA USA
[6] Univ Washington, Seattle, WA 98195 USA
[7] Massachusetts Gen Hosp, Dept Med, Ctr Human Genet Res, Boston, MA 02114 USA
[8] Massachusetts Gen Hosp, Dept Med, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA
[9] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA
[10] Lund Univ, Dept Clin Sci, Malmo, Sweden
[11] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA
[12] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden
基金
美国国家卫生研究院; 瑞典研究理事会;
关键词
LIFE-STYLE INTERVENTION; COMMON VARIANTS; MC4R GENE; OBESITY; RISK; MASS; ASSOCIATION; DEFICIENCY; METFORMIN; GROWTH;
D O I
10.1002/oby.20459
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective: To assess associations and genotype x 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 P-interaction < 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.
引用
收藏
页码:E520 / E526
页数:7
相关论文
共 28 条
[1]   The MC4 receptor and control of appetite [J].
Adan, R. A. H. ;
Tiesjema, B. ;
Hillebrand, J. J. G. ;
la Fleur, S. E. ;
Kas, M. J. H. ;
de Krom, M. .
BRITISH JOURNAL OF PHARMACOLOGY, 2006, 149 (07) :815-827
[2]   Binge eating as a major phenotype of melanocortin 4 receptor gene mutations [J].
Branson, R ;
Potoczna, N ;
Kral, JG ;
Lentes, K ;
Hoehe, MR ;
Horber, FF .
NEW ENGLAND JOURNAL OF MEDICINE, 2003, 348 (12) :1096-1103
[3]  
Bray GA, 2000, DIABETES CARE, V23, P1619
[4]   Relation of central adiposity and body mass index to the development of diabetes in the Diabetes Prevention Program [J].
Bray, George A. ;
Jablonski, Kathleen A. ;
Fujimoto, Wilfred Y. ;
Barrett-Connor, Elizabeth ;
Haffner, Steven ;
Hanson, Robert L. ;
Hill, James O. ;
Hubbard, Van ;
Kriska, Andrea ;
Stamm, Elizabeth ;
Pi-Sunyer, F. Xavier .
AMERICAN JOURNAL OF CLINICAL NUTRITION, 2008, 87 (05) :1212-1218
[5]   Common genetic variation near MC4R is associated with waist circumference and insulin resistance [J].
Chambers, John C. ;
Elliott, Paul ;
Zabaneh, Delilah ;
Zhang, Weihua ;
Li, Yun ;
Froguel, Philippe ;
Balding, David ;
Scott, James ;
Kooner, Jaspal S. .
NATURE GENETICS, 2008, 40 (06) :716-718
[6]   Genetic Predictors of Weight Loss and Weight Regain After Intensive Lifestyle Modification, Metformin Treatment, or Standard Care in the Diabetes Prevention Program [J].
Delahanty, Linda M. ;
Pan, Qing ;
Jablonski, Icatiileen A. ;
Watson, Karol E. ;
McCaffery, Jeanne M. ;
Shuldiner, Alan ;
Kahn, Steven E. ;
Knowler, William C. ;
Florez, Jose C. ;
Franks, Paul W. .
DIABETES CARE, 2012, 35 (02) :363-366
[7]  
Diabetes Prevention Progam, 2005, DIABETES, V54, P1150
[8]   HTR1B, ADIPOR1, PPARGC1A, and CYP19A1 and Obesity in a Cohort of Caucasians and African Americans: An Evaluation of Gene-Environment Interactions and Candidate Genes [J].
Edwards, Todd L. ;
Edwards, Digna R. Velez ;
Villegas, Raquel ;
Cohen, Sarah S. ;
Buchowski, Maciej S. ;
Fowke, Jay H. ;
Schlundt, David ;
Long, Ji Rong ;
Cai, Qiuyin ;
Zheng, Wei ;
Shu, Xiao-Ou ;
Hargreaves, Margaret K. ;
Jeffrey, Smith ;
Williams, Scott M. ;
Signorello, Lisa B. ;
Blot, William J. ;
Matthews, Charles E. .
AMERICAN JOURNAL OF EPIDEMIOLOGY, 2012, 175 (01) :11-21
[9]   Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene [J].
Farooqi, IS ;
Keogh, JM ;
Yeo, GSH ;
Lank, EJ ;
Cheetham, T ;
O'Rahilly, S .
NEW ENGLAND JOURNAL OF MEDICINE, 2003, 348 (12) :1085-1095
[10]   Modulation of Blood Pressure by Central Melanocortinergic Pathways [J].
Greenfield, Jerry R. ;
Miller, Jeffrey W. ;
Keogh, Julia M. ;
Henning, Elana ;
Satterwhite, Julie H. ;
Cameron, Gregory S. ;
Astruc, Beatrice ;
Mayer, John P. ;
Brage, Soren ;
See, Teik Choon ;
Lomas, David J. ;
O'Rahilly, Stephen ;
Farooqi, I. Sadaf .
NEW ENGLAND JOURNAL OF MEDICINE, 2009, 360 (01) :44-52