Genetic Predisposition to Weight Loss and Regain With Lifestyle Intervention: Analyses From the Diabetes Prevention Program and the Look AHEAD Randomized Controlled Trials.

George D Papandonatos, Qing Pan, Nicholas M Pajewski, Linda M Delahanty, Inga Peter, Bahar Erar, Shafqat Ahmad, Maegan Harden, Ling Chen, Pierre Fontanillas, Lynne E Wagenknecht, Steven E Kahn, Rena R Wing, Kathleen A Jablonski, Gordon S Huggins, William C Knowler, Jose C Florez, Jeanne M McCaffery, Paul W Franks

Journal: Diabetes 2016;64(12):4312-21

PMID: 26253612

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Abstract

Clinically relevant weight loss is achievable through lifestyle modification, but unintentional weight regain is common. We investigated whether recently discovered genetic variants affect weight loss and/or weight regain during behavioral intervention. Participants at high-risk of type 2 diabetes (Diabetes Prevention Program [DPP]; N = 917/907 intervention/comparison) or with type 2 diabetes (Look AHEAD [Action for Health in Diabetes]; N = 2,014/1,892 intervention/comparison) were from two parallel arm (lifestyle vs. comparison) randomized controlled trials. The associations of 91 established obesity-predisposing loci with weight loss across 4 years and with weight regain across years 2-4 after a minimum of 3% weight loss were tested. Each copy of the minor G allele of MTIF3 rs1885988 was consistently associated with greater weight loss following lifestyle intervention over 4 years across the DPP and Look AHEAD. No such effect was observed across comparison arms, leading to a nominally significant single nucleotide polymorphism×treatment interaction (P = 4.3 × 10(-3)). However, this effect was not significant at a study-wise significance level (Bonferroni threshold P < 5.8 × 10(-4)). Most obesity-predisposing gene variants were not associated with weight loss or regain within the DPP and Look AHEAD trials, directly or via interactions with lifestyle.

Address: Center for Statistical Sciences, Brown University, Providence, RI.; The Biostatistics Center, George Washington University, Rockville, MD.; Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC.; Diabetes Research Center (Diabetes Unit), Massachusetts General Hospital, Boston, MA Department of Medicine, Harvard Medical School, Boston, MA.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.; Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Skåne University Hospital Malmö, Malmö, Sweden.; Genomics Platform, Broad Institute, Cambridge, MA.; Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.; Look AHEAD Coordinating Center, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC.; Division of Metabolism, Endocrinology & Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, WA.; Weight Control and Diabetes Research Center, The Miriam Hospital and The Warren Alpert Medical School of Brown University, Providence, RI.; Center for Translational Genomics, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA.; National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ.; Diabetes Research Center (Diabetes Unit), Massachusetts General Hospital, Boston, MA Department of Medicine, Harvard Medical School, Boston, MA Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.; Weight Control and Diabetes Research Center, The Miriam Hospital and The Warren Alpert Medical School of Brown University, Providence, RI [email protected] [email protected] [email protected].; Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Skåne University Hospital Malmö, Malmö, Sweden Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA [email protected] [email protected] [email protected].

DOI: 10.2337/db15-0441

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MeSH Terms: Body Mass Index, Combined Modality Therapy, Diabetes Mellitus, Type 2, Diet, Reducing, Eukaryotic Initiation Factors, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Life Style, Longitudinal Studies, Male, Middle Aged, Mitochondrial Proteins, Motor Activity, Obesity, Overweight, Polymorphism, Single Nucleotide, Prediabetic State, Recurrence, Risk, Weight Gain, Weight Loss