title: Genetic Predisposition to Weight Loss and Regain With Lifestyle Intervention: Analyses From the Diabetes Prevention Program and the Look AHEAD Randomized Controlled Trials.
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.
authors.affiliation: Center for Statistical Sciences, Brown University, Providence, RI.
authors.forename: George D
authors.initials: GD
authors.lastname: Papandonatos
authors.affiliation: The Biostatistics Center, George Washington University, Rockville, MD.
authors.forename: Qing
authors.initials: Q
authors.lastname: Pan
authors.affiliation: Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Pajewski
authors.affiliation: Diabetes Research Center (Diabetes Unit), Massachusetts General Hospital, Boston, MA Department of Medicine, Harvard Medical School, Boston, MA.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Delahanty
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
authors.forename: Inga
authors.initials: I
authors.lastname: Peter
authors.affiliation: Center for Statistical Sciences, Brown University, Providence, RI.
authors.forename: Bahar
authors.initials: B
authors.lastname: Erar
authors.affiliation: Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Skåne University Hospital Malmö, Malmö, Sweden.
authors.forename: Shafqat
authors.initials: S
authors.lastname: Ahmad
authors.affiliation: Genomics Platform, Broad Institute, Cambridge, MA.
authors.forename: Maegan
authors.initials: M
authors.lastname: Harden
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
authors.forename: Pierre
authors.initials: P
authors.lastname: Fontanillas
authors.affiliation: Look AHEAD Coordinating Center, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Lynne E
authors.initials: LE
authors.lastname: Wagenknecht
authors.affiliation: Division of Metabolism, Endocrinology & Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, WA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Kahn
authors.affiliation: Weight Control and Diabetes Research Center, The Miriam Hospital and The Warren Alpert Medical School of Brown University, Providence, RI.
authors.forename: Rena R
authors.initials: RR
authors.lastname: Wing
authors.affiliation: The Biostatistics Center, George Washington University, Rockville, MD.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Jablonski
authors.affiliation: Center for Translational Genomics, Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA.
authors.forename: Gordon S
authors.initials: GS
authors.lastname: Huggins
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ.
authors.forename: William C
authors.initials: WC
authors.lastname: Knowler
authors.affiliation: 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.
authors.forename: Jose C
authors.initials: JC
authors.lastname: Florez
authors.affiliation: Weight Control and Diabetes Research Center, The Miriam Hospital and The Warren Alpert Medical School of Brown University, Providence, RI paul.franks@med.lu.se dppmail@bsc.gwu.edu jeanne_mccaffery@brown.edu.
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: McCaffery
authors.affiliation: 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 paul.franks@med.lu.se dppmail@bsc.gwu.edu jeanne_mccaffery@brown.edu.
authors.forename: Paul W
authors.identifier: http://orcid.org/0000-0002-0520-7604
authors.initials: PW
authors.lastname: Franks
mesh_terms: D015992:Body Mass Index; D003131:Combined Modality Therapy; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000517:prevention & control*; D004038:Diet, Reducing; D039642:Eukaryotic Initiation Factors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008019:Life Style; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D009043:Motor Activity; D009765:Obesity / Q000150:complications / Q000235:genetics / Q000517:prevention & control / Q000628:therapy*; D050177:Overweight / Q000150:complications / Q000235:genetics / Q000517:prevention & control / Q000628:therapy*; D020641:Polymorphism, Single Nucleotide; D011236:Prediabetic State / Q000150:complications*; D012008:Recurrence; D012306:Risk; D015430:Weight Gain; D015431:Weight Loss
chemical_list: D039642:Eukaryotic Initiation Factors; C519156:MTIF3 protein, human; D024101:Mitochondrial Proteins