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, GIANT Consortium, 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, Diabetes Prevention Program and the Look AHEAD Research Groups, George D Papandonatos, Qing Pan, Nicholas M Pajewski, Linda M Delahanty, Inga Peter, Bahar Erar, Shafqat Ahmad, Maegan Harden, Ling Chen, Pierre Fontanillas, GIANT Consortium, 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, Diabetes Prevention Program and the Look AHEAD Research Groups

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.

Trial registration: ClinicalTrials.gov NCT00004992 NCT00017953.

© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Figures

Figure 1
Figure 1
Model-based estimates of MTIF3 genotype effects on weight change among 60-year-old participants following lifestyle and control intervention in the Look AHEAD (A) and the DPP (B) trials. Baseline weight chosen to be representative of males and females in each study (see Table 1). Ancestry-informative principal components set at study-specific means.

References

    1. Campos DB, Palin MF, Bordignon V, Murphy BD. The ‘beneficial’ adipokines in reproduction and fertility. Int J Obes 2008;32:223–231
    1. Kuzawa CW. Adipose tissue in human infancy and childhood: an evolutionary perspective. Am J Phys Anthropol 1998;107(Suppl. 27):177–209
    1. Min J, Chiu DT, Wang Y. Variation in the heritability of body mass index based on diverse twin studies: a systematic review. Obes Rev 2013;14:871–882
    1. Speliotes EK, Willer CJ, Berndt SI, et al. .; MAGIC; Procardis Consortium . Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 2010;42:937–948
    1. Locke AE, Kahali B, Berndt SI, et al. .; LifeLines Cohort Study; ADIPOGen Consortium; AGEN-BMI Working Group; CARDIOGRAMplusC4D Consortium; CKDGen Consortium; GLGC; ICBP; MAGIC Investigators; MuTHER Consortium; MIGen Consortium; PAGE Consortium; ReproGen Consortium; GENIE Consortium; International Endogene Consortium . Genetic studies of body mass index yield new insights for obesity biology. Nature 2015;518:197–206
    1. Knowler WC, Barrett-Connor E, Fowler SE, et al. .; Diabetes Prevention Program Research Group . Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393–403
    1. Rubin RR, Fujimoto WY, Marrero DG, et al. .; DPP Research Group . The Diabetes Prevention Program: recruitment methods and results. Control Clin Trials 2002;23:157–171
    1. Delahanty LM, Pan Q, Jablonski KA, et al. .; Diabetes Prevention Program Research Group . Genetic predictors of weight loss and weight regain after intensive lifestyle modification, metformin treatment, or standard care in the Diabetes Prevention Program. Diabetes Care 2012;35:363–366
    1. McCaffery JM, Papandonatos GD, Huggins GS, et al. .; Genetic Subgroup of Look AHEAD; Look AHEAD Research Group . Human cardiovascular disease IBC chip-wide association with weight loss and weight regain in the Look AHEAD trial. Hum Hered 2013;75:160–174
    1. McCaffery JM, Papandonatos GD, Huggins GS, et al. .; Genetic Subgroup of Look AHEAD, Look AHEAD Research Group . . FTO predicts weight regain in the Look AHEAD clinical trial. Int J Obes 2013;37:1545–1552
    1. Pi-Sunyer X, Blackburn G, Brancati FL, et al. .; Look AHEAD Research Group . Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes: one-year results of the Look AHEAD trial. Diabetes Care 2007;30:1374–1383
    1. Wing RR; Look AHEAD Research Group . Long-term effects of a lifestyle intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes mellitus: four-year results of the Look AHEAD trial. Arch Intern Med 2010;170:1566–1575
    1. Ryan DH, Espeland MA, Foster GD, et al. .; Look AHEAD Research Group . Look AHEAD (Action for Health in Diabetes): design and methods for a clinical trial of weight loss for the prevention of cardiovascular disease in type 2 diabetes. Control Clin Trials 2003;24:610–628
    1. Bray G, Gregg E, Haffner S, et al. .; Look Ahead Research Group . Baseline characteristics of the randomised cohort from the Look AHEAD (Action for Health in Diabetes) study. Diab Vasc Dis Res 2006;3:202–215
    1. TIBCO Software, Inc. TIBCO Spotfire SPLUS 8.2 for Solaris/Linux User’s Guide (Version 8.2). Seattle, WA, TIBCO Software, Inc., 2010
    1. Li J, Ji L. Adjusting multiple testing in multilocus analyses using the eigenvalues of a correlation matrix. Heredity 2005;95:221–227
    1. Wing RR, Bolin P, Brancati FL, et al. .; Look AHEAD Research Group . Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med 2013;369:145–154
    1. El-Sayed Moustafa JS, Froguel P. From obesity genetics to the future of personalized obesity therapy. Nat Rev Endocrinol 2013;9:402–413
    1. Herrera BM, Lindgren CM. The genetics of obesity. Curr Diab Rep 2010;10:498–505
    1. Christian BE, Spremulli LL. Evidence for an active role of IF3mt in the initiation of translation in mammalian mitochondria. Biochemistry 2009;48:3269–3278
    1. Behrouz B, Vilariño-Güell C, Heckman MG, et al. .. Mitochondrial translation initiation factor 3 polymorphism and Parkinson’s disease. Neurosci Lett 2010;486:228–230
    1. McCaffery JM, Papandonatos GD, Peter I, et al. .; Genetic Subgroup of Look AHEAD; Look AHEAD Research Group . Obesity susceptibility loci and dietary intake in the Look AHEAD Trial. Am J Clin Nutr 2012;95:1477–1486
    1. Nettleton JA, Follis JL, Ngwa JS, et al. .. Gene × dietary pattern interactions in obesity: analysis of up to 68 317 adults of European ancestry. Hum Mol Genet 2015;24:4728–4738
    1. Li H, Wang Z, Zhou X, et al. .. Far upstream element-binding protein 1 and RNA secondary structure both mediate second-step splicing repression. Proc Natl Acad Sci U S A 2013;110:E2687–E2695
    1. Zhang J, Chen QM. Far upstream element binding protein 1: a commander of transcription, translation and beyond. Oncogene 2013;32:2907–2916
    1. Hsiao HH, Nath A, Lin CY, Folta-Stogniew EJ, Rhoades E, Braddock DT. Quantitative characterization of the interactions among c-myc transcriptional regulators FUSE, FBP, and FIR. Biochemistry 2010;49:4620–4634
    1. Sahm F, Koelsche C, Meyer J, et al. .. CIC and FUBP1 mutations in oligodendrogliomas, oligoastrocytomas and astrocytomas. Acta Neuropathol 2012;123:853–860
    1. Hoe KL, Won M, Chung KS, et al. .. Isolation of a new member of DnaJ-like heat shock protein 40 (Hsp40) from human liver. Biochim Biophys Acta 1998;1383:4–8
    1. Tsai MF, Wang CC, Chang GC, et al. .. A new tumor suppressor DnaJ-like heat shock protein, HLJ1, and survival of patients with non-small-cell lung carcinoma. J Natl Cancer Inst 2006;98:825–838
    1. Franks PW, Jablonski KA, Delahanty LM, et al. .; Diabetes Prevention Program Research Group . Assessing gene-treatment interactions at the FTO and INSIG2 loci on obesity-related traits in the Diabetes Prevention Program. Diabetologia 2008;51:2214–2223
    1. McCarthy MI. Genomics, type 2 diabetes, and obesity. N Engl J Med 2010;363:2339–2350
    1. Franks PW. Gene × environment interactions in type 2 diabetes. Curr Diab Rep 2011;11:552–561

Source: PubMed

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