Genetic predisposition to weight loss and regain with lifestyle intervention: analyses from the diabetes prevention program and the look AHEAD randomized controlled trials
Open accessAbstract
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.
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Physiology of the Weight-Reduced State and Its Impact on Weight Regain
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Unexpected clues emerge about why diets fail
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- Authors
- Papandonatos, G. D., Pan, Q., Pajewski, N. M., Delahanty, L. M., Peter, I., Erar, B., Ahmad, S., Harden, M., Chen, L., Fontanillas, P., GIANT Consortium, Wagenknecht, L. E., Kahn, S. E., Wing, R. R., Jablonski, K. A., Huggins, G. S., Knowler, W. C., Florez, J. C., McCaffery, J. M., Franks, P. W., & Groups, F. T. D. P. P. A. T. L. A. R.
- Affiliations
- Brown University (US)
- George Washington University (US)
- Wake Forest University Health Sciences (US)
- Harvard University (US)
- Icahn School of Medicine at Mount Sinai (US)
- Lund University (SE)
- Broad Institute (US)
- Atrium Health Wake Forest Baptist (US)
- University of Washington (US)
- Tufts Medical Center (US)
- National Institute of Diabetes and Digestive and Kidney Diseases (US)
- Diabetes Research Center (Diabetes Unit), Massachusetts General Hospital, Boston, MA
- Corresponding author
- McCaffery, Jeanne M.
- Franks, Paul W.
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2015-08-07
- Volume
- 64
- Issue
- 12
- Pages
- 4312-4321
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC4657576
- OpenAlex
- W2129893651
- Cited by
- 88
- References
- 35
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 7 · 2023: 12 · 2022: 7 · 2021: 10 · 2020: 10 · 2019: 9 · 2018: 6 · 2017: 7 · 2016: 8 · 2015: 1
- FWCI
- 5.01
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Diabetes (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Site cant be reached (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK072041-02, DK056992-14S1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Nutrition, Genetics, and Disease
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- weight regain, lifestyle intervention, type 2 diabetes prevention, single nucleotide polymorphisms, gene-treatment interaction, Diabetes Prevention Program, Look AHEAD trial, weight loss maintenance
- MeSH terms
- Combined Modality Therapy, Diabetes Mellitus, Type 2, Diet, Reducing, Female, Humans, Life Style, Longitudinal Studies, Male, Middle Aged, Motor Activity, Obesity, Prediabetic State, Recurrence, Risk, Weight Gain, Weight Loss, Body Mass Index, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Mitochondrial Proteins, Eukaryotic Initiation Factors, Overweight, Genetic Association Studies
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