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Genetic Predictors of Weight Loss and Weight Regain After Intensive Lifestyle Modification, Metformin Treatment, or Standard Care in the Diabetes Prevention Program

  1. Linda M. Delahanty, MS, RD1,2,
  2. Qing Pan, PHD3,
  3. Kathleen A. Jablonski, PHD3,
  4. Karol E. Watson, MD, PHD4,
  5. Jeanne M. McCaffery, PHD5,
  6. Alan Shuldiner, MD6,
  7. Steven E. Kahn, MB, CHB7,
  8. William C. Knowler, MD, DRPH8,
  9. Jose C. Florez, MD, PHD1,2,9,10,
  10. Paul W. Franks, PHD, MPHIL, MS11,12 and
  11. for the Diabetes Prevention Program Research Group*⇓
  1. 1Diabetes Research Center, Massachusetts General Hospital, Boston, Massachusetts
  2. 2Department of Medicine, Harvard Medical School, Boston, Massachusetts
  3. 3The Biostatistics Center, George Washington University, Rockville, Maryland
  4. 4David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
  5. 5Weight Control and Diabetes Research Center, The Miriam Hospital and Brown Medical School, Providence, Rhode Island
  6. 6Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, and Program in Genetics and Genomic Medicine, University of Maryland School of Medicine, Baltimore, Maryland
  7. 7Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, Washington
  8. 8National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona
  9. 9Center for Human Genetic Research, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
  10. 10Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts
  11. 11Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University Diabetes Center, Skåne University Hospital, Malmö, Sweden
  12. 12Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts
  1. Corresponding author: Paul W. Franks, paul.franks{at}med.lu.se and dppmail{at}biostat.bsc.gwu.edu.

Abstract

OBJECTIVE We tested genetic associations with weight loss and weight regain in the Diabetes Prevention Program, a randomized controlled trial of weight loss–inducing interventions (lifestyle and metformin) versus placebo.

RESEARCH DESIGN AND METHODS Sixteen obesity-predisposing single nucleotide polymorphisms (SNPs) were tested for association with short-term (baseline to 6 months) and long-term (baseline to 2 years) weight loss and weight regain (6 months to study end).

RESULTS Irrespective of treatment, the Ala12 allele at PPARG associated with short- and long-term weight loss (−0.63 and −0.93 kg/allele, P ≤ 0.005, respectively). Gene–treatment interactions were observed for short-term (LYPLAL1 rs2605100, Plifestyle*SNP = 0.032; GNPDA2 rs10938397, Plifestyle*SNP = 0.016; MTCH2 rs10838738, Plifestyle*SNP = 0.022) and long-term (NEGR1 rs2815752, Pmetformin*SNP = 0.028; FTO rs9939609, Plifestyle*SNP = 0.044) weight loss. Three of 16 SNPs were associated with weight regain (NEGR1 rs2815752, BDNF rs6265, PPARG rs1801282), irrespective of treatment. TMEM18 rs6548238 and KTCD15 rs29941 showed treatment-specific effects (Plifestyle*SNP < 0.05).

CONCLUSIONS Genetic information may help identify people who require additional support to maintain reduced weight after clinical intervention.

Footnotes

  • Clinical trial reg. no. NCT00004992, clinicaltrials.gov.

  • This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc11-1328/-/DC1.

  • ↵*A complete list of centers, investigators, staff, additional methods, results, and list of Diabetes Prevention Program Research Group investigators (Genetics version) can be found in the Supplementary Data online.

  • The opinions expressed are those of the investigators and do not necessarily reflect the views of the Indian Health Service or other funding agencies.

  • Received July 25, 2011.
  • Accepted October 23, 2011.

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. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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  1. Published online before print December 16, 2011, doi: 10.2337/dc11-1328 Diabetes Care February 2012 vol. 35 no. 2 363-366
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