Updated Genetic Score Based on 34 Confirmed Type 2 Diabetes Loci Is Associated With Diabetes Incidence and Regression to Normoglycemia in the Diabetes Prevention Program

  1. for the Diabetes Prevention Program Research Group*
  1. 1Division of Endocrinology, Department of Medicine, Université de Sherbrooke, Sherbrooke, Quebec, Canada
  2. 2The Biostatistics Center, The George Washington University, Rockville, Maryland
  3. 3Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Colorado at Denver School of Medicine, Aurora, Colorado
  4. 4Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts
  5. 5Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts
  6. 6Department of Public Health and Clinical Medicine, Division of Medicine, Genetic Epidemiology and Clinical Research Group, Umeå University Hospital, Umeå, Sweden
  7. 7Department of Clinical Sciences, Lund University Diabetes Center, Lund University, Malmö, Sweden
  8. 8Department of Epidemiology, Colorado School of Public Health, University of Colorado at Denver, Aurora, Colorado
  9. 9Division of Metabolism, Endocrinology and Nutrition, Veterans’ Affairs Puget Sound Health Care System and the University of Washington, Seattle, Washington
  10. 10Baylor College of Medicine, Houston, Texas
  11. 11General Medicine Unit, Massachusetts General Hospital, Boston, Massachusetts
  12. 12Department of Medicine, Harvard Medical School, Boston, Massachusetts
  13. 13Department of Genetics, Harvard Medical School, Boston, Massachusetts
  14. 14Diabetes Research Center (Diabetes Unit), Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
  15. 15Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona
  1. Corresponding author: Jose C. Florez, jcflorez{at}partners.org and dppmail{at}biostat.bsc.gwu.edu.

Abstract

OBJECTIVE Over 30 loci have been associated with risk of type 2 diabetes at genome-wide statistical significance. Genetic risk scores (GRSs) developed from these loci predict diabetes in the general population. We tested if a GRS based on an updated list of 34 type 2 diabetes–associated loci predicted progression to diabetes or regression toward normal glucose regulation (NGR) in the Diabetes Prevention Program (DPP).

RESEARCH DESIGN AND METHODS We genotyped 34 type 2 diabetes–associated variants in 2,843 DPP participants at high risk of type 2 diabetes from five ethnic groups representative of the U.S. population, who had been randomized to placebo, metformin, or lifestyle intervention. We built a GRS by weighting each risk allele by its reported effect size on type 2 diabetes risk and summing these values. We tested its ability to predict diabetes incidence or regression to NGR in models adjusted for age, sex, ethnicity, waist circumference, and treatment assignment.

RESULTS In multivariate-adjusted models, the GRS was significantly associated with increased risk of progression to diabetes (hazard ratio [HR] = 1.02 per risk allele [95% CI 1.00–1.05]; P = 0.03) and a lower probability of regression to NGR (HR = 0.95 per risk allele [95% CI 0.93–0.98]; P < 0.0001). At baseline, a higher GRS was associated with a lower insulinogenic index (P < 0.001), confirming an impairment in β-cell function. We detected no significant interaction between GRS and treatment, but the lifestyle intervention was effective in the highest quartile of GRS (P < 0.0001).

CONCLUSIONS A high GRS is associated with increased risk of developing diabetes and lower probability of returning to NGR in high-risk individuals, but a lifestyle intervention attenuates this risk.

Footnotes

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

  • This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db10-1119/-/DC1.

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

  • *Complete lists of the members of the Diabetes Prevention Program Research Group and the DIAGRAM investigators are provided in the Supplementary Data.

  • Received August 6, 2010.
  • Accepted December 29, 2010.

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. Diabetes vol. 60 no. 4 1340-1348
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