Journal
DIABETES
Volume 60, Issue 4, Pages 1340-1348Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db10-1119
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Funding
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health
- NIDDK [K24 DK080140]
- Indian Health Service
- National Center for Research Resources
- Department of Veterans Affairs
- Massachusetts General Hospital
- Doris Duke Charitable Foundation
- Swedish Research Council
- Novo Nordisk
- Swedish Diabetes Association
- Swedish Heart-Lung Foundation
- GlaxoSmithKline
- [R01 DK072041]
- MRC [G0001164, MC_U106179474] Funding Source: UKRI
- Medical Research Council [MC_U106179474, G0001164] Funding Source: researchfish
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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 lit 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 0.93-0.981; P < 0.0001). At baseline, a higher GRS was associated with a lower insulinogenic index (P < 0.001), confirming an impairment in beta-cell function. We detected no significant interaction between GRS and treatment, but the lifestyle intervention was effective in the highest quartile of ORS (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. Diabetes 60:1340-1348, 2011
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