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

Division of Endocrinology, Department of Medicine, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
Diabetes (Impact Factor: 8.1). 03/2011; 60(4):1340-8. DOI: 10.2337/db10-1119
Source: PubMed


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).
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.
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).
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.

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    • "The SLC30A8 gene encodes a pancreatic islet-specific Zn transporter involved in insulin biosynthesis, maturation, and storage of pancreatic beta cells and is associated with decreased insulin secretion [9]. In addition, as expected [10,11], while most SNPs were not associated with T2D in any one racial/ethnic group, genetic risk scores calculated using all 15 previously-associated SNPs were associated with T2D for each racial/ethnic group. Some data are available on GRS and T2D risk in European-ancestry populations and results were similar to ours. "
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    • "For example, one recent study found that a set of 40 SNPs associated with T2D could predict the risk of younger people for T2D but not for older people [52]. Another study published around the same time found that 34 confirmed that T2D loci were sufficient to predict increased risk for developing the disease [53]. A more recent study has also demonstrated that T2D risk could be predicted using a set of 46 known associated variants [54]. "
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    • "Whereas recent prospective studies in populations of varying age, metabolic status, and ethnicity have shown that genetic risk is associated with incidence of type 2 diabetes (3–8), very few studies have investigated the effect of genetic variants on changes in quantitative glycemic traits over time in large study samples (3,9–11). How changes in BMI and lifestyle may interact with genetic factors to modify glucose homeostasis over time has, moreover, been even less investigated (6,12). Since the effects of common single variants are generally modest and of limited clinical significance, it is more likely that risk assessment of a combination of variants will be useful to identify subgroups at increased risk of type 2 diabetes that would require more aggressive intervention and monitoring. "
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