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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.
Diabetes 60, 1340-1348 (2011)
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.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Genome-wide association; Life-style intervention; Insulin-resistance; Common variants; Susceptibility loci; Risk-factors; Glucose; Reclassification; Polymorphisms; Mellitus
ISSN (print) / ISBN
0012-1797
e-ISSN
1939-327X
Zeitschrift
Diabetes
Quellenangaben
Band: 60,
Heft: 4,
Seiten: 1340-1348
Verlag
American Diabetes Association
Verlagsort
Alexandria, VA.
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed