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Effects of the Type 2 Diabetes-Associated PPARG P12A Polymorphism on Progression to Diabetes and Response to Troglitazone

Center for Human Genetic Research (J.C.F., M.W.S., N.B., D.A.) and Department of Medicine (J.C.F., D.M.N., D.A.), Massachusetts General Hospital, Boston, Massachusetts 02114; Departments of Medicine (J.C.F., D.M.N., D.A.) and Genetics (D.A.), Harvard Medical School, Boston, Massachusetts 02115; Program in Medical and Population Genetics (J.C.F., M.W.S., N.B., D.A.), Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142; The Biostatistics Center (K.A.J.), George Washington University, Rockville, Maryland 20852; Division of Metabolism, Endocrinology and Nutrition, Department of Medicine (S.E.K.), VA Puget Sound Health Care System and University of Washington, Seattle, Washington 98108; Division of Endocrinology and Metabolism, Department of Medicine (H.S.), Albert Einstein College of Medicine, Bronx, New York 10461; Department of Preventive Medicine and Biometrics (R.F.H.), University of Colorado at Denver and Health Sciences Center, Denver, Colorado 80262; and Diabetes Epidemiology and Clinical Research Section (W.C.K.), National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona 85014

Address all correspondence and requests for reprints to: Jose C. Florez, Diabetes Prevention Program Coordinating Center, The Biostatistics Center, George Washington University, 6110 Executive Boulevard, Suite 750, Rockville, Maryland 20852. E-mail: jcflorez{at}partners.org and dppmail{at}biostat.bsc.gwu.edu.

Context: The common P12A polymorphism in PPARG (a target for thiazolidinedione medications) has been consistently associated with type 2 diabetes.

Objective: We examined whether PPARG P12A affects progression from impaired glucose tolerance to diabetes, or responses to preventive interventions (lifestyle, metformin, or troglitazone vs. placebo).

Patients: This study included 3548 Diabetes Prevention Program participants.

Design: We performed Cox regression analysis using genotype at PPARG P12A, intervention, and their interactions as predictors of diabetes incidence. We also genotyped five other PPARG variants implicated in the response to troglitazone and assessed their effect on insulin sensitivity at 1 yr.

Results: Consistent with prior cross-sectional studies, P/P homozygotes at PPARG P12A appeared more likely to develop diabetes than alanine carriers (hazard ratio, 1.24; 95% confidence interval, 0.99–1.57; P = 0.07) with no interaction of genotype with intervention. There was a significant interaction of genotype with body mass index and waist circumference (P = 0.03 and 0.002, respectively) with the alanine allele conferring less protection in more obese individuals. Neither PPARG P12A nor five other variants significantly affected the impact of troglitazone on insulin sensitivity in 340 participants at 1 yr.

Conclusions: The proline allele at PPARG P12A increases risk for diabetes in persons with impaired glucose tolerance, an effect modified by body mass index. In addition, PPARG P12A has little or no effect on the beneficial response to troglitazone.

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