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Submitted on October 18, 2006
Accepted on December 29, 2006
Center for Human Genetic Research and Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Departments of Medicine and Genetics, Harvard Medical School, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts; The Biostatistics Center, George Washington University, Rockville, Maryland; Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, Washington; Division of Endocrinology and Metabolism, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York; Department of Preventive Medicine and Biometrics, University of Colorado at Denver and Health Sciences Center, Denver, Colorado; and Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona
* To whom correspondence should be addressed. E-mail: jcflorez{at}partners.org.
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 (IGT) to diabetes, or responses to preventive interventions (lifestyle, metformin or troglitazone versus placebo).
Patients: 3,548 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 one year.
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% CI 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 (BMI) 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 one year.
Conclusions: The proline allele at PPARG P12A increases risk for diabetes in persons with IGT, an effect modified by BMI. In addition, PPARG P12A has little or no effect on the beneficial response to troglitazone.
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