TY - JOUR
T1 - Effects of the type 2 diabetes-associated PPARG P12A polymorphism on progression to diabetes and response to troglitazone
AU - Florez, Jose C.
AU - Jablonski, Kathleen A.
AU - Sun, Maria W.
AU - Bayley, Nick
AU - Kahn, Steven E.
AU - Shamoon, Harry
AU - Hamman, Richard F.
AU - Knowler, William C.
AU - Nathan, David M.
AU - Altshuler, David
N1 - Funding Information:
The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) provided funding to the clinical centers and the Coordinating Center for the design and conduct of the study; and the collection, management, analysis, and interpretation of the data. The Southwestern American Indian Centers were supported directly by the NIDDK and the Indian Health Service. The General Clinical Research Center Program, National Center for Research Resources supported data collection at many of the clinical centers. Funding for data collection and participant support was also provided by the Office of Research on Minority Health, the National Institute of Child Health and Human Development, the National Institute on Aging, the Centers for Disease Control and Prevention, Office of Research on Women's Health, and the American Diabetes Association. Bristol-Myers Squibb and Parke-Davis provided medication. This research was also supported, in part, by the intramural research program of the NIDDK. LifeScan Inc., Health O Meter, Hoechst Marion Roussel, Inc., Merck-Medco Managed Care, Inc., Merck and Co., Nike Sports Marketing, Slim Fast Foods Co., and Quaker Oats Co. donated materials, equipment, or medicines for concomitant conditions. McKesson BioServices Corp., Matthews Media Group, Inc., and the Henry M. Jackson Foundation provided support services under subcontract with the Coordinating Center. The opinions expressed are those of the investigators and do not necessarily reflect the views of the Indian Health Service or other funding agencies. A complete list of centers, investigators, and staff can be found in Ref. 30 . J.C.F. is supported by NIH Research Career Award 1 K23 DK65978-03. This work was supported, in part, by a Pilot and Feasibility Grant Award from the Boston Area Diabetes Endocrinology Research Center (BADERC) to J.C.F.
PY - 2007/4
Y1 - 2007/4
N2 - 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.
AB - 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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U2 - 10.1210/jc.2006-2275
DO - 10.1210/jc.2006-2275
M3 - Article
C2 - 17213274
AN - SCOPUS:34147106645
SN - 0021-972X
VL - 92
SP - 1502
EP - 1509
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 4
ER -
