Effects of the type 2 diabetes-associated PPARG P12A polymorphism on progression to diabetes and response to troglitazone

Jose C. Florez, Kathleen A. Jablonski, Maria W. Sun, Nick Bayley, Steven E. Kahn, Harry Shamoon, Richard F. Hamman, William C. Knowler, David M. Nathan, David Altshuler

Research output: Contribution to journalArticle

102 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1502-1509
Number of pages8
JournalJournal of Clinical Endocrinology and Metabolism
Volume92
Issue number4
DOIs
StatePublished - Apr 2007

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troglitazone
Medical problems
Polymorphism
Type 2 Diabetes Mellitus
Glucose Intolerance
Genotype
Alanine
Insulin Resistance
Body Mass Index
Alleles
Metformin
Homozygote
Waist Circumference
Proline
Insulin
Life Style
Glucose
Cross-Sectional Studies
Placebos
Regression Analysis

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

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Effects of the type 2 diabetes-associated PPARG P12A polymorphism on progression to diabetes and response to troglitazone. / Florez, Jose C.; Jablonski, Kathleen A.; Sun, Maria W.; Bayley, Nick; Kahn, Steven E.; Shamoon, Harry; Hamman, Richard F.; Knowler, William C.; Nathan, David M.; Altshuler, David.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 92, No. 4, 04.2007, p. 1502-1509.

Research output: Contribution to journalArticle

Florez, JC, Jablonski, KA, Sun, MW, Bayley, N, Kahn, SE, Shamoon, H, Hamman, RF, Knowler, WC, Nathan, DM & Altshuler, D 2007, 'Effects of the type 2 diabetes-associated PPARG P12A polymorphism on progression to diabetes and response to troglitazone', Journal of Clinical Endocrinology and Metabolism, vol. 92, no. 4, pp. 1502-1509. https://doi.org/10.1210/jc.2006-2275
Florez, Jose C. ; Jablonski, Kathleen A. ; Sun, Maria W. ; Bayley, Nick ; Kahn, Steven E. ; Shamoon, Harry ; Hamman, Richard F. ; Knowler, William C. ; Nathan, David M. ; Altshuler, David. / Effects of the type 2 diabetes-associated PPARG P12A polymorphism on progression to diabetes and response to troglitazone. In: Journal of Clinical Endocrinology and Metabolism. 2007 ; Vol. 92, No. 4. pp. 1502-1509.
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AU - Bayley, Nick

AU - Kahn, Steven E.

AU - Shamoon, Harry

AU - Hamman, Richard F.

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AU - Nathan, David M.

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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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