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

ABSTRACT: The common P12A polymorphism in PPARG (a target for thiazolidinedione medications) has been consistently associated with type 2 diabetes.We examined whether PPARG P12A affects progression from impaired glucose tolerance to diabetes, or responses to preventive interventions (lifestyle, metformin, or troglitazone vs. placebo).This study included 3548 Diabetes Prevention Program participants.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.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.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.

SUBMITTER: Florez JC

PROVIDER: S-EPMC2267936 | biostudies-literature | 2007 Apr

REPOSITORIES: biostudies-literature

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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 JC Jablonski Kathleen A KA Sun Maria W MW Bayley Nick N Kahn Steven E SE Shamoon Harry H Hamman Richard F RF Knowler William C WC Nathan David M DM Altshuler David D

The Journal of clinical endocrinology and metabolism 20070109 4

<h4>Context</h4>The common P12A polymorphism in PPARG (a target for thiazolidinedione medications) has been consistently associated with type 2 diabetes.<h4>Objective</h4>We examined whether PPARG P12A affects progression from impaired glucose tolerance to diabetes, or responses to preventive interventions (lifestyle, metformin, or troglitazone vs. placebo).<h4>Patients</h4>This study included 3548 Diabetes Prevention Program participants.<h4>Design</h4>We performed Cox regression analysis using ...[more]

PMID: 17213274

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Project description:BACKGROUND:Peroxisome proliferator-activated receptor gamma (PPAR?) is a major regulator in sepsis. Our previous study identified the enhancer polymorphism rs10865710C/G to be associated with susceptibility to sepsis in trauma patients. We performed two-stage cohort studies integrating biological experiments of potential functional variants that modify susceptibility to traumatic sepsis. METHODS:Improved multiplex ligation detection reaction (iMLDR) was used to genotype rs10865710 in 797 Han Chinese trauma patients in Chongqing. Clinical relevance was validated in 334 patients in Guizhou. The potential function of rs10865710 in transcriptional regulation was explored through a dual luciferase reporter assay and electrophoretic mobility shift assay (EMSA). Expression of PPAR? was assessed by expression quantitative trait locus (e-QTL) and western blot analyses. RESULTS:The association results confirmed rs10865710 to be significantly strongly associated with sepsis risk in trauma patients of the Chongqing and Guizhou cohorts (OR?=?1.41 (1.11-1.79), P?=?0.004 and OR?=?1.45 (1.01-2.09), P?=?0.046, both for allele-dose effect, respectively). A meta-analysis of both cohorts and a previous study indicated strong evidence for this association (OR?=?1.41 (1.17-1.71), P?=?0.0004 for the dominant model, OR?=?1.78 (1.34-2.36), P?<?0.0001 for the recessive model and OR?=?1.38 (1.20-1.58), P?<?0.0001 for the allelic model). Functional experiments verified that rs10865710 was a causative variant influencing enhancer activity (G vs. C, 0.068?±?0.004 vs. 0.096?±?0.002, P?=?0.0005) and CREB2 binding. Expression analysis also indicatevd rs10865710 genotypes to be associated with levels of PPAR? expression (P?=?9.2?×?10-5 for dominant effect and P?=?0.005 for recessive effect). CONCLUSIONS:Our study provides evidence that the enhancer-region polymorphism rs10865710 might influence transcription factor binding and regulate PPAR? expression, thus conferring susceptibility to traumatic sepsis. TRIAL REGISTRATION:ClinicalTrials.gov, NCT01713205. Registered 18 October 2012, retrospectively registered.

Project description:BACKGROUND:We investigated whether intensive glycemic control, combination therapy for dyslipidemia, and intensive blood-pressure control would limit the progression of diabetic retinopathy in persons with type 2 diabetes. Previous data suggest that these systemic factors may be important in the development and progression of diabetic retinopathy. METHODS:In a randomized trial, we enrolled 10,251 participants with type 2 diabetes who were at high risk for cardiovascular disease to receive either intensive or standard treatment for glycemia (target glycated hemoglobin level, <6.0% or 7.0 to 7.9%, respectively) and also for dyslipidemia (160 mg daily of fenofibrate plus simvastatin or placebo plus simvastatin) or for systolic blood-pressure control (target, <120 or <140 mm Hg). A subgroup of 2856 participants was evaluated for the effects of these interventions at 4 years on the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study Severity Scale (as assessed from seven-field stereoscopic fundus photographs, with 17 possible steps and a higher number of steps indicating greater severity) or the development of diabetic retinopathy necessitating laser photocoagulation or vitrectomy. RESULTS:At 4 years, the rates of progression of diabetic retinopathy were 7.3% with intensive glycemia treatment, versus 10.4% with standard therapy (adjusted odds ratio, 0.67; 95% confidence interval [CI], 0.51 to 0.87; P=0.003); 6.5% with fenofibrate for intensive dyslipidemia therapy, versus 10.2% with placebo (adjusted odds ratio, 0.60; 95% CI, 0.42 to 0.87; P=0.006); and 10.4% with intensive blood-pressure therapy, versus 8.8% with standard therapy (adjusted odds ratio, 1.23; 95% CI, 0.84 to 1.79; P=0.29). CONCLUSIONS:Intensive glycemic control and intensive combination treatment of dyslipidemia, but not intensive blood-pressure control, reduced the rate of progression of diabetic retinopathy. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov numbers, NCT00000620 for the ACCORD study and NCT00542178 for the ACCORD Eye study.)

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Dataset Information

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

Publications

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

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