Sequence variation in PPARG may underlie differential response to troglitazone.

Area of Science:

• Pharmacogenomics
• Metabolic Diseases
• Genetics

Background:

• Thiazolidinediones (TZDs) are PPARG agonists for type 2 diabetes treatment and prevention.
• A significant percentage of patients (30-40%) exhibit non-response to TZDs, indicated by a lack of improved insulin sensitivity (Si).
• Differential response to TZD therapy suggests a potential genetic component influencing treatment efficacy.

Purpose of the Study:

• To investigate the hypothesis that variations in the Peroxisome Proliferator-Activated Receptor Gamma (PPARG) gene influence patient response to thiazolidinedione (TZD) therapy.
• To identify specific genetic variants within the PPARG gene associated with TZD non-response in women at risk for type 2 diabetes.

Main Methods:

• Screening of approximately 40 kb of the PPARG gene in 93 Hispanic women with prior gestational diabetes from the Troglitazone In the Prevention Of Diabetes study.
• Genotyping of 131 variants (126 SNPs, 5 indel polymorphisms) and linkage disequilibrium analysis to identify haplotype blocks.
• Defining TZD nonresponse based on the lower tertile change in insulin sensitivity (Si) after 3 months of treatment.

Main Results:

• Eight PPARG variants were significantly associated with TZD response (P < 0.05).
• Three of these variants also correlated with changes in insulin sensitivity (Si) as a continuous variable.
• No significant differences in baseline demographic or clinical measures were observed between responders and nonresponders.

Conclusions:

• Genetic variations within the PPARG gene are suggested to underlie the differential response to TZD therapy.
• Identifying PPARG variants could potentially predict TZD treatment efficacy in women at risk for type 2 diabetes.
• Further research into PPARG genetics may lead to personalized approaches for TZD treatment.