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Sequence Variation in PPARG May Underlie Differential Response to Troglitazone

¹ Genetic Basis of Human Disease Division, Translational Genomics Research Institute, Phoenix, Arizona
² Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California
³ Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California

Thiazolidinediones (TZDs) are peroxisome proliferator–activated receptor- (PPARG) agonists used to treat type 2 diabetes. TZDs can also be used to reduce rates of type 2 diabetes in at-risk individuals. However, a large fraction of TZD-treated patients (30–40%) do not respond to TZD treatment with an improvement in insulin sensitivity (S_i). We hypothesized that variation within the gene encoding PPARG may underlie this differential response to TZD therapy. We screened 40 kb of PPARG in 93 nondiabetic Hispanic women (63 responders and 30 nonresponders) with previous gestational diabetes who had participated in the Troglitazone In the Prevention Of Diabetes study. TZD nonresponse was defined as the lower tertile in change in S_i after 3 months of treatment. Baseline demographic and clinical measures were not different between responders and nonresponders. We identified and genotyped 131 variants including 126 single nucleotide polymorphisms and 5 insertion-deletion polymorphisms. Linkage disequilibrium analysis identified five haplotype blocks. Eight variants were associated with TZD response (P < 0.05). Three variants were also associated with changes in S_i as a continuous variable. Our results suggest that PPARG variation may underlie response to TZD therapy in women at risk for type 2 diabetes.

Abbreviations: BAC, bacterial artificial chromosome; IVGTT, intravenous glucose tolerance test; MAF, minor allele frequency; PPARG, peroxisome proliferator–activated receptor-; SNP, single nucleotide polymorphism; TRIPOD, Troglitazone in the Prevention of Diabetes; TZD, thiazolidinedione

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