Genetic and gene expression studies implicate renin and endothelin-1 in edema caused by peroxisome proliferator-activated receptor γ agonists

Objective Peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists can cause peripheral edema in susceptible individuals. To investigate the mechanistic basis underlying this adverse event we performed a candidate gene analysis of patients enrolled in clinical trials of muraglitazar, an investigational PPAR alpha/gamma dual agonist, and developed a cell culture-based gene expression assay and nonhuman primate model of edema to study the edemagenic properties of PPAR gamma agonists. Methods A total of 213 single nucleotide polymorphisms (SNPs) in 63 genes were genotyped in 730 participants. Chi-square and logistic regression analyses were used to test for association with edema. Transcriptional responses to PPAR gamma agonists were evaluated in Calu-6 cells using quantitative real-time PCR. Male Cynomolgus monkeys were treated with PPAR agonists and were evaluated for edema using MRI. Results SNPs in renin (rs2368564) and endothelin-1 (rs5370) were associated with reduced risk of edema (P = 0.003 and P = 0.028, respectively) and an SNP in beta 1 adrenergic receptor (rs1801253) was associated with increased susceptibility to edema (P = 0.034). Gene expression studies revealed that renin and endothelin-1 were regulated by PPAR gamma in Calu-6 cells. A survey of 10 PPAR gamma agonists further revealed that a compound's in vitro potency was correlated with its edemagenic potential leading to the prediction that one of three previously uncharacterized PPAR gamma agonists would cause less edema. This prediction was validated in a nonhuman primate model of PPAR gamma agonist-induced edema. Conclusion Our results implicate a key role for renin and endothelin-1 in the edema caused by PPAR gamma agonists and demonstrate how knowledge gained from pharmacogenetic studies can be applied in drug discovery.