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

Abstract

OBJECTIVE:

Peroxisome proliferator-activated receptor gamma (PPARgamma) 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 PPARalpha/gamma dual agonist, and developed a cell culture-based gene expression assay and nonhuman primate model of edema to study the edemagenic properties of PPARgamma 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 PPARgamma 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 beta1 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 PPARgamma in Calu-6 cells. A survey of 10 PPARgamma 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 PPARgamma agonists would cause less edema. This prediction was validated in a nonhuman primate model of PPARgamma agonist-induced edema.

CONCLUSION:

Our results implicate a key role for renin and endothelin-1 in the edema caused by PPARgamma agonists and demonstrate how knowledge gained from pharmacogenetic studies can be applied in drug discovery.

• Authors: William J Geese, William Achanzar, Cindy Rubin, Narayanan Hariharan, Peter Cheng, Lindsay Tomlinson, Nicole Ordway, Nicholas C Dracopoli, Terrye Delmonte, Lester Hui, Bala Krishnan, Greg Cosma, Koustubh Ranade
• Journal: Pharmacogenetics and genomics (Pharmacogenet Genomics) Vol. 18 Issue 10 Pg. 903-10 (Oct 2008) ISSN: 1744-6872 [Print] United States
• PMID: 18794727 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Endothelin-1
• Oxazoles
• PPAR gamma
• Renin
• Glycine
• muraglitazar

Topics

• Animals
• Diabetes Mellitus, Type 2 (drug therapy, genetics)
• Edema (metabolism)
• Endothelin-1 (biosynthesis)
• Female
• Gene Expression Regulation
• Glycine (analogs & derivatives, pharmacology)
• Humans
• Macaca fascicularis
• Male
• Oxazoles (pharmacology)
• PPAR gamma (agonists, metabolism)
• Pharmacogenetics (methods)
• Polymorphism, Single Nucleotide
• Regression Analysis
• Renin (biosynthesis)