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


CONCLUSIONS
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.
Geese
William J
WJ
R and D, Bristol Myers Squibb Co, Princeton, New Jersey 08543-5400, USA. william.geese@bms.com
Achanzar
William
W
Rubin
Cindy
C
Hariharan
Narayanan
N
Cheng
Peter
P
Tomlinson
Lindsay
L
Ordway
Nicole
N
Dracopoli
Nicholas C
NC
Delmonte
Terrye
T
Hui
Lester
L
Krishnan
Bala
B
Cosma
Greg
G
Ranade
Koustubh
K
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics*; D004487:Edema / Q000378:metabolism*; D019332:Endothelin-1 / Q000096:biosynthesis*; D005260:Female; D005786:Gene Expression Regulation; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D010080:Oxazoles / Q000494:pharmacology; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism*; D010597:Pharmacogenetics / Q000379:methods*; D020641:Polymorphism, Single Nucleotide; D012044:Regression Analysis; D012083:Renin / Q000096:biosynthesis*
D019332:Endothelin-1; D010080:Oxazoles; D047495:PPAR gamma; D012083:Renin; D005998:Glycine; C500085:muraglitazar