Genetic and gene expression studies implicate renin and endothelin-1 in edema caused by peroxisome proliferator-activated receptor γ agonists
Genetic and gene expression studies implicate renin and endothelin-1 in edema caused by peroxisome proliferator-activated receptor γ agonists
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DOI：
10.1097/fpc.0b013e32830a6ea0
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发表时间：
2008-10-01
影响因子：
2.6
通讯作者：
Ranade, Koustubh
中科院分区：
文献类型：
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作者：
Geese, William J.;Achanzar, William;Ranade, Koustubh
目的 过氧化物酶体增殖物激活受体 γ (PPAR γ) 激动剂可引起易感个体外周水肿。为了调查这一不良事件的机制基础，我们对参加 Muraglitazar（一种研究性 PPAR α/γ 双重激动剂）临床试验的患者进行了候选基因分析，并开发了基于细胞培养的基因表达测定和非人灵长类水肿模型，以研究 PPAR γ 激动剂的水肿特性。方法对 63 个基因中的总共 213 个单核苷酸多态性 (SNP) 进行了基因分型。 730 名参与者。使用卡方和逻辑回归分析来测试与水肿的关联。使用定量实时 PCR 评估 Calu-6 细胞对 PPAR γ 激动剂的转录反应。雄性食蟹猴接受 PPAR 激动剂治疗，并使用 MRI 评估水肿情况。 结果 肾素 (rs2368564) 和内皮素-1 (rs5370) 中的 SNP 与水肿风险降低相关（分别为 P = 0.003 和 P = 0.028），β 1 肾上腺素受体 (rs1801253) 中的 SNP 与水肿风险增加相关。对水肿的易感性（P = 0.034）。基因表达研究表明，Calu-6 细胞中肾素和内皮素-1 受 PPAR gamma 调节。对 10 种 PPAR γ 激动剂的调查进一步表明，一种化合物的体外效力与其致水肿潜力相关，从而预测三种先前未表征的 PPAR γ 激动剂中的一种会引起较少的水肿。这一预测在 PPAR γ 激动剂引起的水肿的非人灵长类动物模型中得到了验证。 结论 我们的结果暗示了肾素和内皮素-1 在 PPAR γ 激动剂引起的水肿中的关键作用，并证明了如何将从药物遗传学研究中获得的知识应用于药物发现。
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.