血压特征基因与噻嗪类利尿剂降压反应：PEAR 和 PEAR-2 研究结果。
Blood pressure signature genes and blood pressure response to thiazide diuretics: results from the PEAR and PEAR-2 studies.
机构信息
Center for Pharmacogenomics, Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, P.O.Box 100484, Gainesville, FL, 32610-0486, USA.
Graduate Program in Genetics and Genomics, University of Florida, Gainesville, FL, USA.
出版信息
BMC Med Genomics. 2018 Jun 20;11(1):55. doi: 10.1186/s12920-018-0370-x.
BACKGROUND
Recently, 34 genes had been associated with differential expression relative to blood pressure (BP)/ hypertension (HTN). We hypothesize that some of the genes associated with BP/HTN are also associated with BP response to antihypertensive treatment with thiazide diuretics.
METHODS
We assessed these 34 genes for association with differential expression to BP response to thiazide diuretics with RNA sequencing in whole blood samples from 150 hypertensive participants from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) and PEAR-2 studies. PEAR white and PEAR-2 white and black participants (n = 50 for each group) were selected based on the upper and lower quartile of BP response to hydrochlorothiazide (HCTZ) and to chlorthalidone.
RESULTS
FOS, DUSP1 and PPP1R15A were differentially expressed across all cohorts (meta-analysis p-value < 2.0 × 10), and responders to HCTZ or chlorthalidone presented up-regulated transcripts. Rs11065987 in chromosome 12, a trans-eQTL for expression of FOS, PPP1R15A and other genes, is also associated with BP response to HCTZ in PEAR whites (SBP: β = - 2.1; p = 1.7 × 10; DBP: β = - 1.4; p = 2.9 × 10).
CONCLUSIONS
These findings suggest FOS, DUSP1 and PPP1R15A as potential molecular determinants of antihypertensive response to thiazide diuretics.
TRIAL REGISTRATION
NCT00246519 , NCT01203852 www.clinicaltrials.gov.
背景
最近，有 34 个基因与血压（BP）/高血压（HTN）的差异表达相关。我们假设，与 BP/HTN 相关的一些基因也与噻嗪类利尿剂降压治疗的 BP 反应有关。
方法
我们使用 RNA 测序评估了这 34 个基因与噻嗪类利尿剂降压反应的差异表达，研究对象为来自 Pharmacogenomic Evaluation of Antihypertensive Responses（PEAR）和 PEAR-2 研究的 150 名高血压参与者的全血样本。PEAR 白人和 PEAR-2 白人和黑人参与者（每组 50 人）是根据盐酸氢氯噻嗪（HCTZ）和氯噻酮降压反应的上下四分位数选择的。
结果
FOS、DUSP1 和 PPP1R15A 在所有队列中均存在差异表达（荟萃分析 p 值<2.0×10），HCTZ 或氯噻酮的反应者呈现上调的转录本。染色体 12 上的 rs11065987 是 FOS、PPP1R15A 和其他基因表达的跨基因表达数量性状位点（eQTL），与 PEAR 白人的 HCTZ 降压反应也相关（SBP：β=-2.1；p=1.7×10；DBP：β=-1.4；p=2.9×10）。
结论
这些发现表明 FOS、DUSP1 和 PPP1R15A 可能是噻嗪类利尿剂降压反应的潜在分子决定因素。
试验注册
NCT00246519，NCT01203852，www.clinicaltrials.gov。
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