Center for Pharmacogenomics and Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, FL, USA.
Graduate Program in Genetics and Genomics, University of Florida, Gainesville, FL, USA.
Sci Rep. 2017 Nov 22;7(1):16068. doi: 10.1038/s41598-017-16343-z.
Thiazide diuretics (TD) are commonly prescribed anti-hypertensives worldwide. However, <40% of patients treated with thiazide monotherapy achieve BP control. This study uses whole transcriptome sequencing to identify novel molecular markers associated with BP response to TD. We assessed global RNA expression levels in whole blood samples from 150 participants, representing patients in the upper and lower quartile of BP response to TD from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) (50 whites) and from PEAR-2 (50 whites and 50 blacks). In each study cohort, we performed poly-A RNA-sequencing in baseline samples from 25 responders and 25 non-responders to hydrochlorothiazide (HCTZ) or chlorthalidone. At FDR adjusted p-value < 0.05, 29 genes were differentially expressed in relation to HCTZ or chlorthalidone BP response in whites. For each differentially expressed gene, replication was attempted in the alternate white group and PEAR-2 blacks. CEBPD (meta-analysis p = 1.8 × 10) and TSC22D3 (p = 1.9 × 10) were differentially expressed in all 3 cohorts, and explain, in aggregate, 21.9% of response variability to TD. This is the first report of the use of transcriptome-wide sequencing data to identify molecular markers of antihypertensive drug response. These findings support CEBPD and TSC22D3 as potential biomarkers of BP response to TD.
噻嗪类利尿剂（TD）是全球常用的抗高血压药物。然而，<40%接受噻嗪单药治疗的患者血压控制达标。本研究使用全转录组测序来鉴定与 TD 降压反应相关的新型分子标志物。我们评估了来自 Pharmacogenomic Evaluation of Antihypertensive Responses（PEAR）（50 名白人）和 PEAR-2（50 名白人及 50 名黑人）中 TD 降压反应处于上四分位数和下四分位数的 150 名参与者的全血样本中的全基因组 RNA 表达水平。在每个研究队列中，我们对 25 名 HCTZ 或氯噻酮的 responder 和 non-responder 基线样本进行了 poly-A RNA-seq。在 FDR 调整的 p 值 < 0.05 时，29 个基因与 HCTZ 或氯噻酮的 BP 反应相关而存在差异表达。对于每个差异表达的基因，我们尝试在另一个白人组和 PEAR-2 黑人组中进行复制。在所有 3 个队列中，CEBPD（meta-analysis p = 1.8 × 10）和 TSC22D3（p = 1.9 × 10）均存在差异表达，它们共同解释了 TD 降压反应变异性的 21.9%。这是首次使用转录组测序数据来鉴定抗高血压药物反应的分子标志物的报道。这些发现支持 CEBPD 和 TSC22D3 作为 TD 降压反应的潜在生物标志物。
