Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, University of Florida, Gainesville, FL.
Bioinformatics Research Center, North Carolina State University, Raleigh, NC.
J Am Heart Assoc. 2017 Dec 29;7(1):e006656. doi: 10.1161/JAHA.117.006656.
Although hydrochlorothiazide (HCTZ) is a well-established first-line antihypertensive in the United States, <50% of HCTZ treated patients achieve blood pressure (BP) control. Thus, identifying biomarkers that could predict the BP response to HCTZ is critically important. In this study, we utilized metabolomics, genomics, and lipidomics to identify novel pathways and biomarkers associated with HCTZ BP response.
First, we conducted a pathway analysis for 13 metabolites we recently identified to be significantly associated with HCTZ BP response. From this analysis, we found the sphingolipid metabolic pathway as the most significant pathway (=5.8E-05). Testing 78 variants, within 14 genes involved in the sphingolipid metabolic canonical pathway, with the BP response to HCTZ identified variant rs6078905, within the gene, as a novel biomarker significantly associated with the BP response to HCTZ in whites (n=228). We found that rs6078905 C-allele carriers had a better BP response to HCTZ versus noncarriers (∆SBP/∆DBP: -11.4/-6.9 versus -6.8/-3.5 mm Hg; ∆SBP =6.7E-04; ∆DBP =4.8E-04). Additionally, in blacks (n=148), we found genetic signals in the genomic region significantly associated with the BP response to HCTZ (<0.05). Last, we observed that rs6078905 significantly affects the baseline level of 4 sphingomyelins (N24:2, N24:3, N16:1, and N22:1; false discovery rate <0.05), from which N24:2 sphingomyelin has a significant correlation with both HCTZ DBP-response (=-0.42; =7E-03) and SBP-response (=-0.36; =2E-02).
This study provides insight into potential pharmacometabolomic and genetic mechanisms underlying HCTZ BP response and suggests that is a potential determinant of the BP response to HCTZ.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00246519.
尽管氢氯噻嗪（HCTZ）在美国是一种被广泛认可的一线降压药，但只有不到 50%的 HCTZ 治疗患者血压得到控制。因此，识别能够预测 HCTZ 降压反应的生物标志物至关重要。在这项研究中，我们利用代谢组学、基因组学和脂质组学来识别与 HCTZ 降压反应相关的新途径和生物标志物。
首先，我们对我们最近确定的与 HCTZ 降压反应显著相关的 13 种代谢物进行了途径分析。通过这项分析，我们发现鞘脂代谢途径是最显著的途径（=5.8E-05）。在与鞘脂代谢经典途径相关的 14 个基因中，我们测试了 78 个变体，发现基因内的变体 rs6078905 与 HCTZ 降压反应之间存在显著关联，这是一种与白人 HCTZ 降压反应显著相关的新型生物标志物（n=228）。我们发现，rs6078905 的 C 等位基因携带者的 HCTZ 降压反应优于非携带者（∆SBP/∆DBP：-11.4/-6.9 与-6.8/-3.5mmHg；∆SBP=6.7E-04；∆DBP=4.8E-04）。此外，在黑人（n=148）中，我们发现与 HCTZ 降压反应显著相关的基因组区域存在遗传信号（<0.05）。最后，我们观察到 rs6078905 显著影响四种神经鞘磷脂的基线水平（N24:2、N24:3、N16:1 和 N22:1；错误发现率<0.05），其中 N24:2 神经鞘磷脂与 HCTZ 舒张压反应（=-0.42；=7E-03）和收缩压反应（=-0.36；=2E-02）均有显著相关性。
本研究深入了解了 HCTZ 降压反应的潜在药代代谢组学和遗传机制，并表明基因是 HCTZ 降压反应的潜在决定因素。
