Shahin Mohamed H, Gong Yan, McDonough Caitrin W, Rotroff Daniel M, Beitelshees Amber L, Garrett Timothy J, Gums John G, Motsinger-Reif Alison, Chapman Arlene B, Turner Stephen T, Boerwinkle Eric, Frye Reginald F, Fiehn Oliver, Cooper-DeHoff Rhonda M, Kaddurah-Daouk Rima, Johnson Julie A
From the Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics (M.H.S., Y.G., C.W.M., J.G.G., R.F.F., R.M.C.-D., J.A.J.) and Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine (T.J.G.), University of Florida, Gainesville; Department of Statistics, Bioinformatics Research Center, North Carolina State University, Raleigh (D.M.R., A.M.-R.); Department of Medicine, University of Maryland, Baltimore (A.L.B.); Department of Medicine, Emory University, Atlanta, GA (A.B.C.); Division of Nephrology and Hypertension, Department of Medicine, College of Medicine, Mayo Clinic, Rochester, MN (S.T.T.); Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, (E.B.); Department of Molecular and Cellular Biology and Genome Center, University of California, Davis (O.F.); and Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC (R.K.-D.).
Hypertension. 2016 Sep;68(3):621-9. doi: 10.1161/HYPERTENSIONAHA.116.07328. Epub 2016 Jul 5.
Hydrochlorothiazide is among the most commonly prescribed antihypertensives; yet, <50% of hydrochlorothiazide-treated patients achieve blood pressure (BP) control. Herein, we integrated metabolomic and genomic profiles of hydrochlorothiazide-treated patients to identify novel genetic markers associated with hydrochlorothiazide BP response. The primary analysis included 228 white hypertensives treated with hydrochlorothiazide from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study. Genome-wide analysis was conducted using Illumina Omni 1 mol/L-Quad Chip, and untargeted metabolomics was performed on baseline fasting plasma samples using a gas chromatography-time-of-flight mass spectrometry platform. We found 13 metabolites significantly associated with hydrochlorothiazide systolic BP (SBP) and diastolic BP (DBP) responses (false discovery rate, <0.05). In addition, integrating genomic and metabolomic data revealed 3 polymorphisms (rs2727563 PRKAG2, rs12604940 DCC, and rs13262930 EPHX2) along with arachidonic acid, converging in the netrin signaling pathway (P=1×10(-5)), as potential markers, significantly influencing hydrochlorothiazide BP response. We successfully replicated the 3 genetic signals in 212 white hypertensives treated with hydrochlorothiazide and created a response score by summing their BP-lowering alleles. We found patients carrying 1 response allele had a significantly lower response than carriers of 6 alleles (∆SBP/∆DBP: -1.5/1.2 versus -16.3/-10.4 mm Hg, respectively, SBP score, P=1×10(-8) and DBP score, P=3×10(-9)). This score explained 11.3% and 11.9% of the variability in hydrochlorothiazide SBP and DBP responses, respectively, and was further validated in another independent study of 196 whites treated with hydrochlorothiazide (DBP score, P=0.03; SBP score, P=0.07). This study suggests that PRKAG2, DCC, and EPHX2 might be important determinants of hydrochlorothiazide BP response.
氢氯噻嗪是最常用的降压药之一；然而，接受氢氯噻嗪治疗的患者中，血压（BP）得到控制的比例不到50%。在此，我们整合了接受氢氯噻嗪治疗患者的代谢组学和基因组图谱，以确定与氢氯噻嗪血压反应相关的新遗传标记。初步分析纳入了来自降压反应药物基因组学评估（PEAR）研究的228名接受氢氯噻嗪治疗的白人高血压患者。使用Illumina Omni 1 mol/L-Quad芯片进行全基因组分析，并使用气相色谱-飞行时间质谱平台对基线空腹血浆样本进行非靶向代谢组学分析。我们发现13种代谢物与氢氯噻嗪的收缩压（SBP）和舒张压（DBP）反应显著相关（错误发现率<0.05）。此外，整合基因组和代谢组数据发现3个多态性位点（rs2727563 PRKAG2、rs12604940 DCC和rs13262930 EPHX2）以及花生四烯酸，它们在netrin信号通路中汇聚（P = 1×10⁻⁵），作为潜在标记，显著影响氢氯噻嗪的血压反应。我们在212名接受氢氯噻嗪治疗的白人高血压患者中成功复制了这3个遗传信号，并通过将其降压等位基因相加创建了一个反应评分。我们发现携带1个反应等位基因的患者的反应明显低于携带6个等位基因的患者（∆SBP/∆DBP：分别为-1.5/1.2与-16.3/-10.4 mmHg，SBP评分，P = 1×10⁻⁸；DBP评分，P = 3×10⁻⁹）。该评分分别解释了氢氯噻嗪SBP和DBP反应变异性的11.3%和11.9%，并在另一项对196名接受氢氯噻嗪治疗的白人的独立研究中得到进一步验证（DBP评分，P = 0.03；SBP评分，P = 0.07）。这项研究表明，PRKAG2、DCC和EPHX2可能是氢氯噻嗪血压反应的重要决定因素。
