全基因组和基于基因的荟萃分析确定影响血压对氢氯噻嗪反应的新基因座。
Genome-Wide and Gene-Based Meta-Analyses Identify Novel Loci Influencing Blood Pressure Response to Hydrochlorothiazide.
作者信息
Salvi Erika, Wang Zhiying, Rizzi Federica, Gong Yan, McDonough Caitrin W, Padmanabhan Sandosh, Hiltunen Timo P, Lanzani Chiara, Zaninello Roberta, Chittani Martina, Bailey Kent R, Sarin Antti-Pekka, Barcella Matteo, Melander Olle, Chapman Arlene B, Manunta Paolo, Kontula Kimmo K, Glorioso Nicola, Cusi Daniele, Dominiczak Anna F, Johnson Julie A, Barlassina Cristina, Boerwinkle Eric, Cooper-DeHoff Rhonda M, Turner Stephen T
机构信息
From the Department of Health Sciences, University of Milan, Italy (E.S., F.R., M.C., M.B., C.B.); Human Genetics and Institute of Molecular Medicine, University of Texas Health Science Center, Houston (Z.W., E.B.); Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy (Y.G., C.W.M., J.A.J., R.M.C.-D.) and Division of Cardiovascular Medicine, Department of Medicine (J.A.J., R.M.C.-D.), University of Florida, Gainesville; Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, United Kingdom (S.P., A.F.D.); Department of Medicine, University of Helsinki and Helsinki University Hospital, Finland (T.P.H., K.K.K.); Nephrology and Dialysis and Hypertension Unit, San Raffaele Scientific Institute, Università Vita Salute San Raffaele, Milano, Italy (C.L., P.M.); Hypertension and Related Disease Centre, AOU-University of Sassari, Italy (R.Z., N.G.); Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (K.R.B.) and Division of Nephrology and Hypertension, Department of Internal Medicine (S.T.T.), Mayo Clinic, Rochester, Minnesota; Institute for Molecular Medicine Finland FIMM, University of Helsinki, Finland (A.-P.S); Department of Clinical Sciences, Lund University, Malmö, Sweden (O.M.); Section of Nephrology, Department of Medicine, University of Chicago, Illinois (A.B.C.); Institute of Biomedical Technologies, National Research Centre of Italy, Segrate, Milan, Italy (D.C.); and Sanipedia srl, Bresso, Italy (D.C.).
出版信息
Hypertension. 2017 Jan;69(1):51-59. doi: 10.1161/HYPERTENSIONAHA.116.08267. Epub 2016 Oct 31.
This study aimed to identify novel loci influencing the antihypertensive response to hydrochlorothiazide monotherapy. A genome-wide meta-analysis of blood pressure (BP) response to hydrochlorothiazide was performed in 1739 white hypertensives from 6 clinical trials within the International Consortium for Antihypertensive Pharmacogenomics Studies, making it the largest study to date of its kind. No signals reached genome-wide significance (P<5×10), and the suggestive regions (P<10) were cross-validated in 2 black cohorts treated with hydrochlorothiazide. In addition, a gene-based analysis was performed on candidate genes with previous evidence of involvement in diuretic response, in BP regulation, or in hypertension susceptibility. Using the genome-wide meta-analysis approach, with validation in blacks, we identified 2 suggestive regulatory regions linked to gap junction protein α1 gene (GJA1) and forkhead box A1 gene (FOXA1), relevant for cardiovascular and kidney function. With the gene-based approach, we identified hydroxy-delta-5-steroid dehydrogenase, 3 β- and steroid δ-isomerase 1 gene (HSD3B1) as significantly associated with BP response (P<2.28×10 ). HSD3B1 encodes the 3β-hydroxysteroid dehydrogenase enzyme and plays a crucial role in the biosynthesis of aldosterone and endogenous ouabain. By amassing all of the available pharmacogenomic studies of BP response to hydrochlorothiazide, and using 2 different analytic approaches, we identified 3 novel loci influencing BP response to hydrochlorothiazide. The gene-based analysis, never before applied to pharmacogenomics of antihypertensive drugs to our knowledge, provided a powerful strategy to identify a locus of interest, which was not identified in the genome-wide meta-analysis because of high allelic heterogeneity. These data pave the way for future investigations on new pathways and drug targets to enhance the current understanding of personalized antihypertensive treatment.
本研究旨在确定影响氢氯噻嗪单药治疗降压反应的新基因座。国际抗高血压药物基因组学研究联盟的6项临床试验对1739名白人高血压患者进行了氢氯噻嗪血压（BP）反应的全基因组荟萃分析，使其成为迄今为止同类研究中规模最大的研究。没有信号达到全基因组显著性水平（P<5×10），并且在2个接受氢氯噻嗪治疗的黑人队列中对提示性区域（P<10）进行了交叉验证。此外，对先前有证据表明参与利尿反应、血压调节或高血压易感性的候选基因进行了基于基因的分析。使用全基因组荟萃分析方法，并在黑人中进行验证，我们确定了2个与间隙连接蛋白α1基因（GJA1）和叉头框A1基因（FOXA1）相关的提示性调控区域，它们与心血管和肾脏功能有关。通过基于基因的方法，我们确定羟基-δ-5-类固醇脱氢酶、3β-和类固醇δ-异构酶1基因（HSD3B1）与血压反应显著相关（P<2.28×10）。HSD3B1编码3β-羟基类固醇脱氢酶，在醛固酮和内源性哇巴因的生物合成中起关键作用。通过汇总所有现有的关于氢氯噻嗪血压反应的药物基因组学研究，并使用2种不同的分析方法，我们确定了3个影响氢氯噻嗪血压反应的新基因座。据我们所知，基于基因的分析从未应用于抗高血压药物的药物基因组学，它提供了一种强大的策略来识别感兴趣的基因座，由于高等位基因异质性，该基因座在全基因组荟萃分析中未被识别。这些数据为未来关于新途径和药物靶点的研究铺平了道路，以增进目前对个性化抗高血压治疗的理解。
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