Genome-Wide Prioritization and Transcriptomics Reveal Novel Signatures Associated With Thiazide Diuretics Blood Pressure Response

Q Medicine

Circulation-Cardiovascular Genetics Pub Date : 2017-01-01 DOI:10.1161/CIRCGENETICS.116.001404

Mohamed H. Shahin, A. C. Sá, A. Webb, Y. Gong, T. Langaee, C. McDonough, A. Riva, Amber L Beitleshees, A. Chapman, J. Gums, S. Turner, E. Boerwinkle, S. Scherer, W. Sadee, R. Cooper-DeHoff, Julie A. Johnson

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引用次数: 12

Abstract

Background— Thiazide diuretics are among the most commonly prescribed antihypertensives. However, <50% of thiazide-treated patients achieve blood pressure (BP) control. Herein, we used different omics (genomics and transcriptomics) to identify novel biomarkers of thiazide diuretics BP response. Methods and Results— Genome-wide analysis included 228 white hypertensives with BP determined at baseline and after 9 weeks of hydrochlorothiazide. Single-nucleotide polymorphisms with P <5×10−5 were prioritized according to their biological function, using RegulomeDB, haploreg, and Genome-Wide Annotation of Variants. The results from the prioritization approach revealed rs10995 as the most likely functional single-nucleotide polymorphism, among single-nucleotide polymorphisms tested, that has been associated with hydrochlorothiazide BP response. The rs10995 G-allele was associated with better BP response to hydrochlorothiazide versus noncarriers (&Dgr; systolic BP/&Dgr; diastolic BP: −12.3/−8.2 versus −6.8/−3.5 mm Hg, respectively, &Dgr; systolic BP P=3×10−4, &Dgr; diastolic BP P=5×10−5). This association was replicated in independent participants treated with chlorthalidone. In addition, rs10995 G-allele was associated with increased mRNA expression of VASP (vasodilator-stimulated phosphoprotein). Moreover, baseline expression of the VASP mRNA was significantly higher in 25 good responders to hydrochlorothiazide compared with 25 poor responders (P=0.01). This finding was replicated in independent participants treated with chlorthalidone (P=0.04). Last, allelic-specific expression analysis revealed a significant but modest imbalance with rs10995 and rs10156, a single-nucleotide polymorphism in high linkage disequilibrium (r2=0.7) with rs10995, which both could contribute to the observed genetic effects by affecting VASP mRNA expression. Conclusions— This study highlights the strength of using different omics to identify novel biomarkers of drug response and suggests VASP as a potential determinant of thiazide diuretics BP response. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00246519 and NCT01203852.

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全基因组优先排序和转录组学揭示与噻嗪类利尿剂血压反应相关的新特征

背景:噻嗪类利尿剂是最常用的抗高血压药物之一。然而，<50%的噻嗪类药物治疗患者血压得到控制。在此，我们使用不同的组学(基因组学和转录组学)来鉴定噻嗪类利尿剂BP反应的新生物标志物。方法和结果-全基因组分析包括228名白人高血压患者，在基线和服用氢氯噻嗪9周后测定血压。使用RegulomeDB、haploreg和Genome-Wide Annotation of Variants对P <5×10−5的单核苷酸多态性根据其生物学功能进行优先排序。优先排序方法的结果显示，在测试的单核苷酸多态性中，rs10995是最可能与氢氯噻嗪BP反应相关的功能性单核苷酸多态性。rs10995 g等位基因对氢氯噻嗪的降压反应优于非携带者(&Dgr;收缩压/ dgr;舒张压:分别为- 12.3/ - 8.2和- 6.8/ - 3.5 mm Hg， &Dgr;收缩压P=3×10−4，&Dgr;舒张压P=5×10−5)。在接受氯噻酮治疗的独立参与者中也出现了这种关联。此外，rs10995 g等位基因与VASP(血管扩张剂刺激磷酸化蛋白)mRNA表达增加相关。此外，25例对氢氯噻嗪反应良好的患者VASP mRNA的基线表达明显高于25例反应不良的患者(P=0.01)。这一发现在氯噻酮治疗的独立受试者中得到了重复(P=0.04)。最后，等位基因特异性表达分析显示，VASP基因与rs10995和rs10156存在显著但适度的不平衡，与rs10995存在高度连锁不平衡的单核苷酸多态性(r2=0.7)，这两种多态性都可能通过影响VASP mRNA的表达来促进所观察到的遗传效应。结论:本研究强调了使用不同组学来鉴定药物反应的新生物标志物的优势，并表明VASP是噻嗪类利尿剂BP反应的潜在决定因素。临床试验注册-网址:http://www.clinicaltrials.gov。唯一标识符:NCT00246519和NCT01203852。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Circulation-Cardiovascular Genetics CARDIAC & CARDIOVASCULAR SYSTEMS-GENETICS & HEREDITY

CiteScore

3.95

自引率

0.00%

发文量

期刊介绍： Circulation: Genomic and Precision Medicine considers all types of original research articles, including studies conducted in human subjects, laboratory animals, in vitro, and in silico. Articles may include investigations of: clinical genetics as applied to the diagnosis and management of monogenic or oligogenic cardiovascular disorders; the molecular basis of complex cardiovascular disorders, including genome-wide association studies, exome and genome sequencing-based association studies, coding variant association studies, genetic linkage studies, epigenomics, transcriptomics, proteomics, metabolomics, and metagenomics; integration of electronic health record data or patient-generated data with any of the aforementioned approaches, including phenome-wide association studies, or with environmental or lifestyle factors; pharmacogenomics; regulation of gene expression; gene therapy and therapeutic genomic editing; systems biology approaches to the diagnosis and management of cardiovascular disorders; novel methods to perform any of the aforementioned studies; and novel applications of precision medicine. Above all, we seek studies with relevance to human cardiovascular biology and disease. Manuscripts are examined by the editorial staff and usually evaluated by expert reviewers assigned by the editors. Both clinical and basic articles will also be subject to statistical review, when appropriate. Provisional or final acceptance is based on originality, scientific content, and topical balance of the journal. Decisions are communicated by email, generally within six weeks. The editors will not discuss a decision about a manuscript over the phone. All rebuttals must be submitted in writing to the editorial office.