Shahin Mohamed H, Sá Ana C, Webb Amy, Gong Yan, Langaee Taimour, McDonough Caitrin W, Riva Alberto, Beitleshees Amber L, Chapman Arlene B, Gums John G, Turner Stephen T, Boerwinkle Eric, Scherer Steven E, Sadee Wolfgang, Cooper-DeHoff Rhonda M, Johnson Julie A
Circ Cardiovasc Genet. 2017 Jan;10(1). doi: 10.1161/CIRCGENETICS.116.001404.
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.
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 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 (Δ systolic BP/Δ diastolic BP: -12.3/-8.2 versus -6.8/-3.5 mm Hg, respectively, Δ systolic BP P=3×10, Δ diastolic BP P=5×10). 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 (r=0.7) with rs10995, which both could contribute to the observed genetic effects by affecting VASP mRNA expression.
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.
URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00246519 and NCT01203852.
噻嗪类利尿剂是最常用的抗高血压药物之一。然而，接受噻嗪类治疗的患者中，血压（BP）得到控制的比例不到50%。在此，我们使用不同的组学（基因组学和转录组学）方法来识别噻嗪类利尿剂血压反应的新生物标志物。
全基因组分析纳入了228名白人高血压患者，在基线和氢氯噻嗪治疗9周后测定血压。根据RegulomeDB、haploreg和变异体全基因组注释，按照生物学功能对P<5×10的单核苷酸多态性进行优先排序。优先排序方法的结果显示，在测试的单核苷酸多态性中，rs10995是最有可能具有功能的单核苷酸多态性，与氢氯噻嗪的血压反应相关。与非携带者相比，rs10995 G等位基因与氢氯噻嗪更好的血压反应相关（收缩压/舒张压变化：分别为-12.3/-8.2与-6.8/-3.5 mmHg，收缩压变化P=3×10，舒张压变化P=5×10）。这种关联在接受氯噻酮治疗的独立参与者中得到了重复验证。此外，rs10995 G等位基因与血管舒张刺激磷蛋白（VASP）的mRNA表达增加相关。而且，与25名氢氯噻嗪治疗效果不佳者相比，25名治疗效果良好者的VASP mRNA基线表达显著更高（P=0.01）。这一发现在接受氯噻酮治疗的独立参与者中也得到了重复验证（P=0.04）。最后，等位基因特异性表达分析显示，rs10995与rs10156（与rs10995处于高连锁不平衡状态，r=0.7的单核苷酸多态性）之间存在显著但适度的失衡，二者均可能通过影响VASP mRNA表达而导致观察到的遗传效应。
本研究突出了使用不同组学方法识别药物反应新生物标志物的优势，并提示VASP是噻嗪类利尿剂血压反应的潜在决定因素。
网址：http://www.clinicaltrials.gov。唯一标识符：NCT00246519和NCT01203852。
