Genome Wide Analysis Approach Suggests Chromosome 2 Locus to be Associated with Thiazide and Thiazide Like-Diuretics Blood Pressure Response.
Genome Wide Analysis Approach Suggests Chromosome 2 Locus to be Associated with Thiazide and Thiazide Like-Diuretics Blood Pressure Response.
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全基因组分析方法表明 2 号染色体位点与噻嗪类和噻嗪类利尿剂的血压反应相关。
DOI：
10.1038/s41598-019-53345-5
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发表时间：
2019
影响因子：
4.6
通讯作者：
Johnson,JulieA
中科院分区：
文献类型：
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作者：
Singh,Sonal;McDonough,CaitrinW;Gong,Yan;Bailey,KentR;Boerwinkle,Eric;Chapman,ArleneB;Gums,JohnG;Turner,StephenT;Cooper-DeHoff,RhondaM;Johnson,JulieA
氯噻酮（CTD）比氢氯噻嗪（HCTZ）更有效地降低高血压患者的血压（BP），尽管两者都受到BP反应变异性的困扰。然而，文献中缺乏关于导致CTD对BP反应的变异性的遗传决定因素。我们对来自抗高血压反应药物基因组学评价-2（PEAR-2）研究的非裔美国人（AA）和欧洲裔美国人（EA）CTD治疗后的BP反应进行了发现全基因组关联分析，并在来自PEAR研究的接受HCTZ治疗的AA和EA独立队列中进行了复制，随后对这两项研究进行了种族特异性荟萃分析。成功复制的SNP在来自PEAR-2和PEAR的β受体阻滞剂治疗的参与者中进一步验证了相反的关联方向。通过蛋白质-蛋白质相互作用网络分析进一步评估复制和验证的信号。在AA队列中，WDR 92中的内含子SNP rs79237970（PPP 3R 1的eQTL）与CTD的DBP反应更好显著相关（p = 5.76 × 10−6，β = −15.75）。该SNP在PEAR中进一步复制（p = 0.00046，β =-9.815），全基因组显著荟萃分析p值为8.49 × 10−9。在PEAR-2美托洛尔（p = 9.9 × 10−3，β = 7.47）和PEAR阿替洛尔（p = 0.04，β = 4.36）的两个β受体阻滞剂治疗队列中，进一步验证了该变体与DBP的相反关联。PPP 3R 1是钙调神经磷酸酶复合物的调节亚基。钙调磷酸酶抑制剂的使用与HTN相关。研究还表明PPP 3R 1基因多态性与AA高血压患者的心室肥厚相关。蛋白质-蛋白质相互作用分析进一步鉴定了重要的高血压相关途径，如磷酸肌醇介导的信号传导和钙调神经磷酸酶-NFAT信号传导级联，作为与PPP 3R 1相关的重要生物学过程，这进一步加强了该信号的潜在重要性。这些数据共同表明，WDR 92和PPP 3 R1是新的候选药物，可能有助于解释噻嗪和噻嗪样利尿剂血压反应的遗传基础，并有助于确定与β受体阻滞剂相比更适合噻嗪和噻嗪样利尿剂的患者，以改善血压管理。这可能进一步有助于推进抗高血压治疗的个性化方法。
Chlorthalidone (CTD) is more potent than hydrochlorothiazide (HCTZ) in reducing blood pressure (BP) in hypertensive patients, though both are plagued with BP response variability. However, there is a void in the literature regarding the genetic determinants contributing to the variability observed in BP response to CTD. We performed a discovery genome wide association analysis of BP response post CTD treatment in African Americans (AA) and European Americans (EA) from the Pharmacogenomic Evaluation of Antihypertensive Responses-2 (PEAR-2) study and replication in an independent cohort of AA and EA treated with HCTZ from the PEAR study, followed by a race specific meta-analysis of the two studies. Successfully replicated SNPs were further validated in beta-blocker treated participants from PEAR-2 and PEAR for opposite direction of association. The replicated and validated signals were further evaluated by protein-protein interaction network analysis. An intronic SNP rs79237970 in theWDR92(eQTL forPPP3R1) was significantly associated with better DBP response to CTD (p = 5.76 × 10−6, β = −15.75) in the AA cohort. This SNP further replicated in PEAR (p = 0.00046, β = −9.815) with a genome wide significant meta-analysis p-value of 8.49 × 10−9. This variant was further validated for opposite association in two β-blockers treated cohorts from PEAR-2 metoprolol (p = 9.9 × 10−3, β = 7.47) and PEAR atenolol (p = 0.04, β = 4.36) for association with DBP. Studies have implicatedWDR92in coronary artery damage.PPP3R1is the regulatory subunit of the calcineurin complex. Use of calcineurin inhibitors is associated with HTN. Studies have also shown polymorphisms inPPP3R1to be associated with ventricular hypertrophy in AA hypertensive patients. Protein-protein interaction analysis further identified important hypertension related pathways such as inositol phosphate-mediated signaling and calcineurin-NFAT signaling cascade as important biological process associated with PPP3R1 which further strengthen the potential importance of this signal. These data collectively suggest thatWDR92andPPP3R1are novel candidates that may help explain the genetic underpinnings of BP response of thiazide and thiazide-like diuretics and help identify the patients better suited for thiazide and thiazide-like diuretics compared to β-blockers for improved BP management. This may further help advance personalized approaches to antihypertensive therapy.