ABSTRACT

Background: Genetic variants of coding genes related to blood pressure regulation participate in the pathogenesis of hypertension and determines the response to specific antihypertensive drugs. G protein-coupled receptor kinase 4 (GRK4) and its variants are of great importance in pathogenesis of hypertension. However, little is known about role of GRK4 variants in determine circadian rhythm of blood pressure and response to candesartan in hypertension. The aim of this study was to analyze the correlation of GRK4 variants and circadian rhythm of blood pressure, and to explore their effect on antihypertensive efficiency of candestartan.

Methods: In this study, a total of 1239 cases were eligible, completed ambulatory blood pressure monitoring (ABPm) observation and exon sequencing of G protein-coupled receptor kinase 4 (GRK4). ABPm was obtained before and after 4-week treatment of candesartan. Diurnal variation of systolic blood pressure and antihypertensive effect of candesartan were then assessed.

Results: Compared to GRK4 wild type (GRK4-WT), patients with GRK4 variants were more likely to be non-dippers (odds ratio (OR) 6.672, 95% confidence interval (CI) 5.124–8.688, P < .001), with GRK4 A142V (OR 5.888, 95% CI 4.332–8.003, P < .001), A486V (OR 7.102, 95% CI 5.334–9.455, P < .001) and GRK4 R65L (OR 3.273, 95% CI 2.271–4.718, P < .001), respectively. Correlation analysis revealed that non-dippers rhythm of blood pressure were associated with GRK4 variants (r = .420, P < .001), with GRK4 A142V (r = .416, P < .001), A486V (r = .465, P < .001) and GRK4 R65L (r = .266, P < .001), respectively. When given 4-week candesartan, patients with GRK4 variants showed better antihypertensive effect as to drop in blood pressure (24 h mSBP, 21.21 ± 4.99 vs 12.34 ± 4.78 mmHg, P < .001) and morning peak (MP-SBP, 16.54 ± 4.37 vs 11.52 ± 4.14 mmHg, P < .001), as well as greater increase in trough to peak ratio (SBP-T/P, .71 ± .07 vs .58 ± .07, P < .001) and smoothness index (SBP-SI, 1.44 ± .16 vs 1.17 ± .11, P < .001) than those with GRK4 WT.

Conclusion: This study indicates that hypertensive patients with GRK4 variants are more likely to be non-dippers. What’s more, patients with GRK4 variants possess a significantly better antihypertensive response to candesartan than those with GRK4 WT.

摘要

背景：与血压调节相关的编码基因的遗传变异参与了高血压的发病机制，并决定了对特定抗高血压药物的反应。G 蛋白偶联受体激酶 4 (GRK4) 及其变体在高血压的发病机制中具有重要意义。然而，关于 GRK4 变体在确定血压昼夜节律和对坎地沙坦对高血压的反应中的作用知之甚少。本研究的目的是分析 GRK4 变异体与血压昼夜节律的相关性，并探讨它们对坎地司他坦降压效果的影响。

方法：本研究共纳入1239例，完成动态血压监测（ABPm）观察和G蛋白偶联受体激酶4（GRK4）外显子测序。在坎地沙坦治疗 4 周前后获得 ABPm。然后评估了收缩压的昼夜变化和坎地沙坦的抗高血压作用。

结果：与 GRK4 野生型 (GRK4-WT) 相比，具有 GRK4 变异的患者更可能是非杓型患者（优势比 (OR) 6.672, 95% 置信区间 (CI) 5.124–8.688, P < .001），与 GRK4 A142V (OR 5.888, 95% CI 4.332–8.003, P < .001)、A486V (OR 7.102, 95% CI 5.334–9.455, P < .001) 和 GRK4 R65L (OR 3.273, 95% CI 2.271–4.718) , P < .001)，分别。相关性分析显示，非杓型血压节律与 GRK4 变异（r = .420，P < .001）、GRK4 A142V（r = .416，P < .001）、A486V（r = .465，P < .001) 和 GRK4 R65L (r = .266, P< .001)，分别。当给予 4 周坎地沙坦时，具有 GRK4 变异体的患者在血压​​下降（24 小时 mSBP，21.21 ± 4.99 vs 12.34 ± 4.78 mmHg，P < .001）和晨峰（MP-SBP，16.54 ± 4.37 vs 11.52 ± 4.14 mmHg, P < .001 )，以及谷峰比 (SBP-T/P, . 71 ± .07 vs .58 ± .07, P < .001 ) 和平滑度指数的更大增加(SBP-SI, 1.44 ± .16 vs 1.17 ± .11, P < .001 ) 高于 GRK4 WT。

结论：本研究表明具有 GRK4 变异体的高血压患者更有可能是非杓型患者。更重要的是，具有 GRK4 变体的患者对坎地沙坦的抗高血压反应明显优于 GRK4 WT 患者。