Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, University of Florida College of Pharmacy, 1600 SW Archer Rd, Room PG-22, Box 100486, Gainesville, FL 32610-0486, USA.
Hypertension. 2012 Oct;60(4):957-64. doi: 10.1161/HYPERTENSIONAHA.112.198721. Epub 2012 Sep 4.
G protein-coupled receptor kinases (GRKs) are important regulatory proteins for many G protein-coupled receptors, but little is known about GRK4 pharmacogenetics. We hypothesized that 3 nonsynonymous GRK4 single-nucleotide polymorphisms, R65L (rs2960306), A142V (rs1024323), and A486V (rs1801058), would be associated with blood pressure response to atenolol, but not hydrochlorothiazide, and would be associated with long-term cardiovascular outcomes (all-cause death, nonfatal myocardial infarction, nonfatal stroke) in participants treated with an atenolol-based versus verapamil-SR-based antihypertensive strategy. GRK4 single-nucleotide polymorphisms were genotyped in 768 hypertensive participants from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) trial. In whites and blacks, increasing copies of the variant 65L-142V haplotype were associated with significantly reduced atenolol-induced diastolic blood pressure lowering (-9.1±6.8 versus -6.8±7.1 versus -5.3±6.4 mm Hg in participants with 0, 1, and 2 copies of 65L-142V, respectively; P=0.0088). One thousand four hundred sixty participants with hypertension and coronary artery disease from the INternational VErapamil SR/Trandolapril STudy (INVEST) were genotyped, and variant alleles of all 3 GRK4 single-nucleotide polymorphisms were associated with increased risk for adverse cardiovascular outcomes in an additive fashion, with 486V homozygotes reaching statistical significance (odds ratio, 2.29 [1.48-3.55]; P=0.0002). These effects on adverse cardiovascular outcomes were independent of antihypertensive treatment. These results suggest that the presence of GRK4 variant alleles may be important determinants of blood pressure response to atenolol and risk for adverse cardiovascular events. The associations with GRK4 variant alleles were stronger in patients who were also ADRB1 389R homozygotes, suggesting a potential interaction between these 2 genes.
G 蛋白偶联受体激酶（GRKs）是许多 G 蛋白偶联受体的重要调节蛋白，但对于 GRK4 的药物遗传学知之甚少。我们假设 3 个非同义 GRK4 单核苷酸多态性，R65L（rs2960306）、A142V（rs1024323）和 A486V（rs1801058），与阿替洛尔的降压反应有关，但与氢氯噻嗪无关，并且与接受阿替洛尔治疗的参与者的长期心血管结局（全因死亡、非致死性心肌梗死、非致死性卒中）有关）与维拉帕米-SR 为基础的抗高血压策略。GRK4 单核苷酸多态性在来自 Pharmacogenomic Evaluation of Antihypertensive Responses（PEAR）试验的 768 名高血压参与者中进行了基因分型。在白人和黑人中，变异型 65L-142V 单倍型的拷贝数增加与阿替洛尔诱导的舒张压降低显著相关（在分别有 0、1 和 2 个 65L-142V 拷贝的参与者中，-9.1±6.8 与-6.8±7.1 与-5.3±6.4 mmHg；P=0.0088）。来自 INternational VErapamil SR/Trandolapril STudy（INVEST）的 1460 名高血压和冠心病患者进行了基因分型，所有 3 个 GRK4 单核苷酸多态性的变异等位基因以累加方式与不良心血管结局的风险增加相关，486V 纯合子达到统计学意义（比值比，2.29 [1.48-3.55]；P=0.0002）。这些对不良心血管结局的影响独立于降压治疗。这些结果表明，GRK4 变异等位基因的存在可能是阿替洛尔降压反应和不良心血管事件风险的重要决定因素。在也是 ADRB1 389R 纯合子的患者中，与 GRK4 变异等位基因的关联更强，这表明这两个基因之间存在潜在的相互作用。
