Zhang Shanchun, Mao Guangyun, Zhang Yan, Tang Genfu, Wen Yufeng, Hong Xiumei, Jiang Shanqun, Yu Yunxian, Xu Xiping
School of Life Science, University of Science and Technology of China, Hefei, Anhui, China.
Clin Ther. 2005 Nov;27(11):1774-84. doi: 10.1016/j.clinthera.2005.11.008.
Individual variations in the pharmacokinetics and pharmacodynamics of antihypertensive drugs are influenced by genetic and environmental factors. The ANP gene, which encodes the precursor of atrial natriuretic peptide (ANP), is among the candidate genes for genetic susceptibility to hypertension.
This study examined the relationship between ANP Val7Met polymorphism (Single Nucleotide Polymorphism database ID: rs5063) and baseline blood pressure (BP), plasma trough irbesartan concentrations, and the antihypertensive efficacy of irbesartan in rural Chinese patients with essential hypertension.
Patients with essential hypertension who had taken no antihypertensive medications within 4 weeks of study initiation received oral irbesartan 150 mg/d for 4 weeks. Genotyping was performed for all patients. BP was measured before dosing on the 1st and 28th days of treatment. Plasma irbesartan concentrations were measured using high-performance liquid chromatography with fluorescent detection. Antihypertensive efficacy was defined as attainment of a diastolic BP (DBP) <90 mm Hg (DBP analysis), a systolic BP (SBP) <140 mm Hg (SBP analysis), and a DBP <90 mm Hg and SBP <140 mm Hg (DBP and SBP analysis).
The study included 756 patients, 621 with the Val/Val genotype and 135 with the Val/Met+Met/Met genotypes. There were no significant differences in age, body mass index, sex, education level, occupation, alcohol consumption, or smoking status between the 2 groups. Patients with the Val/Met+Met/Met genotypes had a significantly lower mean baseline DBP compared with those with the Val/Val genotype (adjusted regression coefficient [SE]: -2.5 [1.0] mm Hg; P = 0.012) and significantly lower mean steady-state plasma trough irbesartan concentrations (adjusted regression coefficient: -12.6 [4.1]; P = 0.002). No significant association was found between antihypertensive efficacy and Val7Met polymorphism in the overall population, but in an analysis by baseline DBP status, patients with the Val/Met+Met/Met genotype a baseline DBP > or =100 mm Hg had significantly smaller reductions in DBP (adjusted regression coefficient: -5.7 [1.4] mm Hg; P < 0.001) and SBP compared with those with the Val/Val genotype and a baseline DBP > or =100 mm Hg (adjusted regression coefficient: -9.8 [2.9] mm Hg; P < 0.001).
The findings of this study suggest that in these rural Chinese patients with essential hypertension, ANP Val7Met polymorphism may be a genetic marker for baseline DBP, plasma irbesartan concentrations, and the antihypertensive efficacy of short-term irbesartan therapy.
降压药物的药代动力学和药效学的个体差异受遗传和环境因素影响。编码心钠素（ANP）前体的ANP基因是高血压遗传易感性的候选基因之一。
本研究探讨了ANP基因Val7Met多态性（单核苷酸多态性数据库ID：rs5063）与中国农村原发性高血压患者的基线血压（BP）、血浆厄贝沙坦谷浓度以及厄贝沙坦的降压疗效之间的关系。
在研究开始4周内未服用过降压药物的原发性高血压患者口服厄贝沙坦150mg/d，共4周。对所有患者进行基因分型。在治疗第1天和第28天给药前测量血压。采用高效液相色谱荧光检测法测定血浆厄贝沙坦浓度。降压疗效定义为舒张压（DBP）<90mmHg（DBP分析）、收缩压（SBP）<140mmHg（SBP分析）以及DBP<90mmHg且SBP<140mmHg（DBP和SBP分析）。
该研究纳入756例患者，其中621例为Val/Val基因型，135例为Val/Met+Met/Met基因型。两组患者在年龄、体重指数、性别教育水平、职业、饮酒或吸烟状况方面无显著差异。Val/Met+Met/Met基因型患者的平均基线DBP显著低于Val/Val基因型患者（调整回归系数[标准误]：-2.5[1.0]mmHg；P=0.012），平均稳态血浆厄贝沙坦谷浓度也显著更低（调整回归系数：-12.6[4.1]；P=0.002）。在总体人群中，未发现降压疗效与Val7Met多态性之间存在显著关联，但在按基线DBP状态进行的分析中，基线DBP≥100mmHg的Val/Met+Met/Met基因型患者的DBP降低幅度（调整回归系数：-5.7[1.4]mmHg；P<0.001）和SBP降低幅度显著小于基线DBP≥100mmHg的Val/Val基因型患者（调整回归系数：-9.8[2.9]mmHg；P<0.001）。
本研究结果表明，在中国农村原发性高血压患者中，ANP基因Val7Met多态性可能是基线DBP、血浆厄贝沙坦浓度以及短期厄贝沙坦治疗降压疗效的遗传标志物。
