Xu Jiayue, Boström Adrian E, Saeed Mohamed, Dubey Raghvendra K, Waeber Gérard, Vollenweider Peter, Marques-Vidal Pedro, Mwinyi Jessica, Schiöth Helgi B
Department of Neuroscience, Division of Functional Pharmacology, Uppsala University, Uppsala, Sweden Department of Obstetrics and Gynecology, Clinic for Reproductive Endocrinology, University Hospital Zurich, Zurich Department of Internal Medicine, University Hospital of Lausanne, University of Lausanne, Lausanne, Switzerland.
Medicine (Baltimore). 2017 Jul;96(30):e7029. doi: 10.1097/MD.0000000000007029.
Hypertension is the leading risk factor for cardiovascular disease and one of the major health concerns worldwide. Genetic factors impact both the risk for hypertension and the therapeutic effect of antihypertensive drugs. Sex- and age-specific variances in the prevalence of hypertension are partly induced by estrogen. We investigated 6 single nucleotide polymorphisms in genes encoding enzymes involved in estrogen metabolism in relation to sex- and age-specific differences in the systolic and diastolic blood pressure (SBP and DBP) outcome under the treatment of diuretics, calcium-channel blockers (CCBs), angiotensin-converting-enzyme inhibitors, and angiotensin-receptor blockers (ARBs).We included 5064 subjects (age: 40-82) from the population-based CoLaus cohort. Participants were genotyped for the catechol-O-methyltransferase gene (COMT) variants rs4680, rs737865, and rs165599; the uridine-diphospho-glucuronosyltransferase 1A gene family (UGT1A) variants rs2070959 and rs887829; and the aromatase gene (CYP19A1) variant rs10046. Binomial and linear regression analyses were performed correcting for age, sex, body mass index, smoking, diabetes, and antihypertensive therapy to test whether the variants in focus are significantly associated with BP.All investigated COMT variants were strongly associated with the effect of diuretics, CCBs, and ARBs on SBP or DBP (P < .05), showing an additive effect when occurring in combination. After Bonferroni correction the polymorphism rs4680 (ValMet) in COMT was significantly associated with lower SBP in participants treated with CCBs (P = .009) with an especially strong impact in elderly individuals (age ≥ 70) alone (Δ = -14.08 mm Hg, P = .0005).These results underline the important role of estrogens and catecholamines in hypertension and the importance of genotype dependent, age-related adjustments of calcium-channel blocker treatment.
高血压是心血管疾病的主要危险因素，也是全球主要的健康问题之一。遗传因素既影响高血压风险，也影响抗高血压药物的治疗效果。高血压患病率的性别和年龄特异性差异部分由雌激素引起。我们研究了编码参与雌激素代谢的酶的基因中的6个单核苷酸多态性，这些多态性与利尿剂、钙通道阻滞剂（CCB）、血管紧张素转换酶抑制剂和血管紧张素受体阻滞剂（ARB）治疗下收缩压和舒张压（SBP和DBP）结果的性别和年龄特异性差异有关。我们纳入了基于人群的CoLaus队列中的5064名受试者（年龄：40 - 82岁）。对参与者进行了儿茶酚-O-甲基转移酶基因（COMT）变体rs4680、rs737865和rs165599；尿苷二磷酸葡萄糖醛酸基转移酶1A基因家族（UGT1A）变体rs2070959和rs887829；以及芳香化酶基因（CYP19A1）变体rs10046的基因分型。进行了二项式和线性回归分析，并对年龄、性别、体重指数、吸烟、糖尿病和抗高血压治疗进行了校正，以测试所关注的变体是否与血压显著相关。所有研究的COMT变体都与利尿剂、CCB和ARB对SBP或DBP的作用密切相关（P < 0.05），当它们同时出现时表现出累加效应。经过Bonferroni校正后，COMT基因中的多态性rs4680（ValMet）与接受CCB治疗的参与者较低的SBP显著相关（P = 0.009），尤其对单独的老年个体（年龄≥70岁）影响强烈（Δ = -14.08 mmHg，P = 0.0005）。这些结果强调了雌激素和儿茶酚胺在高血压中的重要作用，以及钙通道阻滞剂治疗中基因型依赖性、年龄相关调整的重要性。
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