Maitland-van der Zee Anke-Hilse, Turner Stephen T, Schwartz Gary L, Chapman Arlene B, Klungel Olaf H, Boerwinkle Eric
Human Genetics Center, University of Texas Health Science Center, Houston, TX 77030, USA.
Pharmacogenet Genomics. 2005 May;15(5):287-93. doi: 10.1097/01213011-200505000-00003.
To assess the influence of variations in multiple candidate genes on inter-individual variation in diastolic blood pressure (DBP) response to hydrochlorothiazide.
A community-based sample of 585 adults with essential hypertension underwent monotherapy with hydrochlorothiazide for 4 weeks. In a nested case-control design, 195 individuals in the highest tertile of DBP response (responders) and 195 individuals in the lowest tertile of DBP response (non-responders) were genotyped for 45 polymorphisms in 19 candidate genes. For those polymorphisms where the set association approach found to be significantly associated with DBP response, logistic regression was performed to estimate the odds ratio (OR) for response associated variation in the identified genotype/haplotype.
Two polymorphisms in the sodium channel gamma-subunit promotor gene, and a polymorphism in the endothelial nitric oxide synthase gene, were significantly associated with blood pressure response to hydrochlorothiazide. In the final experiment for the set association model P=0.038. In the logistic regression analyses, compared to subjects with the CT/CT haplotype of the SCNN1G gene, those with the GA/GA haplotype had OR 5.21 of being a DBP responder [95% CI 1.65-16.47]. Compared to subjects with the GT genotype of the ENOSA_rs1799983 polymorphism, those with the GG genotype had an OR 2.19 of being a DBP responder [95% CI 1.27-3.77].
Two polymorphisms in the sodium channel gamma-subunit promotor gene, and a polymorphism in the endothelial nitric oxide synthase gene, were associated with significant differences in odds of DBP response to hydrochlorothiazide. Follow-up studies are needed to define the functional genetic variations and their mechanisms of pharmacogenetic effects.
评估多个候选基因的变异对个体间舒张压（DBP）对氢氯噻嗪反应差异的影响。
选取585例原发性高血压成年患者的社区样本，接受氢氯噻嗪单药治疗4周。采用巢式病例对照设计，对DBP反应最高三分位数的195例个体（反应者）和DBP反应最低三分位数的195例个体（无反应者）进行19个候选基因中45个多态性的基因分型。对于那些经集合关联分析发现与DBP反应显著相关的多态性，进行逻辑回归以估计已识别基因型/单倍型中与反应相关变异的优势比（OR）。
钠通道γ亚基启动子基因中的两个多态性以及内皮型一氧化氮合酶基因中的一个多态性与对氢氯噻嗪的血压反应显著相关。在集合关联模型的最终实验中P = 0.038。在逻辑回归分析中，与SCNN1G基因CT/CT单倍型的受试者相比，GA/GA单倍型的受试者成为DBP反应者的OR为5.21 [95%置信区间1.65 - 16.47]。与ENOSA_rs1799983多态性GT基因型的受试者相比，GG基因型的受试者成为DBP反应者的OR为2.19 [95%置信区间1.27 - 3.77]。
钠通道γ亚基启动子基因中的两个多态性以及内皮型一氧化氮合酶基因中的一个多态性与DBP对氢氯噻嗪反应的优势比显著差异相关。需要进行后续研究以确定功能基因变异及其药物遗传学效应机制。
