目标:间隙连接蛋白α5(GJA5),也称为连接蛋白40(Cx40),在血管壁张力的介导中发挥关键作用,GJA5启动子中两个密切相关的多态性(-44G>A和+71A>G)与男性原发性高血压(EH)易感性增强相关。本研究旨在确定GJA5上游调控区内是否存在新的常见多态性(转录本1B),-26A>G(rs10465885),导致EH的风险增加。
方法:对于本次调查,从中国汉族人群中招募了380名无关的EH患者和396名无关的血压正常个体作为对照,他们的GJA5基因型和血浆肾素浓度通过Sanger测序和自动化学发光免疫测定来确定,分别。通过双光报告基因分析在培养的鼠心肌细胞中探索GJA5变体的功能作用。
结果:GJA5变体赋予EH的风险显着增加(OR:2.156;95%CL:1.661-2.797,P<0.0001),与对照组相比,EH患者的血浆肾素水平显着升高(46.3±7.2vs37.4±6.9,P<0.0001)。启动子-荧光素酶分析显示,与野生型对应物相比,携带该变异的次要等位基因的启动子的活性显着降低(165.67±16.85vs61.53±8.67,P=0.0007)。
结论:这些发现表明,GJA5基因上游的新变体(-26A>G)使人类的EH脆弱性显着增加,提示EH的精确预防和治疗的潜在临床意义。
OBJECTIVE: Gap junction protein alpha 5 (GJA5), also termed connexin 40 (Cx40), exerts a pivotal role in the mediation of vascular wall tone and two closely-linked polymorphisms in the GJA5 promoter (-44G>A and +71A>G) have been associated with enhanced susceptibility to essential hypertension (EH) in men. The present investigation aimed to ascertain whether a novel common polymorphism within the upstream regulatory region of GJA5 (transcript 1B), -26A>G (rs10465885), confers an increased risk of EH.
METHODS: For this investigation, 380 unrelated patients with EH and 396 unrelated normotensive individuals employed as control persons were enrolled from the Chinese Han-ethnicity population, and their GJA5 genotypes and plasma renin concentrations were determined by Sanger sequencing and an automated chemiluminescent immunoassay, respectively. The functional effect of the GJA5 variant was explored in cultured murine cardiomyocytes by dual-light reporter gene analysis.
RESULTS: The GJA5 variant conferred a significantly increased risk for EH (OR: 2.156; 95% CL: 1.661-2.797, P < 0.0001), and significantly increased plasma renin levels were measured in patients with EH in comparison with control individuals (46.3±7.2 vs 37.4±6.9, P < 0.0001). A promoter-luciferase analysis revealed significantly diminished activity of the promoter harboring the minor allele for this variation in comparison with its wild-type counterpart (165.67±16.85 vs 61.53±8.67, P = 0.0007).
CONCLUSIONS: These findings indicate that the novel variant upstream of the GJA5 gene (-26A>G) confers a significantly increased vulnerability of EH in humans, suggesting potential clinical implications for precisive prophylaxis and treatment of EH.