A novel GJA5 variant associated with increased risk of essential hypertension

• Published in: American journal of translational research Vol. 15; no. 2; pp. 1259 - 1270
• Main Authors: Wang, Juan, Wang, Xue-Cheng, Gu, Zhao-Hua, Ren, Guang-Wei, Zhao, Xiao-Hong, Qu, Xin-Kai, Xu, Ying-Jia, Yang, Yi-Qing
• Format: Journal Article
• Language: English
• Published: United States e-Century Publishing Corporation 01.01.2023
• Subjects: Original; molecular genetics; Essential hypertension; reporter gene assay; GJA5; renin; gap junction protein
• ISSN: 1943-8141; 1943-8141

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 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 (transcript 1B), -26A>G (rs10465885), confers an increased risk of EH. 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 genotypes and plasma renin concentrations were determined by Sanger sequencing and an automated chemiluminescent immunoassay, respectively. The functional effect of the variant was explored in cultured murine cardiomyocytes by dual-light reporter gene analysis. The 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). These findings indicate that the novel variant upstream of the gene (-26A>G) confers a significantly increased vulnerability of EH in humans, suggesting potential clinical implications for precisive prophylaxis and treatment of EH.