Evaluation of the relationship between T663A polymorphism in the alpha-epithelial sodium channel gene and essential hypertension

Objectives:

To evaluate the relationship between alpha epithelial sodium channel (alpha-ENaC) T663A polymorphism and the risk of essential hypertension.

Methods:

This meta-analysis was conducted between November 2014 and February 2015 in Shanghai Medical Instrumentation College, Shanghai, China. We collected all published available case-control data (N=12) identified through PubMed, Web of Science, Scopus, and Chinese National Knowledge Infrastructure (CNKI) up to December 2014. The pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using the fixed- or random-effect model.

Results:

Although subgroup analysis showed that alpha-ENaC T663A polymorphism was associated with essential hypertension in North American individuals (OR=1.55, 95% CI=1.22-1.98, p=0.0003), our meta-analysis results did not confirm such association overall (OR=1.03, 95% CI=0.92-1.15, p=0.62). The lack of association was further confirmed by the non-superiority test (p<0.0001).

Conclusion:

Alpha-ENaC T663A polymorphism might not be a risk factor for essential hypertension.Hypertension is one of the most important risk factor for cardiovascular disease.1-3 However, its etiology in the vast majority of cases (~90%) is unknown, and thus the essential hypertension term is employed to describe such situations.4 Nowadays, essential hypertension is considered as a multifactorial disease resulting from the interplay of many genetic, environmental, and behavioral factors.5 Among them, sodium has long been deemed as one of the pivotal environmental factors due to its direct regulatory effect on blood pressure.5,6 The amiloride-sensitive epithelial sodium channel (ENaC) lies in the collecting duct of the kidney, and regulates sodium reabsorption. This channel is composed of 3 homologous subunits: alpha, beta, and gamma. Several studies have reported that mutations in beta-ENaC or gamma-ENaC can result in constitutive sodium reabsorption, thus leading to the development of an autosomal-dominant Mendelian hypertensive disorder, Liddle syndrome.7-11 Therefore, some “milder” mutations or functional polymorphisms were assumed to play some etiological roles in essential hypertension. Following this hypothesis, recent studies have reported some potential associated variants.12 Among them, T663A polymorphism in the alpha-ENaC gene has attracted some attention due to its reported ability to influence the channel activity.13,14 The A allele of T663A polymorphism could reduce the surface expression of ENaC, and the T allele of T663A polymorphism could increase ENaC activity.13,14 Accordingly, Ambrosius et al15 observed that the A allele of T663A polymorphism was associated with being normotensive in Blacks and Caucasians. However, a similar study performed in a Japanese population indicated that the A allele of T663A polymorphism was enriched in essential hypertensive patients,16 and Wang et al17 found that there was a lack of association between the T663A polymorphism and essential hypertension in 2 ethnic groups in China. Therefore, there is still a controversy over the association between T663A polymorphism in the alpha-ENaC gene and essential hypertension. Therefore, we performed a meta-analysis to investigate the relationship between alpha-ENaC T663A polymorphism and essential hypertension.