An Updated Meta-Analysis of Endothelial Nitric Oxide Synthase Gene: Three Well-Characterized Polymorphisms with Hypertension

Abstract

BackgroundNumerous individually underpowered association studies have been conducted on endothelial nitric oxide synthase (eNOS) genetic variants across different ethnic populations, however, the results are often irreproducible. We therefore aimed to meta-analyze three eNOS widely-evaluated polymorphisms, G894T (rs1799983) in exon 7, 4b/a in intron 4, and T−786C (rs2070744) in promoter region, in association with hypertension from both English and Chinese publications, while addressing between-study heterogeneity and publication bias.MethodsData were analyzed using Stata software (version 11.0), and random-effects model was applied irrespective of between-study heterogeneity, which was evaluated by subgroup and meta-regression analyses. Publication bias was weighed using the Egger's test and funnel plot.ResultsThere were total 19284/26003 cases/controls for G894T, and 6890/6858 for 4b/a, and 5346/6392 for T−786C polymorphism. Overall comparison of allele 894T with 894G in all study populations yielded a 16% increased risk for hypertension (odds ratio [OR] = 1.16; 95% confidence interval [95% CI]: 1.07–1.27; P = 0.001), and particularly a 32% increased risk (95% CI: 1.16–1.52; P<0.0005) in Asians and a 40% increased risk (95% CI: 1.19–1.65; P<0.0005) in Chinese. Further subgroup analyses suggested that published languages accounted for the heterogeneity for G894T polymorphism. The overall OR of allele 4a versus 4b was 1.29 (95% CI: 1.13–1.46; P<0.0005) in all study populations, and this estimate was potentiated in Asians (OR = 1.42; 95% CI: 1.16–1.72; P<0.0005). For T−786C, ethnicity-stratified analyses suggested a significantly increased risk for −786C allele (OR = 1.25; 95% CI: 1.06–1.47; P = 0.007) and −786CC genotype (OR = 1.69; 95% CI: 1.20–2.38; P = 0.003) in Whites. As an aside, the aforementioned risk estimates reached significance after Bonferroni correction. Finally, meta-regression analysis on other study-level covariates failed to provide any significance for all polymorphisms.ConclusionWe, via a comprehensive meta-analysis, ascertained the role of eNOS G894T and 4b/a polymorphisms on hypertension in Asians, and T−786C polymorphism in Whites.

Polymorphisms of rs1799983 (G>T) and rs1800780 (A>G) of the eNOS gene associated with susceptibility to essential hypertension in the Chinese Hui ethnic population

“…In contrast, the rs2070744 (T>C) variant (T786C mutation) was reported to lack an association with EH in Chinese Kazakh and Japanese groups (Kajiyama et al, 2000;Deng et al, 2007). Consistent with these findings in other ethnic populations, such as Chinese Han (Niu et al, 2011;Chen et al, 2012), Hani (Tang et al, 2008), Yi (Tang et al, 2008), and Uygur (Zhang et al, 2006) in China, polymorphism of rs1799983 (G>T) in the eNOS gene was found to be a risk factor of EH, while rs2070744 (T>C) polymorphism lacked an association with EH, in the Chinese Hui ethnic population in this study. Notably, a positive correlation between rs1800780 (A>G) polymorphism and susceptibility to EH was determined here in the Chinese Hui group.…”

“…An increasing number of genetic studies have demonstrated that DNA polymorphisms in the eNOS gene are associated with coronary artery disease, such as hypertension (Senthil et al, 2005). Previous polymorphic studies revealed a positive association of rs1799983 (G>T) (G894T mutation) of the eNOS gene with susceptibility to EH in various ethnic groups (Chen et al, 2001;Zhang et al, 2006;Khawaja et al, 2007;Tang et al, 2008;Li, 2011;Men et al, 2011;Niu and Qi, 2011). In contrast, the rs2070744 (T>C) variant (T786C mutation) was reported to lack an association with EH in Chinese Kazakh and Japanese groups (Kajiyama et al, 2000;Deng et al, 2007).…”

Influence of fat intake and BMI on the association of rs1799983 NOS3 polymorphism with blood pressure levels in an Iberian population

“…In one hand, this finding suggests a possible ethnic influence on genetic modulation of BP levels responses. On the other hand, as other authors have previously suggested gene-environmental interactions should be analyzed [8].…”

“…A meta-analysis involving 45,287 subjects identified that the T allele of the rs1799983 polymorphism was associated with hypertension predisposition with an odds ratio of 1.20 (p 0.015) [8]. However, when the population was stratified for ethnicity, no significance was reached for Whites (OR 0.99, p 0.828).…”

“…Unfortunately, the results of studies seeking associations of rs1799983 and BP or hypertension have not always been consistent in different populations, which might be due to gene-environmental risk factors interactions [8].…”