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Association of endothelial nitric oxide synthase gene polymorphisms with coronary artery disease: an updated meta-analysis and systematic review.

ABSTRACT: Several association studies of endothelial nitric oxide synthase (NOS3) gene polymorphisms with respect to coronary artery disease (CAD) have been published in the past two decades. However, their association with the disease, especially among different ethnic subgroups, still remains controversial. This prompted us to conduct a systematic review and an updated structured meta-analysis, which is the largest so far (89 articles, 132 separate studies, and a sample size of 69,235), examining association of three polymorphic forms of the NOS3 gene (i.e. Glu298Asp, T786-C and 27 bp VNTR b/a) with CAD. In a subgroup analysis, we tested their association separately among published studies originating predominantly from European, Middle Eastern, Asian, Asian-Indian and African ancestries. The pooled analysis confirmed the association of all the three selected SNP with CAD in three different genetic models transcending all ancestries worldwide. The Glu298Asp polymorphism showed strongest association (OR range = 1.28-1.52, and P<0.00001 for all comparisons), followed by T786-C (OR range = 1.34-1.42, and P<0.00001 for all comparisons) and 4b/a, (OR range = 1.19-1.41, and P ? 0.002 for all comparisons) in our pooled analysis. Subgroup analysis revealed that Glu298Asp (OR range = 1.54-1.87, and P<0.004 for all comparisons) and 4b/a (OR range = 1.71-3.02, and P<0.00001 for all comparisons) have highest degree of association amongst the Middle Easterners. On the other hand, T786-C and its minor allele seem to carry a highest risk for CAD among subjects of Asian ancestry (OR range = 1.61-1.90, and P ? 0.01 for all comparisons).

SUBMITTER: Rai H

PROVIDER: S-EPMC4237457 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Association of endothelial nitric oxide synthase gene polymorphisms with coronary artery disease: an updated meta-analysis and systematic review.

Rai Himanshu H Parveen Farah F Kumar Sudeep S Kapoor Aditya A Sinha Nakul N

PloS one 20141119 11

Several association studies of endothelial nitric oxide synthase (NOS3) gene polymorphisms with respect to coronary artery disease (CAD) have been published in the past two decades. However, their association with the disease, especially among different ethnic subgroups, still remains controversial. This prompted us to conduct a systematic review and an updated structured meta-analysis, which is the largest so far (89 articles, 132 separate studies, and a sample size of 69,235), examining associ ...[more]

PMID: 25409023

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Project description: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.

Project description:BackgroundNitric oxide (NO) has numerous functions in the kidney, including control of renal and glomerular hemodynamics, by interfering at multiple pathological and physiologically critical steps of nephron function. Endothelial NOS (eNOS) gene has been considered a potential candidate gene to diabetic nephropathy (DN) susceptibility. Endothelial nitric oxide synthase gene (eNOS-3) polymorphisms have been associated with DN, however some studies do not confirm this association. The analyzed polymorphisms were 4b/4a, T-786C, and G986T.MethodsThe Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement was used in this report. Case-control studies that had diabetic patients with DN as cases and diabetic patients without nephropathy as controls, as well as that evaluated at least one of the three polymorphisms of interest were considered eligible. All studies published up until December 31st, 2012 were identified by searching electronic databases. Hardy-Weinberg equilibrium assessment was performed. Gene-disease association was measured using odds ratio estimation based on the following genetic contrast/models: (1) allele contrast; (2) additive model; (3) recessive model; (4) dominant model and (4) co-dominant model.ResultsTwenty-two studies were eligible for meta-analysis (4b/a: 15 studies, T-786C: 5 studies, and G984T: 12 studies). Considering 4b/a polymorphism, an association with DN was observed for all genetic models: allele contrast (OR = 1.14, CI: 1.04-1.25); additive (OR = 1.77, CI: 1.37-2.28); recessive (OR = 1.77, CI: 1.38-2,27); dominant (OR = 1.12, CI: 1.01-1.24), with the exception for co-dominance model. As well, T-786C polymorphism showed association with all models, with exception for co-dominance model: allele contrast (OR = 1.22, CI: 1.07-1.39), additive (OR = 1.52, CI: 1.18-1.97), recessive (OR = 1.50, CI: 1.16-1.93), and dominant (OR = 1.11, CI: 1.01-1.23). For the G894T polymorphism, an association with DN was observed in allelic contrast (OR = 1.12, CI: 1.03-1.25) and co-dominance models (OR = 1.13, CI: 1.04-1.37).ConclusionsIn the present study, there was association of DN with eNOS 4b/a and T-786C polymorphism, which held in all genetic models tested, except for co-dominance model. G894T polymorphism was associated with DN only in allele contrast and in co-dominance model. This data suggested that the eNOS gene could play a role in the development of DN.

Project description:ObjectiveBy releasing mediators, like nitric oxide (NO), vascular endothelium is considered so significant in the process of atherosclerotic . In fact, the major functions of NO consist in inhibiting the activation of platelet, relaxing the muscles (vascular and smooth ones), and modulating the growth and the migration of cells (vascular and smooth ones). Therefore, this process makes the endothelial nitric oxide synthase (NOS3) considerably important because it possesses atheroprotective activity. Polymophisms, rs1808593 (10G/T) as well as rs891512 (G24943A) within NOS3 gene, play major role in the coronary artery disease (CAD) development. The aim of the study is to evaluate the relationship between the 10G/T and G24943A polymorphisms and the CAD among Tunisian individuals.MethodsWe included, in this survey, a set of 274 patients suffering from CAD together with 162 normotensive subjects. The PCR-RFLP was applied to analyze the polymorphism of intron 23 (10G/T) gene, while the ASA-PCR was used to analyze the intronic G24943A gene polymorphism. Overall and subgroup analyses were performed. Odds ratio (OR) and 95% confidence interval (CI) were used to evaluate the association between NOS3 10G/T and G24943A polymorphisms as well as CAD risk. Statistical analysis was performed with SPSS V.10.ResultsThe genotype frequencies for G24943A polymorphism differed significantly between the CAD patients and the controls. The former had a frequency of 11.4% for the AA genotype, 34.7% for the GA genotype and 53.9% for the GG genotype. The latter had a frequency of only 2.5% for the AA genotype, 29.7% for the GA genotype and 67.7% for the GG genotype (χ2=7.62; OR=1.79; p=0.006). The CAD patient group showed a significantly-higher frequency of the A allele compared to the controls (0.28 vs. 0.16; χ2=15.20; p<0.001). The odds ratio of CAD for A vs. G allele frequency was statistically significant 1.99 (1.4-2.82) at 95% CI. The genotype distribution for the 3 investigated variants of 10G/T were not significantly different between CAD and control subjects (χ2=1.46; OR=1.72; p=0.22). Whereas, 10G/T has revealed barely allelic (χ2=4.45; OR=2.3; p=0.034) correlation with coronary artery disease Conclusion: The present study was designed so that there would be an association between the CAD and NOS3 polymorphism (G24943A). However, these results have proven that the polymorphism of 10G/T is not associated with CAD in the Tunisian population.

Dataset Information

Association of endothelial nitric oxide synthase gene polymorphisms with coronary artery disease: an updated meta-analysis and systematic review.

Publications

Association of endothelial nitric oxide synthase gene polymorphisms with coronary artery disease: an updated meta-analysis and systematic review.

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