The Relationship of Nitric Oxide Synthase 3(NOS3) Gene Polymorphism in the Risk of Pulmonary Arterial Hypertension: A Systematic Review and Meta-Analysis

Abstract

Background: We performed the present study to better elucidate the correlation of nitric oxide synthase 3 (NOS3) gene polymorphism with the risk of pulmonary arterial hypertension (PAH).

Material/methods: According to the designed search strategy, a systematic literature search was performed through the PubMed, Embase, Web of Science, Cochrane Library, CNKI, VIP and Wan Fang databases to collect published case-control studies on the correlation between NOS3 gene polymorphism and PAH. The search deadline was December 26, 2023. Two reviewers independently screened the literature, extracted data and evaluated the quality according to the inclusion and exclusion criteria. Meta-analysis was performed using RevMan 5.4 software. The odds ratio (OR) and 95% confidence interval (CI) of the genotype distribution were used as the effect indicators.

Results: A total of 11 eligible studies were included, involving three single nucleotide polymorphism (SNP) sites of the NOS3 gene: G894T (rs1799983), 4b/4a (rs61722009), and T-786C (rs2070744). The meta-analysis revealed that for PAH analysis, 4 genetic models of NOS3 G894T polymorphism increased the risk of PAH: the allele model (T vs G, OR=1.9, 95%CI [1.16, 3.11],P= 0.01), the homozygote model (GG vs TT, OR= 1.91, 95%CI [1.04, 3.51], P= 0.04), the heterozygote model (GG vs GT, OR= 3.19, 95%CI [1.65, 6.19], P= 0.0006) and the dominant model (GT+TT vs GG, OR= 3.06, 95%CI [1.54, 6.09], P= 0.001). In the subgroups analysis, the NOS3 G894T polymorphism was found to be associated with the risk of PAH subgroups, including CHD combined with PAH and COPD combined with PAH, Particularly, there is a highly significant correlation with CHD combined with PAH. 2 genetic models of NOS3 4b/4a polymorphism increased the risk of PAH: the homozygote model (BB vs AA, OR= 2.1, 95%CI [1.02, 4.35], P= 0.04) and the recessive model (BB+BA vs AA, OR= 2.55, 95%CI [1.27, 5.11], P= 0.009). In the subgroups analysis, the NOS3 4b/4a polymorphism was found to be associated with the susceptibility of CHD combined with PAH. The results of the combined analysis of each gene model of NOS3 T-786C gene polymorphism sites were not statistically significant, and their P values were all>0.05. The NOS3 G894T and NOS3 4b/4a gene polymorphism had been found to be associated with the risk of PAH in different regional and racial subgroups. In contrast to the NOS3 G894T gene polymorphism, which increased the risk of PAH development in the yellow race subgroup, the NOS3 4b/4a gene polymorphism reduced the risk of PAH development in the white race subgroup and was a protective factor.

Conclusions: The NOS3 G894T (rs1799983) and NOS3 4b/4a (rs61722009) gene polymorphism have a strong correlation with the risk of PAH, with this association varying among different regions and ethnicities. However, it is still necessary to expand the sample size and conduct further studies to confirm whether the NOS3 T-786C (rs2070744) polymorphism tends to increase the incidence of PAH.

Keywords: Chronic Obstructive Pulmonary Disease; Congenital Heart Disease; Meta-Analysis; Nitric Oxide Synthase 3; Pulmonary Arterial Hypertension; Single Nucleotide Polymorphism.