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 27bp 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).
Highlights
Endothelial-derived nitric oxide (NO) has been known to be a major contributor in vascular regulation and has been amply implicated with coronary artery disease (CAD)
This association is evident by the obtained pooled odds ratio (OR) in allelic comparison (OR = 1.29, Z value = 6.33 and p,0.00001). (Table 3 and Figure 2) The same pattern of association is seen for almost all the ancestral groups, where generally higher ORs are seen in recessive models as compared to their dominant models. (Table 3 and Figures S1 and S2) Consistent to the seen pattern, the T allele showed a significant association with CAD in almost all ancestral groups, barring the Africans which had only 1 study. (Table 3 and Figure 2) In the case of Allele C vs. T (T786-C) polymorphism, our pooled as well as subgroup results suggested an increased risk in genotypes carrying the minor (C) allele
Contrary to the trends seen in case of Glu298Asp and 4b/a, we observed that for T786-C, Asians followed by Europeans showed highest degree of associations across all three genetic models. (Table 3 and Figure 3) The presence of 4a allele of 4b/ a polymorphism resulted in an increased risk for CAD in the pooled analysis (OR = 1.20) and among two ancestral groups viz. Middle Eastern (OR = 1.71) and Asian (OR = 1.25). (Table 3 and Figure 4) Here too, genotypes carrying .1, 4a alleles showed notably higher risk in pooled analysis as well as in the Middle Eastern and Asian subgroups
Summary
Endothelial-derived nitric oxide (NO) has been known to be a major contributor in vascular regulation and has been amply implicated with coronary artery disease (CAD). NO is an important relaxing factor in the human body and is involved in a variety of different important physiological functions It is synthesized in the human body from L-arginine by at least three isoforms of NO synthase (NOS), viz. [1] NO causes vascular relaxation, it suppresses platelet and leucocyte adhesion to the vascular endothelium [2,3,4] and reduces smooth muscle cell proliferation and migration [5]. It scavenges superoxide radicals [2] and limits the oxidation of atherogenic low density lipoproteins [3] resulting in an overall vasoprotective effect.
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