Glu298Asp variant of endothelial nitric oxide synthase gene and acute or early presentation of coronary artery disease: An updated systematic review and meta-analysis

Abstract

Abstract Background Several published reports have attested the association of Glu298Asp polymorphism (rs1799983) residing in the endothelial nitric oxide synthase (NOS3) gene with lower levels of circulating nitric oxide as well as coronary artery disease (CAD). However, its association status with acute or early presentation of CAD such as acute/sub-acute myocardial infarction, acute coronary syndrome, premature CAD and unstable angina is still unclear. Purpose Against this background, we conducted an updated systematic review and a study level meta-analysis to assess the association of NOS3 Glu298Asp polymorphism with acute or early CAD. Methods A comprehensive online search to identify relevant studies and sub-studies was performed on several databases including PubMed, EMBASE, MEDLINE, Scopus, Cochrane library and Web of Science and later stratified into two ancestral subgroups: ‘European ancestry’ and ‘All other ancestries combined’. Study level odds ratios (ORs) and their 95% confidence intervals (CI) were pooled using random effects employing a Z test. Results Out of a total of 193 distinct records identified through online search, 36 articles with 38 different studies, with a total sample of 27,244 (11,444 cases / 15,800 controls) were included for quantitative synthesis. (Figure 1.) Pooled results suggested significant associations of NOS3 Glu298Asp polymorphism with acute or early CAD through dominant as well as allelic genetic models (p≤0.004), driven by the ‘All other ancestries combined’ subgroup. Our ‘All other ancestries combined’ subgroup demonstrated an additional risk of 36% and 37% for acute or early CAD, through dominant and allelic genetic models respectively (OR= 1.36, 95%CI= 1.12, 1.65, p= 0.002 and OR= 1.37, 95%CI= 1.14, 1.64, p= 0.0007 respectively). On the other hand, the European ancestry subgroup failed to show any meaningful associations. Sensitivity analysis (Figure 2.) and a substudy for myocardial infarction endpoint further attested our observed associations. Conclusions Our present meta-analysis indicates the association of NOS3 Glu298Asp polymorphism with acute or early presentation of CAD, predominantly driven by ‘All other ancestries combined’ subgroup. In contrast, ‘European ancestry’ subgroup does not demonstrate any significant association. Further large-scale investigations are required to confirm our derived results.Figure 1.Figure 2.