Ancestry- and Age-Dependent Effects of NOS3 Polymorphisms on Coronary Heart Disease Risk: A Meta-analysis

The relevance of NOS3 common polymorphisms to coronary heart disease (CHD) risk is inconsistent among different studies, and little is known about the contribution of the genetic variants to the disease development across ancestries and age groups. To address this, we performed a comprehensive meta-analysis stratified by age and ancestry, including 123 eligible studies (29,040 cases and 26,694 controls). Random- or fixed-effects models were applied, based on heterogeneity statistics, to assess the association between the selected polymorphisms (rs1799983 and rs2070744) and CHD risk under various genetic models; p-values were corrected for multiple comparisons. Our findings indicate that the effect of both polymorphisms on the CHD risk varies across ancestries and age groups. In individuals under 55 years, rs1799983, but not rs2070744, showed a marginally significant association with CHD risk in the pooled analysis. However, neither variant appears to be involved in CHD development within any tested ancestry, including East Asian, European, Greater Middle Eastern, and South Asian populations. In individuals over 55 years, rs1799983 was significantly associated with an increased risk of CHD in East Asian, European, and Greater Middle Eastern populations, while rs2070744 contributed to CHD risk in East Asians and Europeans. Among all ancestries, both polymorphisms showed the strongest associations with the disease risk in East Asians, with no significant association observed in the American population. This meta-analysis advances our understanding of the impact of well-known NOS3 variants on CHD incidence across diverse age and ancestry groups. It proposes that the genetic risk of CHD associated with rs1799983 and rs2070744 might be more prominent in older individuals with prolonged environmental exposures. Such insights are critical for developing genetic screening panels to efficiently identify individuals who are genetically at high risk for CHD development.