Ischemic heart disease (IHD) is among the leading causes of death worldwide. Methylenetetrahydrofolate reductase (MTHFR) polymorphisms have been associated with IHD risk, but the findings presented with heterogeneity. The purpose of the present meta-analysis was to provide an updated evaluation by integrating machine-learning based analytics to examine the potential source of heterogeneity on the associations between MTHFR polymorphisms and the risk of various subtypes of IHD, as well as the possible impact of air pollution on MTHFR polymorphisms and IHD risks. A comprehensive search of various databases was conducted to locate 123 studies (29,697 cases and 31,028 controls) for MTHFR C677T, and 18 studies (7158 cases and 5482 controls) for MTHFR A1298C. Overall, MTHFR 677 polymorphisms were risks for IHD (TT: Risk ratio (RR) = 1.23, p < 0.0001; CT: RR = 1.04, p = 0.0028, and TT plus CT: RR = 1.09, p < 0.0001). In contrast, MTHFR 677 CC wildtype was protective against IHD (RR = 0.91, p < 0.00001) for overall populations. Three countries with elevated IHD risks from MTHFR C677T polymorphism with RR >2 included India, Turkey, and Tunisia. Meta-predictive analysis revealed that increased air pollution was associated with increased MTHFR 677 TT and CT polymorphisms in both the case and control group (p < 0.05), with the trend of increased IHD risk resulting from increased air pollution. These results associate the potential inflammatory pathway with air pollution and the folate pathway with MTHFR polymorphism. Future intervention studies can be designed to mitigate MTHFR enzyme deficiencies resulting from gene polymorphisms to prevent IHDs for at-risk populations.
Keywords: air pollution; ischemic heart disease; meta-prediction; methylenetetrahydrofolate reductase gene (MTHFR).