Association of APOE ε4 gene polymorphisms with myocardial infarction susceptibility: an updated meta-analysis with ethnicity stratification and credibility ceiling analysis

Abstract Background Myocardial infarction (MI) is a leading cause of disability and death worldwide. Apolipoprotein E ( APOE ) plays a key role in lipid metabolism, and its genetic polymorphisms have been implicated in atherosclerosis and coronary artery diseases. However, the association between the APOE ε4 polymorphism and MI risk remains inconsistent across populations. Methods A comprehensive meta-analysis of case–control studies evaluating the association between MI risk and APOE ε4 polymorphisms was conducted in accordance with the PRISMA guidelines. Relevant English-language studies were identified using the PubMed, Web of Science, Google Scholar, and CNKI databases. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated under allelic, dominant, heterozygous, and homozygous genetic models using fixed- or random-effects models, as appropriate. Ethnicity-based subgroup analyses, sensitivity analyses, publication bias assessments, and credibility ceiling analyses were performed to evaluate robustness. Results A total of 36 eligible studies comprising 13,791 MI cases and 12,854 controls were included in the analysis. Overall analysis showed that the APOE ε4 allele was significantly associated with an increased MI risk (OR = 1.40, 95% CI: 1.22–1.62). Consistent risk-enhancing effects were observed in the dominant, heterozygous, and homozygous models, with evidence of a gene-dose relationship. Subgroup analyses demonstrated a stronger, more consistent association in Asian populations, whereas associations in Caucasian populations were weaker and more heterogeneous. Sensitivity analyses, including the exclusion of studies that deviated from Hardy–Weinberg equilibrium, confirmed the stability of the findings. Egger’s regression test suggested potential publication bias, and trim-and-fill analysis attenuated the pooled effect estimates. Credibility ceiling analysis demonstrated that the overall allelic and dominant associations remained statistically significant across credibility ceilings of up to 20%, supporting the robustness of the observed ε4-related associations. Conclusions This meta-analysis supports an association between the APOE ε4 polymorphism and increased susceptibility to myocardial infarction, particularly in Asian populations. However, evidence of potential publication bias suggests that the magnitude of this association should be interpreted cautiously and confirmed in future large-scale multiethnic studies.