A sweeping new meta-analysis of 36 case-control studies covering 13,791 myocardial infarction patients and 12,854 controls has concluded that the apolipoprotein E ε4 allele is significantly associated with an increased susceptibility to heart attack. The pooled analysis, published on 8 October 2026 in the Egyptian Journal of Medical Human Genetics, reports that people carrying the ε4 variant had roughly 1.4 times the odds of myocardial infarction compared with carriers of the more common ε3 allele, with an overall odds ratio of 1.40 and a 95 percent confidence interval of 1.22 to 1.62. The association was strongest in Asian populations and considerably weaker, and statistically non-significant, in Caucasian populations.
The research team, led by Praveen Kumar Chandra Sekar and Ramakrishnan Veerabathiran, conducted the work in accordance with the PRISMA 2021 reporting guidelines and registered the review protocol with the International Prospective Register of Systematic Reviews under ID CRD420261298241. They searched PubMed, Web of Science, Google Scholar and the Chinese CNKI database for English-language case-control studies published up to 31 January 2026, using combinations of keywords such as apolipoprotein E, myocardial infarction and polymorphism. From an initial pool of 1,563 records, duplicates were removed, titles and abstracts were screened, and full texts were assessed against predefined inclusion criteria, ultimately yielding the 36 studies included in the final synthesis.
The APOE gene encodes a protein involved in the transport and metabolism of fats, and its levels significantly influence low-density lipoprotein cholesterol and triglycerides. The gene exists in three common alleles, ε2, ε3 and ε4, which combine into six possible genotypes. Prior research summarized in the paper indicates that individuals carrying one copy of ε4 generally show a modest increase in cardiovascular risk, while those carrying two copies tend to experience a greater adverse effect on lipid metabolism and higher susceptibility to atherosclerotic disease. Because lipid metabolism is integral to the development of atherosclerosis, the ε4 variant has long been considered a plausible genetic candidate for myocardial infarction susceptibility, although individual studies have produced inconsistent results.
The authors argue that earlier meta-analyses suffered from important limitations. Most evaluated studies published before 2020, omitting more recent evidence; most relied on allelic or simple genotype comparisons rather than multiple genetic inheritance models; and ethnicity-specific differences were not consistently evaluated, even though allele frequencies and linkage disequilibrium patterns differ widely across ethnic groups. The new analysis addressed these gaps by pooling data under four genetic models, stratifying results by ethnicity, and applying a statistical technique rarely used in cardiovascular genetics called credibility ceiling analysis, which tests whether pooled findings survive increasingly conservative assumptions about how many individual studies may have estimated their effects in the wrong direction.
The statistical work was performed using Review Manager version 5.4, with the ε3 allele and ε3/ε3 genotype serving as reference categories. Between-study heterogeneity was assessed with Cochran’s Q test and the I-squared statistic, with values above 50 percent considered substantial, and random-effects models were applied where significant heterogeneity was present. Beyond the headline allelic result, the dominant model, comparing ε4 carriers against non-carriers, yielded an odds ratio of 1.50 (95 percent CI 1.29 to 1.75) with considerable heterogeneity of I-squared equal to 77 percent. The heterozygous comparison of ε3/ε4 against ε3/ε3 gave an odds ratio of 1.32 (95 percent CI 1.15 to 1.52), while the homozygous comparison of ε4/ε4 against ε3/ε3 produced the largest estimate, an odds ratio of 2.24 (95 percent CI 1.49 to 3.37). The authors interpret this gradient as evidence of a gene-dose relationship, in which each additional copy of the ε4 allele confers progressively greater susceptibility.
Ethnicity-stratified results revealed a striking divergence. Among Asian populations, the allelic model produced a strong, statistically significant association with an odds ratio of 1.91 (95 percent CI 1.49 to 2.45) and moderate heterogeneity of 68 percent, while the dominant model yielded an odds ratio of 2.18 (95 percent CI 1.72 to 2.76). In Caucasian populations, by contrast, the allelic association was weak and not statistically significant, with an odds ratio of 1.13 (95 percent CI 0.96 to 1.33) and substantial heterogeneity of 81 percent, and the dominant model gave a smaller odds ratio of 1.21 (95 percent CI 1.03 to 1.43). The tests for subgroup differences were statistically significant in both models, suggesting that ethnicity may modify the association, potentially through differences in allele frequency distributions, linkage disequilibrium patterns, environmental exposures, lifestyle factors or gene-environment interactions.
Several robustness checks supported the core finding. Sensitivity analyses that sequentially removed individual studies left the pooled estimates essentially unchanged. Excluding studies whose control groups deviated from Hardy-Weinberg equilibrium produced an even larger pooled allelic odds ratio of 1.77 (95 percent CI 1.43 to 2.21). A quality-based subgroup analysis using the Newcastle-Ottawa Scale showed significant associations in both high-quality studies, with an odds ratio of 1.33 (95 percent CI 1.13 to 1.56), and moderate-quality studies, with an odds ratio of 1.53 (95 percent CI 1.16 to 2.00), and no significant difference between the two quality strata. Credibility ceiling analysis at ceilings of 5, 10, 15 and 20 percent, which adjusts study-specific variances under the assumption that a given fraction of studies may have misestimated the direction of their effects, showed that the overall allelic and dominant associations remained statistically significant across all tested levels, with pooled allelic odds ratios ranging from 1.39 at baseline to 1.41 at the 20 percent ceiling.
The robustness picture, however, was not uniformly reassuring. Egger’s regression test for the allelic model indicated potential publication bias with a P value of 0.0443, and a subsequent trim-and-fill analysis imputed eight potentially missing studies, after which the pooled effect estimate was attenuated to an odds ratio of 1.18 (95 percent CI 0.97 to 1.44) that was no longer statistically significant. This suggests that small-study effects or unpublished negative findings may have inflated the apparent magnitude of the association. The credibility ceiling analysis also revealed differential robustness by ethnicity: in the Asian subgroup both the allelic and dominant models remained significant across all ceiling levels, whereas in the Caucasian subgroup the allelic model lost statistical significance at the 10 percent ceiling and the dominant model at the 15 percent ceiling, indicating greater sensitivity to residual bias and study-level uncertainty in that population.
The authors discuss plausible biological mechanisms while explicitly cautioning that the meta-analysis cannot establish causality. The ε4 allele has been linked to alterations in lipid metabolism, impaired lipoprotein clearance, elevated circulating low-density lipoprotein cholesterol and a more atherogenic lipid profile, which may promote lipid accumulation in the arterial wall and accelerate atherosclerotic lesion development. The allele has also been associated with increased oxidative stress, endothelial dysfunction and enhanced pro-inflammatory signaling, processes that contribute to vascular injury, plaque formation and plaque instability. The authors further speculate that population-specific dietary habits, lifestyle factors, interactions with other cardiometabolic susceptibility genes and even gut microbiota composition may partly explain the stronger associations observed in Asian populations, though they note these possibilities require future research integrating host genetics, nutrition and microbiome profiling.
The study carries substantial limitations that the authors detail at length. Substantial residual heterogeneity persisted in several genetic models, particularly among Caucasian populations, and broad ethnic categories do not capture the considerable genetic, geographic and environmental diversity within Asian and Caucasian groups. Several countries were represented by only a single study, individual-level data were unavailable, and most included studies reported unadjusted genotype or allele frequencies rather than estimates adjusted for major cardiovascular risk factors such as age, sex, smoking, hypertension, diabetes and dyslipidemia, meaning the pooled estimates primarily reflect crude genetic associations subject to residual confounding and population stratification. Only English-language studies were included, which may have introduced language bias, and the possibility of partial cohort overlap could not be ruled out. The authors conclude that the findings should be interpreted as evidence of an association, particularly robust in Asian populations, rather than definitive proof of causation, and that large-scale, multiethnic, prospective and functionally oriented studies are needed to confirm the role of the APOE ε4 polymorphism in myocardial infarction susceptibility.
Subject of Research: A meta-analysis of the association between the APOE ε4 gene polymorphism and myocardial infarction susceptibility across ethnic groups
Article Title: Association of APOE ε4 gene polymorphisms with myocardial infarction susceptibility: an updated meta-analysis with ethnicity stratification and credibility ceiling analysis
Article References: Chandra Sekar, P. K., & Veerabathiran, R. (2026). Association of APOE ε4 gene polymorphisms with myocardial infarction susceptibility: an updated meta-analysis with ethnicity stratification and credibility ceiling analysis. Egyptian Journal of Medical Human Genetics, 27(1), Article 86. https://doi.org/10.1186/s43042-026-00916-7
Image Credits: AI Generated
DOI: 10.1186/s43042-026-00916-7
Keywords: APOE ε4, myocardial infarction, meta-analysis, genetic susceptibility, case-control studies, ethnicity stratification, publication bias, credibility ceiling analysis, lipid metabolism, atherosclerosis, odds ratio, Hardy-Weinberg equilibrium
News Source: Juliet Wilcox. (October 28, 2026). APOE ε4 Carriers Face Higher Heart Attack Risk, Large Genetic Review Finds. Scienmag.
