Apolipoprotein E 4 Polymorphism As a Risk Factor for Ischemic Stroke: A Systematic Review and Meta-Analysis

Introduction: Rising studies indicate that the apolipoprotein E (APOE) gene is related to the susceptibility of ischemic stroke (IS). However, certain consensus is limited by the lack of a large sample size of researches. This meta-analysis was performed to explore the potential association between the APOE gene and IS.

Methods: To identify relevant case control studies in English publications by October 2020, we searched PubMed, Embase, Web of Science, and the Cochrane Library. Pooled odds ratios (ORs) with fixed- or random-effect models and corresponding 95% confidence intervals (CIs) were calculated to analyze potential associations.

Results: A total of 55 researches from 32 countries containing 12207 IS cases and 27742 controls were included. The association between APOE gene 4 mutation and IS was confirmed (4 vs. 3 allele: pooled OR = 1.374, 95% CI, 1.214-1.556; 2/4 vs. 3/3: pooled OR = 1.233, 95% CI, 1.056-1.440; 3/4 vs. 3/3: pooled OR = 1.340, 95% CI, 1.165-1.542; 4/4 vs. 3/3: pooled OR = 1.833, 95% CI, 1.542-2.179; and APOE 4 carriers vs. non-4 carriers: pooled OR = 1.377; 95% CI, 1.203-1.576). Interestingly, APOE 4 mutation showed a dose-response correlation with IS risk (4/4 vs. 2/4: pooled OR = 1.625; 95% CI, 1.281-2.060; 4/4 vs. 3/4: pooled OR = 1.301; 95% CI, 1.077-1.571). Similar conclusions were drawn in the small artery disease (SAD) subtype, but not in large artery atherosclerosis (LAA) or in cardioaortic embolism (CE), by subgroup analysis.

Conclusions: These observations reveal that specific APOE 4 mutation was significantly associated with the risk of IS in a dose-dependent manner, while APOE 4 mutation was related to SAD subtype onset without a cumulative effect.