Abstract
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 ε4 mutation and IS was confirmed (ε4 vs. ε3 allele: pooled OR = 1.374, 95% CI, 1.214-1.556; ε2/ε4 vs. ε3/ε3: pooled OR = 1.233, 95% CI, 1.056-1.440; ε3/ε4 vs. ε3/ε3: pooled OR = 1.340, 95% CI, 1.165-1.542; ε4/ε4 vs. ε3/ε3: pooled OR = 1.833, 95% CI, 1.542-2.179; and APOE ε4 carriers vs. non-ε4 carriers: pooled OR = 1.377; 95% CI, 1.203-1.576). Interestingly, APOE ε4 mutation showed a dose-response correlation with IS risk (ε4/ε4 vs. ε2/ε4: pooled OR = 1.625; 95% CI, 1.281-2.060; ε4/ε4 vs. ε3/ε4: 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 ε4 mutation was significantly associated with the risk of IS in a dose-dependent manner, while APOE ε4 mutation was related to SAD subtype onset without a cumulative effect.
Highlights
Rising studies indicate that the apolipoprotein E (APOE) gene is related to the susceptibility of ischemic stroke (IS).certain consensus is limited by the lack of a large sample size of researches
We further investigated on the correlation of APOE gene polymorphisms and risks of IS subtypes by making comparisons in five genetic models, with a particular focus on the APOE ε4 mutation
The result of APOE ε4 homozygosis versus ε4 heterozygote comparisons (ε4/ε4 vs. ε2/ε4 and ε4/ε4 vs. ε3/ε4) was a matter of concern: APOE ε4 mutation could not cause a cumulative effect in generating higher risk of small artery disease (SAD) onset, as showed in Figures 3(f) and 3(g)
Summary
Ischemic stroke (IS) is a disturbing problem worldwide, which is attributable to its leading role in disability and mortality worldwide, regardless of age, ethnicity, or gender [1]. Genetic inheritance provides a guide to the identification of high-risk individual. It deserves to investigate candidate gene polymorphisms in IS pathophysiological pathways. The product of the APOE gene is a polymorphic protein named apolipoprotein E, which modulates the translocation of the cholesterol and other lipids among highly diverse cells [5], involved with neuroinflammation [6] and myelin integrity maintenance [7]. APOE polymorphisms and its risk associations with coronary artery disease [9], hypertension [10], diabetes [11], and carotid arterial atherosclerosis [12] are widely debated. Individual studies of the association between IS and APOE polymorphisms have been explored extensively. We firstly revealed the correlation of the APOE gene and three IS subtypes (large artery atherosclerosis (LAA), small artery disease (SAD), and cardioaortic embolism (CE))
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