Does apolipoprotein E genotype influence the risk of ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage? Systematic review and meta-analyses of 31 studies among 5961 cases and 17,965 controls

Abstract

Background and purpose: Apolipoprotein E genotype (APOE) is associated with cholesterol metabolism, ischemic heart disease, and cerebral amyloid angiopathy, and so may affect risk of both ischemic and hemorrhagic stroke.

Methods: We comprehensively sought and identified studies of the association of apoE with ischemic stroke (IS), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH). We did meta-analyses to assess the evidence for an association between APOE and the various pathological types and subtypes of stroke, and assessed the effects of several methodological criteria.

Results: We analyzed data from 31 eligible studies (26 IS, 8 ICH, and 3 SAH) in 5961 cases and 17 965 controls. epsilon4 allele-containing (epsilon4+) genotypes were significantly associated with IS (odds ratio [OR], 1.11; 95% CI, 1.01 to 1.22) and SAH (OR, 1.42; 95% CI, 1.01 to 1.99) and nonsignificantly with ICH (OR, 1.16; 95% CI, 0.93 to 1.44), whereas epsilon2+ genotypes were associated with ICH (OR, 1.32; 95% CI, 1.01 to 1.74). Associations appeared stronger with epsilon4+ genotypes for large artery compared with other IS subtypes and for Asian compared with white populations, and with epsilon2+ genotypes for lobar compared with deep hemorrhages. However, we found no association between epsilon4+ genotypes and IS when we analyzed only larger studies (>200 cases; OR, 0.99; 95% CI, 0.88 to 1.11) or studies without control selection bias (OR, 0.99; 95% CI, 0.85 to 1.17).

Conclusions: Publication and selection biases make existing studies of APOE and stroke unreliable. Further, very large, methodologically rigorous studies are needed.

Figure 1

Flow chart illustrating numbers of studies (and cases and controls) included in the meta-analyses.

Figure 2

Meta-analysis of case-control studies of effects of APOE ∊4+ genotype on IS. Studies are shown in order of publication date, the earliest first. The OR for each study is shown as a square, the area of which is proportional to its variance, so that larger studies have larger squares. Horizontal lines denote 95% CIs. The summary OR is shown as a diamond, the width of which represents its 95% CI.

Figure 3

Meta-analysis of case-control studies of effects of APOE ∊4+ genotype on IS-pooled results for various subgroups. The OR for each subgroup is shown as a square for which the area is proportional to its variance, so that larger studies have larger squares. Horizontal lines denote 95% CIs. Formal heterogeneity between IS subtypes was not calculable because of double counting of control groups. *Heterogeneity between 3 groups: χ²2df=5.6; P=0.06. †Heterogeneity between 2 groups: χ²1df=12.0; P=0.0005. ‡Heterogeneity between 2 groups: χ²1df=2.9; P=0.09. ¶Heterogeneity between 2 groups: χ²1df=1.5; P=0.2. §Heterogeneity between 3 groups: χ²2df=0.1; P=0.9.

Figure 4

a, Meta-analysis of case-control studies of effects of APOE ∊2+ genotype on ICH. Notation as for Figure 2. Heterogeneity between 6 studies: χ²5df=9.3; P=0.1. b, Meta-analysis of case-control studies of effects of APOE ∊2+ genotype on ICH subdivided by location (lobar and deep). The summary OR for each location is shown as a diamond, the width of which represents its 95% CI. Formal heterogeneity between hemorrhage locations not calculable because of double counting of control groups.

Figure 5

a, Meta-analysis of case-control studies of effects of APOE ∊4+ genotype on ICH. Notation as for Figure 2. Heterogeneity between 6 studies: χ²5df=1.9; P=0.9. b, Metaanalysis of case-control studies of effects of APOE ∊4+ genotype on ICH subdivided by location (lobar and deep). Notation as for Figure 4b.