Association between apolipoprotein E genotype and carotid intima-media thickness may suggest a specific effect on large artery atherothrombotic stroke

Abstract

Background and purpose: Apolipoprotein E genotype (APOE) influences cholesterol levels and ischemic heart disease. Although there is no convincing overall association with ischemic stroke, APOE may influence large artery (atherothrombotic) stroke, for which carotid intima-media thickness (CIMT) is an informative intermediate phenotype. We therefore performed a systematic review and meta-analysis of the association between APOE and CIMT.

Methods: We sought all published studies assessing the association between APOE and CIMT. From each study, we extracted available data on study methods, subjects' characteristics, and mean (and standard deviation) CIMT for each genotype or genotype group. We calculated study-specific and random effects pooled differences in mean CIMT between genotype groups, and assessed heterogeneity between studies and predefined subgroups using I(2) and chi(2) statistics.

Results: Meta-analysis of 22 published studies (30,879 subjects) showed a significant association between APOE and CIMT (pooled mean difference epsilon 4- versus epsilon 2-allele containing genotypes 46 microm, 95% CI 29 to 62, P<0.00001). We found evidence of small study (mainly publication) bias, with a diminished (but still highly statistically significant) association in studies of >1000 subjects (pooled mean difference 17 microm, 95% CI 12 to 23, P<0.00001). The association was larger among high vascular risk and eastern Asian populations, but this may simply reflect the smaller size of these studies.

Conclusions: Our results show a clear association of APOE with CIMT, even though publication bias means that this is overestimated by the published literature. These findings suggest the possibility of a specific association with large artery ischemic stroke.

Figure 1

Flow diagram of study selection and exclusion process.

Figure 2

Study-specific and pooled mean differences of the CIMT between E4 and E2 genotypes (ordered by publication date). The sizes of the squares are proportional to the statistical weight given to each study. The horizontal lines represent 95% CI. The width of the diamond represents the 95% CI of the pooled estimate. Heterogeneity between studies: I²=80%.

Figure 3

Pooled mean differences of the CIMT between E4 and E2 genotypes: results for various subgroups. The size of the squares is proportional to the number of subjects. Horizontal lines represent 95% CI.