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 χ 2 statistics. Results— Meta-analysis of 22 published studies (30 879 subjects) showed a significant association between APOE and CIMT (pooled mean difference ε4- versus ε2-allele containing genotypes 46 μm, 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 μm, 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. Conclusion— 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.