Twin and family history studies suggest a genetic component to the risk of all 3 main pathological types of stroke (ischemic stroke [IS], intracerebral hemorrhage [ICH], and subarachnoid hemorrhage [SAH]).1-4
Genes influencing stroke risk may act through the modification of known risk factors (such as hypertension)5,6
or through novel pathways.
Studies investigating genetic risk factors for human stroke have generally taken a candidate gene case-control approach, studying polymorphisms, the functional consequences of which make them likely to influence stroke risk.7,8
Because stroke is complex and pathologically heterogeneous, there are a large number of potential candidate genes (eg, those involved in coagulation, cholesterol metabolism, and blood pressure regulation).7,8
The relative risk associated with any candidate gene is therefore likely to be small, probably not >1.5 at most, meaning that candidate gene studies in stroke, as for ischemic heart disease, need several thousand cases and controls to be able to identify reliably any real associations.9,10
Studying several candidate genes or comparing genetic influences between stroke subtypes or other subgroups needs even larger numbers.11
Many candidate gene studies in stroke have been completed, but they have generally been too small to reach reliable conclusions, and many have had other methodological shortcomings, for example, in the selection of an appropriate control group.7,8,12
The apolipoprotein E gene
(apoE for protein, APOE
for gene) is one of the most widely studied genes in vascular and neurodegenerative diseases.13
Its protein product, apoE, is a glycoprotein with 3 common isoforms, E2, E3, and E4, encoded by the alleles
4, giving rise to 6 genotypes, with the genotype
3 occurring in about one half to two thirds of people in most populations. The protein plays a major role in lipid transport and metabolism and is also significantly expressed in brain.
4 allele-containing (
4+) genotypes are associated with increased total cholesterol levels, whereas
2 allele-containing (
2+) genotypes are associated with decreased levels.13
This may partly explain why
4 carriers have an increased risk of ischemic heart disease and the observed association in some studies with markers of atherosclerosis (eg, carotid intima-media thickness).14,15
These associations might suggest that
4 carriers should be at increased risk of IS, particularly large artery atherothrombotic stroke. However, studies of APOE
and IS have produced conflicting results.7,8,16
Studies of cerebral vascular pathology in human brain autopsy and biopsy specimens have suggested that APOE
influences cerebral amyloid angiopathy, which is thought to account for a substantial proportion of lobar ICHs in the elderly. It appears that although the
4 allele enhances amyloid deposition in blood vessels, the
2 allele predisposes to vasculopathic changes leading to rupture of amyloid laden vessels.17,18
Thus, one might expect
2 carriers to have increased susceptibility to ICH, especially in a lobar location.
A few studies have published data on APOE and SAH. Although variation in susceptibility to vasculopathic changes could conceivably explain an association, we are not aware of any evidence for this.
In this article, we use systematic review and meta-analysis methods to assess the potential association between APOE and the various pathological types and subtypes of stroke.