Published Online
on December 29, 2005

A more recent version of this article appeared on February 1, 2006

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Submitted on July 21, 2005
Revised on October 3, 2005
Accepted on October 21, 2005

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

Cathie Sudlow DPhil, FRCP^*; Nahara Ananí Martínez González MSc; Jennifer Kim; and Catriona Clark

From the Division of Clinical Neurosciences (C.S., N.A.M.G.), Medical Genetics Section (C.S.), and Medical School (J.K., C.C.), University of Edinburgh, United Kingdom.

^* To whom correspondence should be addressed. E-mail: cathie.sudlow{at}ed.ac.uk.

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. 4 allele-containing (4+) 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 2+ genotypes were associated with ICH (OR, 1.32; 95% CI, 1.01 to 1.74). Associations appeared stronger with 4+ genotypes for large artery compared with other IS subtypes and for Asian compared with white populations, and with 2+ genotypes for lobar compared with deep hemorrhages. However, we found no association between 4+ 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.

Key words: apolipoproteins E • genetics • meta-analysis • stroke

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