title: 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: OBJECTIVE
  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.
authors.affiliation: Division of Clinical Neurosciences, University of Edinburgh, United Kingdom. cathie.sudlow@ed.ac.uk
authors.forename: Cathie
authors.initials: C
authors.lastname: Sudlow
authors.forename: Nahara Ananí
authors.initials: NA
authors.lastname: Martínez González
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kim
authors.forename: Catriona
authors.initials: C
authors.lastname: Clark
mesh_terms: D000328:Adult; D000368:Aged; D001057:Apolipoproteins E / Q000235:genetics*; D002543:Cerebral Hemorrhage / Q000235:genetics*; D003627:Data Interpretation, Statistical; D016206:Databases, Bibliographic; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007511:Ischemia / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D012306:Risk; D012307:Risk Factors; D012984:Software; D020521:Stroke / Q000235:genetics*; D013345:Subarachnoid Hemorrhage / Q000235:genetics*
chemical_list: D001057:Apolipoproteins E