title: APOE genotype and extent of bleeding and outcome in lobar intracerebral haemorrhage: a genetic association study.
abstract: BACKGROUND
  Carriers of APOE ε2 and ε4 have an increased risk of intracerebral haemorrhage (ICH) in lobar regions, presumably because of the effects of these gene variants on risk of cerebral amyloid angiopathy. We aimed to assess whether these variants also associate with severity of ICH, in terms of haematoma volume at presentation and subsequent outcome.
  
  
  METHODS
  We investigated the association of APOE ε2 and ε4 with ICH volume and outcomes in patients with primary ICH in three phases: a discovery phase of 865 individuals of European ancestry from the Genetics of Cerebral Hemorrhage on Anticoagulation study, and replication phases of 946 Europeans (replication 1) and 214 African-Americans (replication 2) from an additional six studies. We also assessed the association of APOE variants with ICH volume and outcomes in meta-analyses of results from all three phases, and the association of APOE ε4 with mortality in a further meta-analysis including data from previous reports. Admission ICH volume was quantified on CT scan. We assessed functional outcome (modified Rankin scale score 3-6) and mortality at 90 days. We used linear regression to establish the effect of genotype on haematoma volume and logistic regression to assess the effect on outcome from ICH.
  
  
  RESULTS
  For patients with lobar ICH, carriers of the APOE ε2 allele had larger ICH volumes than did non-carriers in the discovery phase (p=2·5×10(-5)), in both replication phases (p=0·008 in Europeans and p=0·016 in African-Americans), and in the meta-analysis (p=3·2×10(-8)). In the meta-analysis, each copy of APOE ε2 increased haematoma size by a mean of 5·3 mL (95% CI 4·7-5·9; p=0·004). Carriers of APOE ε2 had increased mortality (odds ratio [OR] 1·50, 95% CI 1·23-1·82; p=2·45×10(-5)) and poorer functional outcomes (modified Rankin scale score 3-6; 1·52, 1·25-1·85; p=1·74×10(-5)) compared with non-carriers after lobar ICH. APOE ε4 was not associated with lobar ICH volume, functional outcome, or mortality in the discovery phase, replication phases, or meta-analysis of these three phases; in our further meta-analysis of 2194 patients, this variant did not increase risk of mortality (1·08, 0·86-1·36; p=0·52). APOE allele variants were not associated with deep ICH volume, functional outcome, or mortality.
  
  
  CONCLUSIONS
  Vasculopathic changes associated with the APOE ε2 allele might have a role in the severity and clinical course of lobar ICH. Screening of patients who have ICH to identify the ε2 variant might allow identification of those at increased risk of mortality and poor functional outcomes.
  
  
  BACKGROUND
  US National Institutes of Health-National Institute of Neurological Disorders and Stroke, Keane Stroke Genetics Research Fund, Edward and Maybeth Sonn Research Fund, and US National Center for Research Resources.
authors: Hemorrhagic Stroke Research Group, Massachusetts General Hospital, Boston, MA, USA.
authors: Alessandro
authors: A
authors: Biffi
authors: Christopher D
authors: CD
authors: Anderson
authors: Jeremiasz M
authors: JM
authors: Jagiella
authors: Helena
authors: H
authors: Schmidt
authors: Brett
authors: B
authors: Kissela
authors: Björn M
authors: BM
authors: Hansen
authors: Jordi
authors: J
authors: Jimenez-Conde
authors: Caroline R
authors: CR
authors: Pires
authors: Alison M
authors: AM
authors: Ayres
authors: Kristin
authors: K
authors: Schwab
authors: Lynelle
authors: L
authors: Cortellini
authors: Joanna
authors: J
authors: Pera
authors: Andrzej
authors: A
authors: Urbanik
authors: Javier M
authors: JM
authors: Romero
authors: Natalia S
authors: NS
authors: Rost
authors: Joshua N
authors: JN
authors: Goldstein
authors: Anand
authors: A
authors: Viswanathan
authors: Alexander
authors: A
authors: Pichler
authors: Christian
authors: C
authors: Enzinger
authors: Raquel
authors: R
authors: Rabionet
authors: Bo
authors: B
authors: Norrving
authors: David L
authors: DL
authors: Tirschwell
authors: Magdy
authors: M
authors: Selim
authors: Devin L
authors: DL
authors: Brown
authors: Scott L
authors: SL
authors: Silliman
authors: Bradford B
authors: BB
authors: Worrall
authors: James F
authors: JF
authors: Meschia
authors: Chelsea S
authors: CS
authors: Kidwell
authors: Joseph P
authors: JP
authors: Broderick
authors: Steven M
authors: SM
authors: Greenberg
authors: Jaume
authors: J
authors: Roquer
authors: Arne
authors: A
authors: Lindgren
authors: Agnieszka
authors: A
authors: Slowik
authors: Reinhold
authors: R
authors: Schmidt
authors: Daniel
authors: D
authors: Woo
authors: Jonathan
authors: J
authors: Rosand
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D053329:Apolipoprotein E2 / Q000235:genetics*; D002540:Cerebral Cortex / Q000473:pathology*; D002543:Cerebral Hemorrhage / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D053329:Apolipoprotein E2