Apolipoprotein E epsilon 2 is associated with new hemorrhage risk in brain arteriovenous malformations.
OBJECTIVE
Patients with brain arteriovenous malformation (AVM) are at life-threatening risk of intracranial hemorrhage (ICH). Identification of genetic variants associated with increased new ICH risk would facilitate risk stratification and guide therapeutic intervention.


METHODS
Brain AVM patients evaluated at University of California, San Francisco or Kaiser Permanente Northern California were followed longitudinally. Primary outcome was new ICH after diagnosis; censoring events were any AVM treatment or last follow-up examination. The association of ApoE epsilon2 and epsilon4 genotype with new ICH was evaluated by Kaplan-Meier survival analysis and further characterized via a Cox proportional hazards model.


RESULTS
We genotyped 284 brain AVM patients (50% women; 57% Caucasian; median follow-up time, 0.3 yr) including 18 patients with a history of new ICH). ApoE epsilon2, but not ApoE epsilon4 genotype, was associated with new ICH (P = 0.0052). ApoE epsilon2 carriers had fivefold increased risk of new ICH (hazard ratio, 5.09; 95% confidence interval, 1.46-17.7; P = 0.010; Cox proportional hazards model adjusting for race/ethnicity and clinical presentation). Subset analysis in the largest homogenous ethnic subcohort (Caucasians) confirmed the increased risk of new ICH in ApoE epsilon2 carriers (hazard ratio, 8.71; 95% confidence interval, 1.4-53.9; P = 0.020; multivariate model adjusting for clinical presentation).


CONCLUSIONS
ApoE genotype may influence the risk of ICH in the natural course of brain AVM. The identification of genetic predictors of ICH risk may facilitate estimation of AVM natural history risk and individualize clinical decision-making and therapeutic recommendations.
Pawlikowska
Ludmila
L
The Cardiovascular Research Institute, University of California, San Francisco 94110, USA.
Poon
K Y Trudy
KY
Achrol
Achal S
AS
McCulloch
Charles E
CE
Ha
Connie
C
Lum
Kristen
K
Zaroff
Jonathan G
JG
Ko
Nerissa U
NU
Johnston
S Claiborne
SC
Sidney
Stephen
S
Marchuk
Douglas A
DA
Lawton
Michael T
MT
Kwok
Pui-Yan
PY
Young
William L
WL
D000328:Adult; D053329:Apolipoprotein E2; D001057:Apolipoproteins E / Q000235:genetics*; D001165:Arteriovenous Malformations / Q000150:complications / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D020300:Intracranial Hemorrhages / Q000209:etiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D018807:Polymorphism, Single-Stranded Conformational; D012307:Risk Factors
D053329:Apolipoprotein E2; D001057:Apolipoproteins E