Association of tumor necrosis factor-alpha-238G>A and apolipoprotein E2 polymorphisms with intracranial hemorrhage after brain arteriovenous malformation treatment.
OBJECTIVE
We previously reported specific genotypes of polymorphisms in two genes, tumor necrosis factor-alpha (TNF-alpha-238G > A) and Apolipoprotein E (ApoE e2), as independent predictors of new intracranial hemorrhage (ICH) in the natural course of untreated brain arteriovenous malformations. We hypothesized that the risk of posttreatment ICH would also be greater in patients with brain arteriovenous malformations with these genotypes.


METHODS
Two hundred fifteen patients undergoing brain arteriovenous malformation treatment (embolization, arteriovenous malformation resection, radiosurgery, or any combination of these) were genotyped and followed longitudinally. Association of genotype with new symptomatic ICH after initiation of treatment was assessed using Cox proportional hazards adjusted for treatment type, demographics, and established ICH risk factors censored at the time of the last follow-up evaluation or death.


RESULTS
The cohort was 48% male and 55% Caucasian, and 52% had an ICH before the initiation of treatment; the mean age +/- standard deviation was 36.6 +/- 17.2 years. Posttreatment ICH occurred in 34 (16%) patients with a median follow-up period of 1.9 years (interquartile range, 1.6 yr). After adjustment, the risk of posttreatment ICH was greater for TNF-alpha-238 AG genotype (hazard ratio [HR], 3.5; 95% confidence interval [CI], 1.3-9.8; P = 0.016) and ApoE e2 (HR, 3.2; 95% CI, 1.0-9.7; P = 0.042). Similar trends for the TNF-alpha-238 AG genotype were seen in surgery (HR, 4.2; 95% CI, 0.6-28.8; P = 0.14) and radiosurgery subsets (HR, 3.8; 95% CI, 0.7-19.4; P = 0.11). An effect of ApoE e2 was seen in radiosurgery subsets (HR, 10.9; 95% CI, 1.3-93.7; P = 0.030), but not in surgery subsets (HR, 1.4; 95% CI, 0.3-7.4; P = 0.67).


CONCLUSIONS
Despite a variety of different mechanisms for posttreatment hemorrhage, these data suggest that the TNF-alpha and ApoE genotypes may contribute common phenotypes of enhanced vascular instability that increase the risk of hemorrhagic outcome.
Achrol
Achal S
AS
Center for Cerebrovascular Research and Department of Anesthesia and Perioperative Care, University of California, San Francisco, California 94110, USA.
Kim
Helen
H
Pawlikowska
Ludmila
L
Trudy Poon
K Y
KY
McCulloch
Charles E
CE
Ko
Nerissa U
NU
Johnston
S Claiborne
SC
McDermott
Michael W
MW
Zaroff
Jonathan G
JG
Lawton
Michael T
MT
Kwok
Pui-Yan
PY
Young
William L
WL
D000293:Adolescent; D000328:Adult; D053329:Apolipoprotein E2 / Q000235:genetics*; D001165:Arteriovenous Malformations / Q000150:complications / Q000235:genetics* / Q000628:therapy; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D020300:Intracranial Hemorrhages / Q000209:etiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D053329:Apolipoprotein E2; D014409:Tumor Necrosis Factor-alpha