Polymorphisms in genes involved in inflammatory and angiogenic pathways and the risk of hemorrhagic presentation of brain arteriovenous malformations.
OBJECTIVE
Accurate estimates of intracranial hemorrhage (ICH) risk in patients harboring brain arteriovenous malformation (BAVM) are needed to evaluate interventional strategies and to help guide clinical management. Identification of genetic polymorphisms associated with ICH would facilitate risk stratification in BAVM patients.


METHODS
We identified patients with BAVM and documented clinical presentation, demographic data, venous drainage pattern, and BAVM size. Patients were genotyped for 5 polymorphisms in 3 inflammatory cytokine genes, and 9 polymorphisms in 5 angiogenesis-related genes. Association of genotype with risk of hemorrhagic BAVM presentation was evaluated using logistic regression analysis.


RESULTS
We genotyped 180 patients with BAVM (53% female, 57% white, mean age at diagnosis 35+/-17 years, 41% presenting with ICH). BAVM patients homozygous for the interleukin 6 (IL6)-174G allele had a greater risk of ICH presentation (OR, 2.62, P=0.003) than IL6-174C carriers. In a multivariate logistic regression model, IL6-174G>C genotype, small BAVM size, and exclusively deep venous drainage were independent predictors of ICH presentation. A similar univariate trend was noted for the TNFalpha-308 GG genotype (P=0.055). The other polymorphisms genotyped were not associated with ICH.


CONCLUSIONS
A polymorphism in the inflammatory cytokine IL6, but not polymorphisms in angiogenesis-related genes, was associated with ICH presentation of BAVM. Further studies are needed to define the role of inflammatory cytokines in the pathogenesis of BAVM hemorrhage.
Cardiovascular Research Institute, University of California, San Francisco, Calif 94110, USA.
Ludmila
L
Pawlikowska
Mary N
MN
Tran
Achal S
AS
Achrol
Charles E
CE
McCulloch
Connie
C
Ha
Denise L
DL
Lind
Tomoki
T
Hashimoto
Jonathan
J
Zaroff
Michael T
MT
Lawton
Douglas A
DA
Marchuk
Pui-Yan
PY
Kwok
William L
WL
Young
D000328:Adult; D005260:Female; D005838:Genotype; D006801:Humans; D007249:Inflammation / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics*; D002538:Intracranial Arteriovenous Malformations / Q000150:complications* / Q000235:genetics; D020300:Intracranial Hemorrhages / Q000209:etiology* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D018919:Neovascularization, Physiologic / Q000235:genetics; D011110:Polymorphism, Genetic; D018570:Risk Assessment
D015850:Interleukin-6