Published Online
on December 1, 2005

A more recent version of this article appeared on January 1, 2006

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Submitted on August 2, 2005
Revised on August 29, 2005
Accepted on September 2, 2005

Tumor Necrosis Factor--238G>A Promoter Polymorphism Is Associated With Increased Risk of New Hemorrhage in the Natural Course of Patients With Brain Arteriovenous Malformations

Achal S. Achrol BS; Ludmila Pawlikowska PhD; Charles E. McCulloch PhD; K. Y. Trudy Poon MS; Connie Ha BS; Jonathan G. Zaroff MD; S. Claiborne Johnston MD, PhD; Chanhung Lee MD, PhD; Michael T. Lawton MD; Stephen Sidney MD, MS; Douglas A. Marchuk PhD; Pui-Yan Kwok MD, PhD; William L. Young MD^*; for the UCSF BAVM Study Project

From the Departments of Anesthesia and Perioperative Care and Center for Cerebrovascular Research (A.S.A., K.Y.P., C.L., W.L.Y.), Cardiovascular Research Institute (L.P., C.H., P.Y.K.), Departments of Epidemiology and Biostatistics (C.E.M., S.C.J.), Neurology (S.C.J., W.L.Y.), Medicine (J.G.Z.), Neurological Surgery (M.T.L., W.L.Y.), University of California, San Francisco, California; Division of Research, Kaiser-Permanente Medical Care Program, Oakland, Calif (S.S.); and the Department of Genetics, Duke University Medical Center, Durham, NC (D.A.M.).

^* To whom correspondence should be addressed. E-mail: ccr{at}anesthesia.ucsf.edu.

Background and Purpose--Identification of single-nucleotide polymorphisms (SNPs) associated with increased risk of new intracranial hemorrhage (ICH) after brain arteriovenous malformation (BAVM) diagnosis would facilitate risk stratification and identify potential targets for therapeutic intervention.

Methods--Patients with BAVM were longitudinally followed. Primary outcome was new ICH after diagnosis; censoring events were last follow-up or any BAVM treatment. We genotyped 4 promoter SNPs in 2 inflammatory cytokine genes: interleukin-6 (IL-6-174G>C; IL-6-572G>C) and tumor necrosis factor- (TNF--238G>A; TNF--308G>A). Association of genotype with risk of new ICH was screened using ²; SNPs associated with new ICH were further characterized using Cox proportional hazards.

Results--We genotyped 280 patients (50% female; 59% white, mean±SD age at diagnosis 37±17 years; 40% presenting with ICH). TNF--238G>A was associated with increased risk of new ICH after diagnosis (²; P=0.003). After adjusting for age, race/ethnicity, and clinical presentation, the risk of new ICH was increased for patients with TNF--238 AG genotype (hazard ratio, 4.01; P=0.015). No other SNP was found to be associated with new ICH.

Conclusion--A TNF- SNP was associated with increased risk of new ICH in the natural course of BAVMs. The role of inflammatory cytokines in the pathogenesis of BAVM hemorrhage merits further study.

Key words: cerebral hemorrhage • genetics • vascular malformations

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