Tumor necrosis factor-alpha-238G>A promoter polymorphism is associated with increased risk of new hemorrhage in the natural course of patients with brain arteriovenous malformations.

Abstract

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-alpha (TNF-alpha-238G>A; TNF-alpha-308G>A). Association of genotype with risk of new ICH was screened using chi2; 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-alpha-238G>A was associated with increased risk of new ICH after diagnosis (chi2; P=0.003). After adjusting for age, race/ethnicity, and clinical presentation, the risk of new ICH was increased for patients with TNF-alpha-238 AG genotype (hazard ratio, 4.01; P=0.015). No other SNP was found to be associated with new ICH.

CONCLUSIONS:

A TNF-alpha 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.

• Authors: Achal S Achrol, Ludmila Pawlikowska, Charles E McCulloch, K Y Trudy Poon, Connie Ha, Jonathan G Zaroff, S Claiborne Johnston, Chanhung Lee, Michael T Lawton, Stephen Sidney, Douglas A Marchuk, Pui-Yan Kwok, William L Young, UCSF BAVM Study Project
• Journal: Stroke (Stroke) Vol. 37 Issue 1 Pg. 231-4 (Jan 2006) ISSN: 1524-4628 [Electronic] United States
• PMID: 16322490 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Interleukin-6
• Tumor Necrosis Factor-alpha

Topics

• Adult
• Arteriovenous Malformations (genetics, pathology)
• Brain (pathology)
• Female
• Genotype
• Haplotypes
• Hemorrhage (genetics)
• Humans
• Interleukin-6 (genetics)
• Male
• Middle Aged
• Models, Statistical
• Polymorphism, Single Nucleotide
• Promoter Regions, Genetic
• Proportional Hazards Models
• Risk
• Time Factors
• Tumor Necrosis Factor-alpha (genetics)