EPHB4 gene polymorphisms and risk of intracranial hemorrhage in patients with brain arteriovenous malformations

Document Type

Article

Abstract

Background-Brain arteriovenous malformations (BAVMs) are a tangle of abnormal vessels directly shunting blood from the arterial to venous circulation and an important cause of intracranial hemorrhage (ICH). EphB4 is involved in arterial-venous determination during embryogenesis; altered signaling could lead to vascular instability resulting in ICH. We investigated the association of single-nucleotide polymorphisms (SNPs) and haplotypes in EPHB4 with risk of ICH at clinical presentation in patients with BAVM. Methods and Results-Eight haplotype-tagging SNPs spanning =29 kb were tested for association with ICH presentation in 146 white patients with BAVM (phase I: 56 ICH, 90 non-ICH) using allelic, haplotypic, and principal components analysis. Associated SNPs were then genotyped in 102 additional cases (phase II: 37 ICH, 65 non-ICH), and data were combined for multivariable logistic regression. Minor alleles of 2 SNPs were associated with reduced risk of ICH presentation (rs314313-C, P=0.005; rs314308-T, P=0.0004). Overall, haplotypes were also significantly associated with ICH presentation (X2=17.24, 6 df, P=0.008); 2 haplotypes containing the rs314308 T allele (GCCTGGGT, P=0.003; GTCTGGGC, P=0.036) were associated with reduced risk. In principal components analysis, 2 components explained 91% of the variance and complemented haplotype results by implicating 4 SNPs at the 5' end, including rs314308 and rs314313. These 2 SNPs were replicated in the phase II cohort, and combined data resulted in greater significance (rs314313, P=0.0007; rs314308, P=0.00008). SNP association with ICH presentation persisted after adjusting for age, sex, BAVM size, and deep venous drainage. Conclusions-EPHB4 polymorphisms are associated with risk of ICH presentation in patients with BAVM, warranting further study. © 2009 American Heart Association, Inc.

Publication Date

10-1-2009

Publication Title

Circulation: Cardiovascular Genetics

ISSN

1942325X

E-ISSN

19423268

Volume

2

Issue

5

First Page

476

Last Page

482

PubMed ID

20031623

Digital Object Identifier (DOI)

10.1161/CIRCGENETICS.109.883595

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