EPHB4 Gene Polymorphisms and Risk of Intracranial Hemorrhage in Patients With Brain Arteriovenous Malformations

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 (χ ² =17.24, 6 df , P =0.008); 2 haplotypes containing the rs314308 T allele (GCC T GGGT, P =0.003; GTC T GGGC, 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.