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

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 approximate to 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 (chi(2) = 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. (Circ Cardiovasc Genet. 2009;2:476-482.)