Abstract
Abnormal endothelial proliferation and angiogenesis may contribute to brain arteriovenous malformation (BAVM) formation. G protein-coupled receptor 124 (GPR124) mediates embryonic central nervous system angiogenesis; thus, we investigated the association of single nucleotide polymorphisms (SNPs) and haplotypes in GPR124 with risk of BAVM. Ten tagging SNPs spanning 39 kb of GPR124 were genotyped in 195 Caucasian BAVM patients and 243 Caucasian controls. SNP and haplotype association with risk of BAVM was screened using chi (2) analysis. Associated variants were further evaluated using multivariable logistic regression, adjusting for age and sex. The minor alleles of three GPR124 SNPs adjacent to exon 2 and localized to a 16-kb region of high linkage disequilibrium were associated with reduced risk of BAVM (rs7015566 A, P = 0.001; rs7823249 T, P = 0.014; rs12676965 C, P = 0.007). SNP rs7015566 (intron 1) remained associated after permutation testing (additive model P = 0.033). Haplotype analysis revealed a significant overall association (chi (2) = 12.55, 4 degrees of freedom, P = 0.014); two haplotypes (ATCC, P = 0.006 and GGCT, P = 0.008) were associated with risk of BAVM. We genotyped a known synonymous SNP (rs16887051) in exon 2; however, genotype frequency did not differ between cases and controls. Sequencing of conserved GPR124 regions revealed a novel insertion/deletion polymorphism in intron 2. Immunohistochemistry confirmed GPR124 expression in the endothelium with no qualitative difference in expression between BAVM cases and controls. SNP rs7015566 mapping to intron 1 of GPR124 was associated with BAVM susceptibility among Caucasians. Future work is focused on investigating this gene region.