Abstract
We performed a genomewide linkage study of intracranial aneurysm (IA) in 104 Japanese affected sib pairs and positive evidence of linkage on chromosomes 5q22-31, 7q11, and 14q22 were found. The best evidence of linkage was detected at D7S2472, in the vicinity of the elastin gene (ELN). We extensively analyzed a 4.6Mb linkage region around D7S2472 by genotyping 166 single nucleotide polymorphisms (SNPs). SNP and haplotype-based association studies revealed a susceptibility locus for IA on a single LD block covering the 3' untranslated region (3'UTR) of ELN and the entire region of LIMK1. An association study showed that the ELN 3'UTR G (+659) C SNP has the strongest association to IA and constitutes a tag-SNP for an at-risk haplotype, which contains two functional SNPs, ELN 3'UTR (+502) A insertion and LIMK1 promoter C (-187) T SNP. Functional analyses demonstrated that both SNPs decrease transcript levels, either through accelerated ELN mRNA degradation or through decreased LIMK1 promoter activity. Elastin and LIMK1 protein are involved in the actin depolymerization signaling pathway, therefore, it is suggested that a combined effect of the SNPs in the at-risk haplotype may weaken the vascular wall and promote the development of IA.
