Cerebrovascular Disease : Recent Progress in Research and Clinical Practice (4) : Genetics of Intracranial Aneurysms

Rupture of intracranial aneurysms (IAs) causes subarachnoid hemorrhage (SAH), a devastating condition with high mortality and morbidity. Genetic factors as well as environmental factors play an important role in the pathogenesis of IA and SAH. We first performed a genome-wide linkage study of IA in 104 Japanese affected sibpairs in which positive evidence of linkage was found at 5q22-31, 7q11, and 14q22. Other genome-wide linkage studies have identified genetic loci for IA on 19ql3.3 in a Finnish study, 17cen, 19ql3, and Xp22 in a Japanese study, on 2p13, 1p34.3-36.13, 11q24-25,14q23-31, and 5p15.2-14.3 Iq34.3 with the use of large families in which IA is inherited as a simple Mendelian trait. We extensively analyzed a 4.6 Mb linkage region around D7S2472 on 7q11 by genotyping 168 single nucleotide polymorphisms (SNPs). SNP haplotype-based association studies revealed a susceptibility locus for IA on a single LD block covering the 3\u27-untranslated region of ELN and the entire region of LIMK1. We have identified the ELN 3\u27-UTR G (+639) C SNP as a genetic susceptibility allele for IA, which occurs in an at-risk haplotype containing two functional SNPs that reduce the transcript levels of ELN and LIMK1, respectively. Other candidate genes have been studied by association analysis using cases and controls in different populations, but no specific genes have so far been identified as showing a clear association with IA. Further genetic association and linkage studies with more large-scale populations are needed to unravel the genetic risk factors of IA. These studies should also be combined with investigations of gene function