脳動脈瘤の分子遺伝学

Molecular genetics of intracranial aneurysm

　脳動脈瘤破裂により，くも膜下出血をきたす。脳動脈瘤は遺伝背景の強い疾患であることが知られている。筆者らは脳動脈瘤の遺伝要因を同定することにより，脳動脈瘤発生メカニズムの解明を目指した。116対の罹患同胞対を用いたゲノム全域連鎖解析により5，7，14番染色体に遺伝子座を特定でき，最も強い連鎖を認めた7番染色体において，詳細な連鎖不平衡マッピングを行い，エラスチン，コラーゲン1A2遺伝子の関与を明らかにした。

　Rupture of intracranial aneurysms（IA）causes subarachnoid hemorrhage, a devastating condition with high morbidity and mortality. Although IA has a substantial genetic component, there has been little attention to the genetic determinants. We performed a genome-wide linkage study of IA in 104 Japanese affected sib-pairs in which positive evidence of linkage at chromosome 5q22-31, 7q11, and 14q22 were found. The best evidence of linkage is detected at D7S2472, in the vicinity of the elastin gene（ELN）, a positional candidate gene for IA. In association study, multiple SNPs identified in ELN were associated with IA. Also collagen 1A1gene was locating on 7q11 and the gene was screened as a functional candidate gene. We have shown that a non-synonymous SNP is associated with IA and a functional alteration with the variant was demonstrated.