アカガワ　ヒロユキ   AKAGAWA HIROYUKI   赤川　浩之    所属   研究施設 研究施設    職種   准教授
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	A haplotype spanning two genes, ELN and LIMK1, decreases their transcripts and confers susceptibility to intracranial aneurysms.
掲載誌名	正式名：Human molecular genetics 略　 称：Hum Mol Genet ISSNコード：0964-6906(Print)0964-6906(Linking)
巻・号・頁	15(10),pp.1722-34
著者・共著者	Akagawa Hiroyuki, Tajima Atsushi, Sakamoto Yoshiko, Krischek Boris, Yoneyama Taku, Kasuya Hidetoshi, Onda Hideaki, Hori Tomokatsu, Kubota Motoo, Machida Toshio, Saeki Naokatsu, Hata Akira, Hashiguchi Kazunari, Kimura Eizou, Kim Chul-Jin, Yang Tae-Ki, Lee Jong-Young, Kimm Kuchan, Inoue Ituro
担当区分	筆頭著者
発行年月	2006/05
概要	The rupture of an intracranial aneurysm (IA) results in subarachnoid hemorrhage, a catastrophic neurological condition with high morbidity and mortality. Following-up on our previous genome-wide linkage study in Japanese population, we extensively analyzed a 4.6 Mb linkage region around D7S2472 on 7q11 by genotyping 168 single nucleotide polymorphisms (SNPs). SNP association and window scan 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 with 404 IA patients and 458 non-IA controls revealed that the ELN 3'-UTR G(+659)C SNP has the strongest association to IA (P=0.000002) and constitutes a tag-SNP for an at-risk haplotype, whichcontains two functional SNPs, the ELN 3'-UTR (+502) A insertion and the LIMK1 promoter C(-187)T SNP. These allelic and haplotype-based associations were confirmed in a Korean population. Ex vivo and in vitro analyses demonstrate that the functional impact of both SNPs is the decrease of transcript levels, either through accelerated ELN mRNA degradation or through decreased LIMK1 promoter activity. Elastin and LIMK1 protein are involved in the same actin depolymerization signaling pathway; therefore, these lines of evidence suggest a combined effect of the SNPs in the at-risk haplotype possibly by weakening the vascular wall and promoting the development of IA.
DOI	10.1093/hmg/ddl096
文献番号	16611674