title: A haplotype spanning two genes, ELN and LIMK1, decreases their transcripts and confers susceptibility to intracranial aneurysms.
abstract: 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, which contains 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.
authors.affiliation: Division of Genetic Diagnosis, The Institute of Medical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Akagawa
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tajima
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Sakamoto
authors.forename: Boris
authors.initials: B
authors.lastname: Krischek
authors.forename: Taku
authors.initials: T
authors.lastname: Yoneyama
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Kasuya
authors.forename: Hideaki
authors.initials: H
authors.lastname: Onda
authors.forename: Tomokatsu
authors.initials: T
authors.lastname: Hori
authors.forename: Motoo
authors.initials: M
authors.lastname: Kubota
authors.forename: Toshio
authors.initials: T
authors.lastname: Machida
authors.forename: Naokatsu
authors.initials: N
authors.lastname: Saeki
authors.forename: Akira
authors.initials: A
authors.lastname: Hata
authors.forename: Kazunari
authors.initials: K
authors.lastname: Hashiguchi
authors.forename: Eizou
authors.initials: E
authors.lastname: Kimura
authors.forename: Chul-Jin
authors.initials: CJ
authors.lastname: Kim
authors.forename: Tae-Ki
authors.initials: TK
authors.lastname: Yang
authors.forename: Jong-Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Kuchan
authors.initials: K
authors.lastname: Kimm
authors.forename: Ituro
authors.initials: I
authors.lastname: Inoue
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D000368:Aged; D044466:Asian People; D016022:Case-Control Studies; D002478:Cells, Cultured; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D004549:Elastin / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D002532:Intracranial Aneurysm / Q000235:genetics*; D007564:Japan; D007723:Korea; D054461:Lim Kinases; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011494:Protein Kinases / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; D004549:Elastin; D011494:Protein Kinases; C515892:LIMK1 protein, human; D054461:Lim Kinases