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Human Molecular Genetics Advance Access originally published online on April 12, 2006
Human Molecular Genetics 2006 15(10):1722-1734; doi:10.1093/hmg/ddl096
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© The Author 2006. Published by Oxford University Press. All rights reserved.
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact: journals.permissions@oxfordjournals.org

A haplotype spanning two genes, ELN and LIMK1, decreases their transcripts and confers susceptibility to intracranial aneurysms

Hiroyuki Akagawa1, Atsushi Tajima1, Yoshiko Sakamoto1, Boris Krischek1, Taku Yoneyama1, Hidetoshi Kasuya2, Hideaki Onda2, Tomokatsu Hori2, Motoo Kubota3, Toshio Machida3, Naokatsu Saeki3, Akira Hata4, Kazunari Hashiguchi5, Eizou Kimura5, Chul-Jin Kim6, Tae-Ki Yang6, Jong-Young Lee7, Kuchan Kimm7 and Ituro Inoue1,8,*

1Division of Genetic Diagnosis, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan, 2Department of Neurosurgery, Neurological Institute, Tokyo Women's Medical University, Tokyo, Japan, 3Department of Neurosurgery and 4Department of Public Health, School of Medicine, Chiba University, Chiba, Japan, 5Kousei General Hospital, Tokyo, Japan, 6Department of Neurosurgery, Chonbuk National University, Chonju, Korea, 7Center for Genome Science, National Institute of Health, Seoul, Korea and 8Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Kawaguchi, Japan

* To whom correspondence should be adressed at: Division of Genetic Diagnosis, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, 108-8639 Tokyo, Japan. Tel: +81 354495325; Fax: +81 354495764; Email: ituro{at}ims.u-tokyo.ac.jp

Received February 20, 2006; Accepted March 31, 2006

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.


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