Copyright © 2008 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 82, Issue 5, 1122-1129, 01 May 2008
doi:10.1016/j.ajhg.2008.03.013
Article
A Functional Polymorphism in THBS2 that Affects Alternative Splicing and MMP Binding Is Associated with Lumbar-Disc Herniation
Yuichiro Hirose1, 2, Kazuhiro Chiba2, Tatsuki Karasugi1, 3, Masahiro Nakajima1, Yoshiharu Kawaguchi4, Yasuo Mikami5, Tatsuya Furuichi1, Futoshi Mio1, 2, Atsushi Miyake1, 2, Takeshi Miyamoto2, Kouichi Ozaki6, Atsushi Takahashi7, Hiroshi Mizuta3, Toshikazu Kubo5, Tomoatsu Kimura4, Toshihiro Tanaka6, Yoshiaki Toyama2 and Shiro Ikegawa1, 
, 
1 Laboratory for Bone and Joint Diseases, SNP Research Center, RIKEN, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
2 Department of Orthopaedic Surgery, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
3 Department of Orthopaedic and Neuro-Musculoskeletal Surgery, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
4 Department of Orthopaedic Surgery, Faculty of Medicine, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194, Japan
5 Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
6 Laboratory for Cardiovascular Diseases, SNP Research Center, RIKEN, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
7 Laboratory for Statistics, SNP Research Center, RIKEN, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
Corresponding authorAbstract
Lumbar-disc herniation (LDH), one of the most common musculoskeletal diseases, has strong genetic determinants. Recently, several genes that encode extracellular matrix (ECM) proteins in the intervertebral disc have been reported to associate with LDH. Thrombospondins (THBSs) 1 and 2 are good candidates for the LDH susceptibility gene: They are intervertebral disc ECM proteins that regulate the effective levels of matrix metalloproteinases (MMPs) 2 and 9, which are key effectors of ECM remodeling. Here, we report that THBS2 is associated with LDH in Japanese populations. An intronic SNP in THBS2 (IVS10-8C → T; rs9406328) showed significant association (p = 0.0000028) with LDH in two independent Japanese populations. This SNP, located in a polypyrimidine tract upstream of the 3′ splice site of intron 10, exerts allelic differences on exon 11 skipping rates in vivo, with the susceptibility allele showing increased skipping. Skipping of exon 11 results in decreased THBS2 interaction with MMP2 and MMP9. Further, a missense SNP in MMP9 (Q279R; rs17576) is also strongly associated with LDH in the Japanese population (p = 0.00049) and shows a combinatorial effect with THBS2 (odds ratio 3.03, 95% confidence interval 1.58–5.77). Thus, a splicing-affecting SNP in THBS2 and a missense SNP in MMP9 are associated with susceptibility to LDH. Our data indicate that regulation of intervertebral disc ECM metabolism by the THBS2-MMP system plays an essential role in the etiology and pathogenesis of LDH.
Article Information
PubMed
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