A Functional Polymorphism in THBS2 that Affects Alternative Splicing and MMP Binding Is Associated with Lumbar-Disc Herniation

Yuichiro Hirose, Kazuhiro Chiba, Tatsuki Karasugi, Masahiro Nakajima, Yoshiharu Kawaguchi, Yasuo Mikami, Tatsuya Furuichi, Futoshi Mio, Atsushi Miyake, Takeshi Miyamoto, Kouichi Ozaki, Atsushi Takahashi, Hiroshi Mizuta, Toshikazu Kubo, Tomoatsu Kimura, Toshihiro Tanaka, Yoshiaki Toyama, Shiro Ikegawa

Research output: Contribution to journalArticlepeer-review

96 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1122-1129
Number of pages8
JournalAmerican Journal of Human Genetics
Issue number5
Publication statusPublished - 2008 May 9
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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