A functional SNP in CILP, encoding cartilage intermediate layer protein, is associated with susceptibility to lumbar disc disease

Shoji Seki, Yoshiharu Kawaguchi, Kazuhiro Chiba, Yasuo Mikami, Hideki Kizawa, Takeshi Oya, Futoshi Mio, Masaki Mori, Yoshinari Miyamoto, Ikuko Masuda, Tatsuhiko Tsunoda, Michihiro Kamata, Toshikazu Kubo, Yoshiaki Toyama, Tomoatsu Kimura, Yusuke Nakamura, Shiro Ikegawa

Research output: Contribution to journalArticle

166 Citations (Scopus)

Abstract

Lumbar disc disease (LDD) is caused by degeneration of intervertebral discs of the lumbar spine. One of the most common musculoskeletal disorders 1, LDD has strong genetic determinants2-4. Using a case-control association study, we identified a functional SNP (1184T→C, resulting in the amino acid substitution 1395T) in CILP, which encodes the cartilage intermediate layer protein, that acts as a modulator of LDD susceptibility. CILP was expressed abundantly in intervertebral discs, and its expression increased as disc degeneration progressed. CILP colocalized with TGF-β1 in clustering chondrocytes and their territorial matrices in intervertebral discs. CILP inhibited TGF-β1-mediated induction of cartilage matrix genes through direct interaction with TGF-β1 and inhibition of TGF-β1 signaling. The susceptibility-associated 1184C allele showed increased binding and inhibition of TGF-β1. Therefore, we conclude that the extracellular matrix protein CILP regulates TGF-β signaling and that this regulation has a crucial role in the etiology and pathogenesis of LDD. Our study also adds to the list of connective tissue diseases that are associated with TGF-β.

Original languageEnglish
Pages (from-to)607-612
Number of pages6
JournalNature genetics
Volume37
Issue number6
DOIs
Publication statusPublished - 2005 Jun 1

    Fingerprint

ASJC Scopus subject areas

  • Genetics

Cite this

Seki, S., Kawaguchi, Y., Chiba, K., Mikami, Y., Kizawa, H., Oya, T., Mio, F., Mori, M., Miyamoto, Y., Masuda, I., Tsunoda, T., Kamata, M., Kubo, T., Toyama, Y., Kimura, T., Nakamura, Y., & Ikegawa, S. (2005). A functional SNP in CILP, encoding cartilage intermediate layer protein, is associated with susceptibility to lumbar disc disease. Nature genetics, 37(6), 607-612. https://doi.org/10.1038/ng1557