title: A functional SNP in CILP, encoding cartilage intermediate layer protein, is associated with susceptibility to lumbar disc disease.
abstract: Lumbar disc disease (LDD) is caused by degeneration of intervertebral discs of the lumbar spine. One of the most common musculoskeletal disorders, LDD has strong genetic determinants. Using a case-control association study, we identified a functional SNP (1184T --> C, resulting in the amino acid substitution I395T) 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-beta1 in clustering chondrocytes and their territorial matrices in intervertebral discs. CILP inhibited TGF-beta1-mediated induction of cartilage matrix genes through direct interaction with TGF-beta1 and inhibition of TGF-beta1 signaling. The susceptibility-associated 1184C allele showed increased binding and inhibition of TGF-beta1. Therefore, we conclude that the extracellular matrix protein CILP regulates TGF-beta 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-beta.
authors.affiliation: Laboratory for Bone and Joint Diseases, SNP Research Center, The Institute of Physical and Chemical Research (RIKEN), 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Seki
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Kawaguchi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Chiba
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Mikami
authors.forename: Hideki
authors.initials: H
authors.lastname: Kizawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Oya
authors.forename: Futoshi
authors.initials: F
authors.lastname: Mio
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Ikuko
authors.initials: I
authors.lastname: Masuda
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tsunoda
authors.forename: Michihiro
authors.initials: M
authors.lastname: Kamata
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Kubo
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Toyama
authors.forename: Tomoatsu
authors.initials: T
authors.lastname: Kimura
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegawa
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002884:Chromosomes, Human, Pair 15; D004198:Disease Susceptibility; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D007405:Intervertebral Disc Displacement / Q000235:genetics*; D008159:Lumbar Vertebrae; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011755:Pyrophosphatases / Q000235:genetics*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D016326:Extracellular Matrix Proteins; D016212:Transforming Growth Factor beta; C114607:CILP protein, human; D011755:Pyrophosphatases