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

• Published in: Nature genetics Vol. 37; no. 6; pp. 607 - 612
• Main Authors: Ikegawa, Shiro, Seki, Shoji, Kawaguchi, Yoshiharu, Chiba, Kazuhiro, Mikami, Yasuo, Kizawa, Hideki, Oya, Takeshi, Mio, Futoshi, Mori, Masaki, Miyamoto, Yoshinari, Masuda, Ikuko, Tsunoda, Tatsuhiko, Kamata, Michihiro, Kubo, Toshikazu, Toyama, Yoshiaki, Kimura, Tomoatsu, Nakamura, Yusuke
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.06.2005
• Subjects: Adolescent; Adult; Aged; Amino acids; Back pain; Cartilage; Case-Control Studies; Chemonucleolysis; Chromosomes, Human, Pair 15; Collagen; Degenerative disc disease; Disease Susceptibility; Etiology; Extracellular matrix; Extracellular Matrix Proteins - genetics; Female; Genes; Genetic aspects; Health aspects; Humans; Intervertebral Disc Displacement - genetics; Intervertebral disk; Lumbar Vertebrae; Magnetic resonance imaging; Male; Medicine; Middle Aged; Mutation; Orthopedics; Pathogenesis; Physiological aspects; Polymorphism, Single Nucleotide; Proteins; Pyrophosphatases - genetics; Research centers; Risk factors; Signal Transduction; Single nucleotide polymorphisms; Spine; Transforming Growth Factor beta - metabolism; Japan
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng1557

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-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.