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

• Published in: American journal of human genetics Vol. 82; no. 5; pp. 1122 - 1129
• Main Authors: Hirose, Yuichiro, Chiba, Kazuhiro, Karasugi, Tatsuki, Nakajima, Masahiro, Kawaguchi, Yoshiharu, Mikami, Yasuo, Furuichi, Tatsuya, Mio, Futoshi, Miyake, Atsushi, Miyamoto, Takeshi, Ozaki, Kouichi, Takahashi, Atsushi, Mizuta, Hiroshi, Kubo, Toshikazu, Kimura, Tomoatsu, Tanaka, Toshihiro, Toyama, Yoshiaki, Ikegawa, Shiro
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.05.2008; University of Chicago Press; Cell Press; American Society of Human Genetics
• Subjects: Adult; Alternative Splicing; Binding sites; Biological and medical sciences; Cells, Cultured; Extracellular Matrix - metabolism; Female; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genetic Predisposition to Disease; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Humans; Intervertebral Disc Displacement - genetics; Intervertebral Disc Displacement - metabolism; Lumbar Vertebrae; Male; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - metabolism; Medical genetics; Medical sciences; Metabolism; Middle Aged; Molecular and cellular biology; Musculoskeletal diseases; Pathogens; Polymorphism; Polymorphism, Single Nucleotide; Protein Binding; Proteins; Thrombospondins - genetics; Thrombospondins - metabolism; Japan; Hernia; Human; Alternative splicing; Association; Lumbar spine; Genetics; Intervertebral disk; Polymorphism
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2008.03.013

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.