title: A functional polymorphism in THBS2 that affects alternative splicing and MMP binding is associated with lumbar-disc herniation.
abstract: 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.
authors.affiliation: Laboratory for Bone and Joint Diseases, SNP Research Center, RIKEN, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Hirose
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Chiba
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Karasugi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nakajima
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Kawaguchi
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Mikami
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Furuichi
authors.forename: Futoshi
authors.initials: F
authors.lastname: Mio
authors.forename: Atsushi
authors.initials: A
authors.lastname: Miyake
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miyamoto
authors.forename: Kouichi
authors.initials: K
authors.lastname: Ozaki
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mizuta
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Kubo
authors.forename: Tomoatsu
authors.initials: T
authors.lastname: Kimura
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Tanaka
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Toyama
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegawa
mesh_terms: D000328:Adult; D017398:Alternative Splicing; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007405:Intervertebral Disc Displacement / Q000235:genetics* / Q000378:metabolism; D008159:Lumbar Vertebrae; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D019699:Thrombospondins / Q000235:genetics* / Q000378:metabolism; D000099262:Thrombospondin 2
chemical_list: D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D019699:Thrombospondins; D000099262:Thrombospondin 2; C522361:MMP2 protein, human