A functional polymorphism in THBS2 that affects alternative splicing and MMP binding is associated with lumbar-disc herniation.
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.
Hirose
Yuichiro
Y
Laboratory for Bone and Joint Diseases, SNP Research Center, RIKEN, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Chiba
Kazuhiro
K
Karasugi
Tatsuki
T
Nakajima
Masahiro
M
Kawaguchi
Yoshiharu
Y
Mikami
Yasuo
Y
Furuichi
Tatsuya
T
Mio
Futoshi
F
Miyake
Atsushi
A
Miyamoto
Takeshi
T
Ozaki
Kouichi
K
Takahashi
Atsushi
A
Mizuta
Hiroshi
H
Kubo
Toshikazu
T
Kimura
Tomoatsu
T
Tanaka
Toshihiro
T
Toyama
Yoshiaki
Y
Ikegawa
Shiro
S
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
D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D019699:Thrombospondins; D000099262:Thrombospondin 2; C522361:MMP2 protein, human