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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.

journal_name

Am J Hum Genet

journal_title

American journal of human genetics

authors

Hirose Y,Chiba K,Karasugi T,Nakajima M,Kawaguchi Y,Mikami Y,Furuichi T,Mio F,Miyake A,Miyamoto T,Ozaki K,Takahashi A,Mizuta H,Kubo T,Kimura T,Tanaka T,Toyama Y,Ikegawa S

doi

10.1016/j.ajhg.2008.03.013

subject

Has Abstract

pub_date

2008-05-01 00:00:00

pages

1122-9

issue

5

eissn

0002-9297

issn

1537-6605

pii

S0002-9297(08)00223-1

journal_volume

82

pub_type

杂志文章

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