A functional polymorphism in THBS2 that affects alternative splicing and MMP binding is associated with lumbar-disc herniation
A functional polymorphism in THBS2 that affects alternative splicing and MMP binding is associated with lumbar-disc herniation
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DOI：
10.1016/j.ajhg.2008.03.013
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发表时间：
2008-05-01
影响因子：
9.8
通讯作者：
Ikegawa, Shiro
中科院分区：
文献类型：
--
作者：
Hirose, Yuichiro;Chiba, Kazuhiro;Ikegawa, Shiro
腰椎间盘突出症（LDH）是最常见的肌肉骨骼疾病之一，具有很强的遗传决定因素。最近，据报道，椎间盘中编码细胞外基质 (ECM) 蛋白的几个基因与 LDH 相关。血小板反应蛋白 (THBS) I 和 2 是 LDH 易感基因的良好候选者：它们是椎间盘 ECM 蛋白，可调节基质金属蛋白酶 (MMP) 2 和 9 的有效水平，而基质金属蛋白酶 (MMP) 2 和 9 是 ECM 重塑的关键效应物。在这里，我们报告 THBS2 与日本人群中的 LDH 相关。 THBS2 中的内含子 SNP (IVS10-8C -> T; rs9406328) 显示与两个独立的日本人群中的 LDH 显着相关 (p = 0.0000028)。该 SNP 位于内含子 10 3' 剪接位点上游的聚嘧啶束中，对外显子 11 体内跳跃率产生等位基因差异，易感性等位基因显示跳跃增加。外显子 11 的跳过导致 THBS2 与 MMP2 和 MMP9 的相互作用减少。此外，MMP9（Q279R；rs17576）中的错义 SNP 也与日本人群中的 LDH 密切相关（p = 0.00049），并显示出与 THBS2 的组合效应（比值比 3.03，95% 置信区间 1.58-5.77）。因此，THBS2 中影响剪接的 SNP 和 MMP9 中错义 SNP 与 LDH 易感性相关。我们的数据表明，THBS2-MMP 系统对椎间盘 ECM 代谢的调节在 LDH 的病因和发病机制中起着重要作用。
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) I 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.