A functional single nucleotide polymorphism in the core promoter region of CALM1 is associated with hip osteoarthritis in Japanese
A functional single nucleotide polymorphism in the core promoter region of CALM1 is associated with hip osteoarthritis in Japanese
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DOI：
10.1093/hmg/ddi093
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发表时间：
2005-04-15
影响因子：
3.5
通讯作者：
Ikegawa, S
中科院分区：
文献类型：
--
作者：
Mototani, H;Mabuchi, A;Ikegawa, S
骨关节炎（OA）是一种常见的骨骼疾病，是老年人致残的主要原因。骨性关节炎的特点是逐渐丧失关节软骨，但骨性关节炎的病因和发病机制在很大程度上是未知的。流行病学和遗传学研究表明，遗传因素在OA中起重要作用。为了确定OA的易感基因，我们使用基于基因的单核苷酸多态性（snp）进行了一项大规模的病例对照关联研究。在两个独立的病例对照人群中，我们发现髋OA与位于钙调蛋白（CaM） 1基因（CALM1）内含子3的SNP （IVS3-293C > T）之间存在显著关联（P=9.8x10(-7)）。CALM1在培养的软骨细胞和关节软骨中表达，在OA中表达增加。随后的连锁不平衡图谱鉴定出5个snp与IVS3-293C > T有显著关联，其中一个（-16C > T）位于CALM1的核心启动子区域。功能分析表明，易感性-16T等位基因在体外和体内均可降低CALM1的转录。在软骨细胞中抑制CaM可降低主要软骨基质基因Col2a1和Agc1的表达。这些结果表明，通过调节软骨形成活性，CALM1的转录水平与髋关节OA的易感性相关。我们的研究结果揭示了软骨细胞中calm1介导的信号通路是治疗OA的一个新的潜在靶点。
Osteoarthritis (OA), a common skeletal disease, is a leading cause of disability among the elderly populations. OA is characterized by gradual loss of articular cartilage, but the etiology and pathogenesis of OA are largely unknown. Epidemiological and genetic studies have demonstrated that genetic factors play an important role in OA. To identify susceptibility genes for OA, we performed a large-scale, case-control association study using gene-based single nucleotide polymorphisms (SNPs). In two independent case-control populations, we found significant association (P=9.8x10(-7)) between hip OA and a SNP (IVS3-293C > T) located in intron 3 of the calmodulin (CaM) 1 gene (CALM1). CALM1 was expressed in cultured chondrocytes and articular cartilage, and its expression was increased in OA. Subsequent linkage-disequilibrium mapping identified five SNPs showing significant association equivalent to IVS3-293C > T. One of these (-16C > T) is located in the core promoter region of CALM1. Functional analyses indicate that the susceptibility -16T allele decreases CALM1 transcription in vitro and in vivo. Inhibition of CaM in chondrogenic cells reduced the expression of the major cartilage matrix genes Col2a1 and Agc1. These results suggest that the transcriptional level of CALM1 is associated with susceptibility for hip OA through modulation of chondrogenic activity. Our findings reveal the CALM1-mediated signaling pathway in chondrocytes as a novel potential target for treatment of OA.