Genomewide linkage study and identification of susceptibility of ossification of the posterior longitudinal ligament of the spine

全基因组连锁研究及脊柱后纵韧带骨化易感性鉴定

• 批准号: 13470301
• 负责人: INOUE Ituro
• 金额: $ 10.56万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470301/
• 关键词: genomewide linkage; association study; OPLL; collagen; 後縦靭帯骨化症; 羅患同胞対連鎖解析

Ossification of the posterior longitudinal ligament (OPLL) of the spine is a subset of "bone forming" diseases, characterized by ectopic ossification in the spinal ligaments. We performed a genomewide linkage study with 142 affected sib-pairs to identify genetic loci related to OPLL. In multipoint linkage analysis using GENEHUNTER-PLUS, evidence of linkage to OPLL was detected on chromosomes 1p, 6p, 11q, 14q, 16q, and 21q. The best evidence of linkage was detected near D21S1903 on chromosome 21q22.3 (maximum Z_<Ir> = 3.97), therefore the linkage region was extensively investigated for linkage disequilibrium analysis with single nucleotide polymorphisms (SNPs) covering 20 Mb. One hundred-fifty positional candidate genes lie in the region and 600 gene-based SNPs were genotyped. There were positive allelic associations with 7 genes (P < 0.01) in 280 patients and 210 controls and 4 of the 7 genes were clustered within a region of 750 kb, about 1.2 Mb telomeric from D21S1903. Extensive linkage disequilibrium and association studies of the 4 genes indicated that SNPs in the collagen 6A1 gene (COL6A1) were strongly associated with OPLL (P = 0.000003). Haplotype analysis with 3 SNPs in COL6A1 gave a single point P value of 0.0000007. Pinpointing the susceptibility to OPLL by genomewide linkage and linkage disequilibrium studies permits us to investigate the pathogenesis of OPLL, which might lead to the development of novel therapeutic tools.

脊柱后纵韧带骨化（OPLL）是“骨形成”疾病的一个子集，其特征是脊柱韧带异位骨化。我们对142对受影响的兄弟姐妹进行了全基因组连锁研究，以确定与OPLL相关的遗传位点。在genehunt - plus的多点连锁分析中，在1p、6p、11q、14q、16q和21q染色体上检测到与OPLL连锁的证据。在染色体21q22.3的D21S1903附近检测到连锁的最佳证据（最大Z_<Ir> = 3.97），因此对该连锁区域进行了广泛的连锁不平衡分析，单核苷酸多态性（SNPs）覆盖20 Mb。该区域有150个位置候选基因，600个基于基因的SNPs被基因分型。在280例患者和210例对照中，有7个基因的等位基因呈显著正相关（P < 0.01），其中4个基因聚集在距离D21S1903约1.2 Mb的750 kb区域内。对这4个基因的大量连锁不平衡和关联研究表明，胶原蛋白6A1基因（COL6A1）的snp与OPLL密切相关（P = 0.000003）。COL6A1单倍型分析3个snp的单点P值为0.0000007。通过全基因组连锁和连锁不平衡研究确定对OPLL的易感性，使我们能够研究OPLL的发病机制，这可能会导致新的治疗工具的开发。

项目成果

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Havelka S：“弥漫性特发性骨骼骨质肥厚 (DISH) 和脊柱后纵韧带骨化 (OPLL) 是否有遗传相关性？”Annal。

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Shimo-onoda K、Tanaka T、Furushima K、Nakajima T、Toh S、Harata S、Yone K、Komiya S、Adachi H、Nakamura E、Fujimiya H、Inoue I：“Akaike 连锁不平衡替代度量的信息标准”

Shimo-onoda K.: "Akaike's information criterion for an alternative measure of linkage disequilibrium"J. Hum. Genet.. 47. 649-655 (2002)

Shimo-onoda K.：“赤池信息标准用于连锁不平衡的替代测量”J。

Maeda S, Ishidou Y, Koga H, Taketomi E, Ikari K, Komiya S, Takeda J, Sakou T, and Inoue I: "Functional impact of human collagen α 2 (X1) gene polymorphism in pathogenesis of ossification of the posterior longitudinal ligament of the spine"J. Bone. Miner.

Maeda S、Ishidou Y、Koga H、Taketomi E、Ikari K、Komiya S、Takeda J、Sakou T 和 Inoue I：“人胶原蛋白 α 2 (X1) 基因多态性在后纵韧带骨化发病机制中的功能影响脊柱”J. Bone. Miner.

Maeda S, Nobukuni T, Shimo-onoda K, Hayashi K, Yone K, Komiya S, Inoue I: "Sortilin is up-regulated during osteoblastic differentiation of mesenchymal stem cells and promotes extracellular matrix mineralization"J Cell Pysiol. 193. 73-79 (2002)

Maeda S、Nobukuni T、Shimo-onoda K、Hayashi K、Yone K、Komiya S、Inoue I：“Sortilin 在间充质干细胞的成骨细胞分化过程中上调，并促进细胞外基质矿化”J Cell Pysiol。