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Genetic studies of ossification of the posterior longitudinal ligament of the spine

脊柱后纵韧带骨化的遗传学研究

基本信息

批准号：
10470301
负责人：
INOUE Ituro
金额：
$ 8.19万
依托单位：
The University of Tokyo (2000)Gunma University (1998-1999)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

项目摘要

Ossification of the posterior longitudinal ligament of the spine(OPLL)is the leading cause of myelopathy in Japan. In earlier studies, we provided genetic linkage and allelic association evidence of distinct differences in the human collagen α2(XI)gene(COL11A2)that might constitute inherited predisposition to OPLL.A strong allelic association with non-OPLL(P=0.0003)was observed with an intron 6 polymorphism(Intron 6(-4A)), where the intron 6(-4A)allele is more frequently observed in non-OPLL subjects than in OPLL patients. In addition, five distinct SNPs, identified in COL11A2, were combined to construct possible haplotypes by use of a maximum likelihood program. Estimated haplotype frequency was compared between OPLL patients and non-OPLL controls and gender-specific association of COL11A2 haplotype with OPLL was observed. The most commonly observed haplotype was significantly increased in male patients(p=0.0003)but not in female patients(p=0.21). OPLL is a complex disease, and several genetic factors other COL11A2 are probably involved in the etiology, so the more extensive candidate gene approach was performed. We selected a total of 88 candidate genes based on two separate investigations. 24 genes differentially regulated during osteoblastic differentiation were selected by cDNA microarray analysis, and subjected to linkage analysis. We also selected 64 candidate genes that are possibly involved in bone metabolism or related conditions. Microsatellite markers, locating close to or within the candidate genes were obtained in the latest online information. With these markers we performed non-parametric linkage study with 126 OPLL sib-pairs to identify genetic loci responsible in OPLL.

脊柱后纵韧带骨化（OPLL）是日本脊髓病的主要原因。在早期的研究中，我们提供了遗传连锁和等位基因关联的证据，证明人类胶原α2（XI）基因（COL11A2）的显著差异可能构成OPLL的遗传易感性。内含子6多态性（内含子6(-4A)）与非OPLL存在强烈的等位基因关联（P=0.0003），其中内含子6（-4A）等位基因在非OPLL受试者中比在OPLL患者中更常见。此外，利用最大似然程序，将在COL11A2中鉴定出的五个不同的snp组合起来构建可能的单倍型。比较了OPLL患者和非OPLL对照组的估计单倍型频率，并观察了COL11A2单倍型与OPLL的性别特异性关联。最常见的单倍型在男性患者中显著增加（p=0.0003），而在女性患者中无显著增加（p=0.21）。OPLL是一种复杂的疾病，除COL11A2外，多种遗传因素可能与病因有关，因此我们采用了更广泛的候选基因方法。我们根据两个独立的调查共选择了88个候选基因。通过基因芯片分析选择成骨细胞分化过程中的24个差异调控基因，并进行连锁分析。我们还选择了64个可能参与骨代谢或相关疾病的候选基因。微卫星标记位于候选基因附近或候选基因内。利用这些标记，我们对126对OPLL兄弟姐妹进行了非参数连锁研究，以确定与OPLL有关的遗传位点。