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

在日本，脊柱后纵韧带骨化（OPLL）是脊髓病的主要原因。在早期的研究中，我们提供了人类胶原蛋白α2（Xi）基因（COL 11 A2）的明显差异的遗传连锁和等位基因关联证据，这些差异可能构成OPLL的遗传易感性。（P=0.0003）与内含子6多态性（内含子6（-4A）），其中内含子6（-4A）等位基因在非OPLL受试者中比在OPLL患者中更频繁地观察到。此外，五个不同的SNPs，确定在COL 11 A2，结合使用最大似然程序构建可能的单倍型。在OPLL患者和非OPLL对照之间比较估计的单倍型频率，并观察到COL 11 A2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），但在女性患者中没有显著增加（p=0.21）。OPLL是一种复杂的疾病，除COL 11 A2外，可能还有多种遗传因素参与其病因学，因此进行了更广泛的候选基因研究。我们根据两项独立的调查共选择了88个候选基因。利用基因芯片技术筛选出24个在成骨细胞分化过程中差异表达的基因，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。在最新的在线信息中获得了位于候选基因附近或候选基因内部的微卫星标记。利用这些标记对126个OPLL同胞对进行了非参数连锁研究，以确定OPLL的遗传位点。

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.