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Systematic analysis of polymorphisms and linkage dsequilibrium in the osteoporosis susceptibility genes

骨质疏松易感基因多态性及连锁不平衡的系统分析

基本信息

批准号：
15390466
负责人：
EZURA Yoichi
金额：
$ 3.97万
依托单位：
Tokyo Medical and Dental University, Medical Research Institute. (2004)Nippon Medical School (2003)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

To clarify the genomic linkage of polymorphisms in the candidate gene loci of osteoporosis susceptibility genes, 12 candidate gene loci were selected through our original investigation of large scale single nucleotide polymorphism (SNP) association study using thousands of population subjects. By extracting multiple useful SNPs distributing throughout and beyond the loci in some cases, we analyzed linkage disequilibrium (LD) of those loci. Analyzed loci were the vitamin D binding protein gene (DBP), interleukin-1 receptor associated kinase 1 gene (IRAK1), tumor necrosis factor receptor-associated factor interacting protein gene (I-TRAF), gonadotropin releasing hormone gene (GnRH), glutaminyl-peptide cyclotransferase (QPCT), low density lipoprotein receptor-related protein 5 gene (LRP5), proopiomelanocortin gene (POMC), leukemia inhibitory factor receptor gene (LIFR), adducin 1 gene (ADD1), bone morphogenetic protein 8 gene (BMP8), heat shock protein 1A gene (HSPAIA), and the osteoclast-associated receptor gene (OSCAR). Analyses on some regions was difficult because of the existence of neighboring duplicated genes, like BMP8, however long range PCR usually solved the problem. By analyzing the indices of LD, D' and r2, we generally detected a single LD block covering the entire locus in each gene, however in several gene loci like LRP5 locus multiple block was observed. By clarifying the extent and the degree of LD in those loci, and selecting representative tag-SNPs in each LD blocks, we continued the association study using larger subject groups, to understand the genetic contribution of these candidate gene polymorphisms for bone mass determination.

为阐明骨质疏松症易感基因候选基因位点多态性的基因组连锁，通过对数千名人群的大规模单核苷酸多态性（SNP）关联研究，筛选出12个候选基因位点。通过提取多个有用的SNPs分布在整个和以外的位点，在某些情况下，我们分析了这些位点的连锁不平衡（LD）。分析的位点是维生素D结合蛋白基因（DBP）、白细胞介素-1受体相关激酶1基因（IRAK 1）、肿瘤坏死因子受体相关因子相互作用蛋白基因（I-TRAF）、促性腺激素释放激素基因（GnRH）、精氨酸肽环转移酶（QPCT）、低密度脂蛋白受体相关蛋白5基因（LRP 5）、阿黑皮素原基因（POMC）、白血病抑制因子受体基因（LIFR）、内收蛋白1基因（ADD 1）、骨形态发生蛋白8基因（BMP 8）、热休克蛋白1A基因（HSPAIA）和破骨细胞相关受体基因（OSCAR）。由于邻近重复基因的存在，如BMP 8，某些区域的分析是困难的，而长距离PCR通常解决了这个问题。通过对LD、D'和r2指标的分析，我们通常在每个基因中检测到一个覆盖整个位点的LD块，但在LRP 5位点等几个基因位点中观察到多个块。通过阐明这些位点中LD的程度和范围，并在每个LD区块中选择代表性的tag-SNP，我们继续使用更大的受试者群体进行关联研究，以了解这些候选基因多态性对骨量测定的遗传贡献。