骨质疏松（OP）是我国面临的日益严重的健康问题。OP 受复杂的遗传调控，.但目前绝大多数遗传因子并未被鉴定。启动子区域是基因调控的关键元件之一。申请者前期研究发现大量启动子区域的遗传多态性位点与骨质疏松关联。本项目拟选取前50 个与椎骨骨密度（BMD）有显著关联信号的单核苷酸多态性（SNP），并在一个具有5,000 健康个体的独立大样本中，验证这50 个SNP 与骨质疏松表型的是否具重复关联信号；对有重复关联信号的SNP 进行SNP生物学功能预测；并经凝胶电泳迁移率实验、荧光素酶表达实验、等位基因特异的mRNA 和蛋白质表达等实验，探讨SNP 与表型关联的功能机制，从而清晰阐明启动区域的遗传变异位点决定骨质疏松的复杂机制。本研究可进一步阐明和理解骨质疏松症的遗传致病机理，为骨质疏松症的早期预测、预警和诊断以及寻找新的药物设计靶点提供新的思路和理论依据。

Osteoporosis (OP) is a very serious health problem in China.OP is under very strong genetic determination, but most of genetic factors underlying OP are not identified. Promoter region is one of key components for gene expression regulation. Based on the genetic associations of OP and genetic polymorphisms in the promoter regions detected in our previous studies, this study will investigate functional mechanisms underlying the associations and detect fundamental molecular regulation mechanisms of genetic sites on OP. We will first test replication associations in another independent sample with 5,000 subjects for the top 50 SNPs with significant association signals detected in the previous studies; predict biological functions for replication SNPs; and then perform electrophoretic mobility shift assay, luciferase assay, and allele-specific exprssions of mRNAs or proteins. This study will increase our understanding on the genetic mechanism underlying OP and provide a clue for future prevention, intervention and drug design.