钙离子重吸收调节关键基因与地方性氟骨症的遗传关联分析及机制研究

氟骨症是氟中毒最为严重的一种疾病表现形式，重者可致残，严重影响患者的生活质量及身心健康。国内外多项研究表明氟骨症与遗传因素相关，个体的遗传背景会影响氟在体内的代谢。申请人前期研究提示钙离子重吸收调节通路基因在氟骨症发生过程中可能起到关键作用。据此，本研究拟在地方性氟中毒高发地区的汉族氟骨症患者及对照人群中对钙离子重吸收调节通路中的关键基因进行关联分析，初步筛选出与氟骨症相关的标签SNP（tag SNP)位点。随后在同地区蒙古族、藏族氟骨症样本中对相关位点进行独立人群验证。最后，对获得的疾病相关位点在两翼区域进行重测序，筛选罕见突变，进行分子细胞水平的功能机制解析。本研究将为阐释氟骨症的发病机制及寻找防治干预靶点提供依据和支持。

Skeletal fluorosis is the most serious manifestation of fluorosis, which can lead to disability and affect the life quality and mental health of patients. Researches around the world have indicated an association between skeletal fluorosis and genetics that individual’s genetic background can influence the metabolism of fluoride within the body. Besides, our preliminary study demonstrated that genes in endocrine and other factor-regulated calcium reabsorption pathway might play a pivotal role in the development of skeletal fluorosis. In this study, we plan to conduct an association study in skeletal fluorosis patients and unaffected controls recruited from endemic fluoriosis areas, aiming to identify susceptibility tag SNPs of genes in calcium reabsorption pathway. All the associated SNPs will be genotyped again in Mongolian and Tibetan samples from the same area, respectively. Subsequently, we will sequence the upstream and downstream of SNPs that are associated with skeletal fluorosis and screen for rare mutations. Finally, functional experiments will be performed at cell levels. Our study will provide scientific evidence and support to the mechanism research and seeking prevention target for skeletal fluorosis.