遗传及免疫因素在汉族人特发性甲状旁腺功能减退症发病机制中的作用

Hypoparathyroidism is an uncommon endocrine disorder characterized by hypocalcemia and hyperphosphatemia caused by parathyroid hormone deficiency, which increases morbidity and mortality. The conventional treatment of hypoparathyroidism has some shortage. The etiology of idiopathic hypoparathyroidism (IHP) is still unclear and the relevant study is still lacking. Despite of its rarity, IHP is a natural model of PTH deficiency, which can be used to study the function and its regulation of parathyroid glands. Studies on IHP may supply new target of common mineral bone disorders such as osteoporosis. The present study integrates clinical and basic study to obtain the whole genome and small RNA expression spectrum of IHP patients via new generation of high-flux sequencing technique, detect their serum autoantibody and peripheral lymphocytes subtypes to explore the role of genetics and autoimmunity in the pathogenesis of IHP. From the above data, we can also get the new construction of etiology of hypoparathyroidism in Han Nationality to analyze the clinical characteristics of each type of hypoparathyroidism. The predisposing genes and diagnostic markers will be screened from levels of genome mutation, small RNA regulation and autoimmune in this study, which may help to improve the diagnosis and treatment of hypoparathyroidism in China.

甲状旁腺功能减退症是由于甲状旁腺素不足引起的钙磷代谢异常性疾病，严重影响患者生存质量，目前国内外缺乏对特发性甲旁减（IHP）的相关研究，现有治疗手段存在缺陷。虽然IHP发病率不高，却是研究甲状旁腺功能及其调控机制的天然人体模型，为探索发病率较高的钙磷代谢紊乱性疾病新治疗靶点提供依据。本研究拟整合临床和基础研究：1.采用新一代高通量测序技术，绘制IHP患者全基因组和small RNA表达谱，检测其外周血自身抗体及淋巴细胞亚型，以寻找影响IHP发病易感性的遗传因素，了解自身免疫机制在发病中的作用，为探索新的治疗干预手段提供依据。2.获得汉族人群甲旁减新的病因构成数据，分析不同病因甲旁减的临床特点，提高国内甲旁减的诊断水平。本课题从基因组突变、small RNA 调控以及自身免疫等多种研究层面，筛查IHP的易感基因和疾病标志物，从多种组学层面上探索IHP的发病机制，对提高IHP的诊疗水平很重要。

甲状旁腺功能减退症为相对少见的内分泌疾病，国内缺乏其流行病学资料，且认识不足，导致多数患者长期漏诊、误诊。除手术、浸润性疾病等原因导致的获得性甲旁减外，遗传及免疫因素在甲旁减发病机制中起到重要作用。本研究全面分析了汉族人非手术致甲旁减患者的临床特征、治疗方案及疗效、长期并发症情况等，进一步提高临床甲旁减的诊疗水平。分别在儿童/青少年起病患者和成年起病的既往诊断特发性甲旁减患者中，筛查出可能为先天或遗传性甲旁减的病例，采用目的基因二代测序技术，筛查甲旁减发病相关的基因，进一步明确病因，治疗临床治疗方案的调整。同时，通过两者突变率的比较，提示儿童/青少年起病甲旁减患者进行相关基因筛查、明确病因是十分必要的。另一方面，免疫因素在甲旁减发病中起到一定作用。本研究采用ELISA定量测定技术，比较特发性甲旁减患者和健康对照者血清中钙敏感受体抗体水平差异。此外，本研究试图通过绘制特发性甲旁减患者microRNA表达谱，探索其在发病机制中的作用。从多种组学层面探索甲旁减的发病机制，提高甲旁减的诊疗水平。