基因拷贝数变异在甲状腺疾病易感人群筛查中的作用研究

Iodine deficiency and iodine excess will result in thyroid damage, especially to the approximately 15% of the total population, who are susceptible to thyroid disorders. These people require a relatively narrower iodine intake range. If they were detected in an earlier stage and be given special iodine supplement measures, the side effects of salt iodization would be minimised. Since thyroid diseases are complex disease, the discovery of susceptibility genes will prevent the disease from an earlier stage. Our group have found that thyroid disease incidence increases in iodine excess area in past investigations. The relation of some specific genes' expression and SNPS with subclinical thyroid diseases and thyroid dysfunction were discovered in our previous studies. In this project, the differences of genome-wide CNV between thyroid dysfunction group and general population were studied by SNP probe method. Base on this result, thyroid related genes were selected and their CNV of thyroid dysfunction group were investigated by quantitative PCR method. As a result, the susceptible CNV of thyroid disease were selected preliminary. Then A thyroid-disease- susceptible CNV map was proposed. This project would play an important role for seeking thyroid disorders susceptible group, promote the understanding of related disease pathogenesis, and also provide new targets for the diagnosis and treatment of thyroid disease.

碘缺乏和碘过量对于甲状腺的健康均不安全，特别是对人群中存在的15％左右的甲状腺疾病易感人群，这部分人对碘摄入量要求范围较窄，如能尽早发现，采取有针对性的补碘措施，将使食盐加碘防治碘缺乏病的副作用降至最低。甲状腺疾病多为复杂疾病，发现易感基因可及早预防疾病的发生。本课题组在以往的现场调查中发现碘过量地区人群甲状腺疾病发病率增加，在基因研究中发现一些基因的表达和SNP，与亚临床甲状腺疾病和甲状腺功能失调相关。本课题拟采用SNP探针法进行全基因组CNV关联分析，比较甲功异常人群与正常人群全基因组CNV差异；在此基础上选择甲状腺相关基因，采用定量PCR法开展甲功异常人群甲状腺相关基因研究，初步选出甲状腺疾病易感人群的CNV；提出甲状腺疾病易感人群CNV图谱。本研究对于甲状腺疾病易感人群的发现可能发挥重要作用，并将促进对相关疾病发病机制的认识，还可为甲状腺疾病的诊断和治疗提供新的靶标。

甲状腺疾病易感人群对于碘摄入的适宜范围比普通人群窄，因此及早发现他们，采取有针对性的补碘措施，将对绝大多数人受益的食盐加碘防治碘缺乏病措施的副作用降至最低，真正做到分类指导、科学补碘。基因拷贝数变异（CNV）是产生个体间遗传差异和人类遗传多样性的一个重要来源，对于甲状腺疾病易感人群的发现可能发挥重要的作用。为了评价CNV在甲状腺疾病发生中的贡献，本项目在补碘地区、适碘地区和高碘地区开展流行病学调查，筛选出甲功异常者；采用病例对照研究方法，进行全基因组CNV关联分析；根据分析结果及相关文献，选择自身免疫性甲状腺疾病、亚临床甲减、TSH 水平异常、甲状腺结节等不同人群，对全部病例和相应对照进行候选基因CNV的验证。主要研究结果如下：一是通过全基因组CNV关联研究，发现了病例组与对照组全基因组CNV的差异，在病例组共发现CNV片段2789个，其中扩增片段809个、缺失片段1980个；在对照组共发现CNV片段2555个，其中扩增片段844个、缺失片段1711个。二是通过甲状腺疾病易感人群相关基因CNV验证研究，发现免疫调控相关基因SIRPB1、IL9R和细胞生长相关基因GPC5和ASB11 CNV是自身免疫性甲状腺疾病的危险因素；TSHR CNV是TSH水平异常和甲状腺结节发生的危险因素；X染色体免疫相关基因TLR7 CNV是亚临床甲减发病的危险因素；发现不同碘水平时CNV在甲状腺疾病易感人群中存在差异；发现女性亚临床甲减病例组TLR7 CNV明显高于对照组。三是在进行人群研究时，发现甲状腺疾病患者的血清碘水平有高于甲状腺功能正常成人的趋势，相对稳定的血清碘在评价个体碘营养方面有较高的评估价值。四是在动物实验部分，发现ASB11、SLC6A7、TSHR在自身免疫性甲状腺炎发生中有一定的作用。这些发现对于评价相关基因CNV在甲状腺疾病发生中的贡献以及为甲状腺疾病易感人群的发现提供了一定的科学依据，促进了对甲状腺相关疾病的发病机制的认识，对相关甲状腺疾病的诊断和治疗具有一定的参考价值。