广西地区先天性甲状腺功能减低症的遗传与环境因素研究

Congenital hypothyroidism (CH) resulting children mental retardatin and short stature, is one of the most common pediatric endocrine diseases, the CH prevalence is 1:835 in Guangxi by neonatal screening, at the range of the highest in the country. Genetic heterogeneity and the unique geographical environmental factors of Guangxi may be the important reasons of highest prevalence. This project intends to comprehensive genetic and environmental factors to investigate the pathogenic factors of CH.200 cases will be performended DNA sequencing in exon and promoter of TSHR, Pax-8, DUOX2, SLC5A5, TPO and TG genes, in order to find the genetc and molecular abnormalities in those CH pathogenic or candidate genes and then through the 1200 cases of large sample case - control to verify the pathogenic gene and mutation sites to explore the status of genetic factors in the prevalence of CH. In addition，urinary iodine and living water iodine will be measured and mothers' history of thyroid disease will be investigated to understand the role of environmental factors in high prevalence of CH. Molecular genetics and environmental factors are integrated to analyze and research to understand the genetic and environmental factors in congenital hypothyroidism.Therefore, we can take the pertinent measures to further reduce the prevalence of CH in Guangxi and improve the quality of birth.

先天性甲状腺功能减低症（CH）导致儿童智力落后与生长障碍，是儿科最常见的内分泌疾病之一。新生儿疾病筛查显示广西地区患病率高达1：835，位居全国首位。遗传的异质性及广西独特的地理环境可能是广西地区CH高发的原因。本项目拟通过分子遗传学研究，对200例CH患者的TSHR、Pax-8、DUOX2、SLC5A5、TPO、TG等基因外显子及启动子测序，分析广西CH患者的主要致病基因及候补基因的分子异常，再通过1200例大样本病例-对照，对致病基因及突变位点进行验证，探讨遗传因素在CH患病中的地位。另外，通过测定患儿尿碘及生活水样的碘含量调查, 对患者母亲甲状腺疾病史调查等，了解环境因素在CH高患病率中的作用。通过综合分子遗传学及环境因素分析与研究，了解广西地区遗传与环境因素在先天性甲状腺功能减低症中的地位，采取针对性的防治措施，进一步降低广西地区CH的患病率，提高出生人口素质。

先天性甲状腺功能减低症（CH）是新生儿常见内分泌疾病，其全球发病率约为1/2000-1/4000，环境因素和遗传因素是导致CH的重要病因。本项目通过二代测序分析，对382 例 CH 患者的 TSHR、PAX8、DUOX2、SLC5A5、TPO、TG 等12个基因外显子及启动子测序，同时通过结合患者临床表型、实验室检测，建立基因型与表型关系。研究发现约53.7%的患者检测有上述基因可疑致病变异位点。DUOX2和TG基因的突变频率最高，分别为31.4%和14.7%。PAX8基因呈显性遗传，其杂合突变即可导致CH，患者病情较重，绝大多数表型为永久性CH。TSHR基因单个杂合突变表现为高TSH血症，当合并TG/DUOX2杂合突变，可表现为CH。患者可发生DUOX2单个变异位点、两个甚至三个及以上变异位点。随着DUOX2变异位点增加，患者病情也呈现愈发严重的趋势。为了解广西沿海、平原、山区 8-10岁儿童碘营养状况，探讨环境因素在CH病因学中的影响，本课题对广西沿海、平原、山区2 073名8-10岁儿童尿碘水平进行检测，发现广西尿碘水平处于适宜水平。通过综合分子遗传学及环境因素分析与研究，了解广西地区遗传与环境因素在先天性甲状腺功能减低症中的地位，同时建立了PAX8、TSHR、DUOX2等基因的基因型与临床表型关系，进一步加深了对CH病因学的了解，为今后采取针对性的防治措施，进一步降低广西地区 CH 的患病率，提高出生人口素质奠定了理论基础。