β中间型地中海贫血（地贫）的贫血程度介于轻型和重型之间，表型差异大，其发病机制一直不清。本课题在前期研究中发现中间型地贫患者与HbF有关外还与铁代谢相关基因的变异有关。本申请假设：铁相关调节基因是中间型地贫表型多样性的修饰基因。为此，拟在人群水平上利用本组前期积累的大样本地贫患者遗传和临床信息资源，采用case-only设计探讨受试者血浆中HbF 、Hepicidin和铁浓度等指标，进一步采用测序检测TMPRSS6、BMP6和HFE基因的结构变异，经大样本病例群体的基因分型，生物信息学功能和遗传统计学分析，比较基因型-表型的关联，获得中间型地贫与铁代谢相关基因的变异有关的证据。并在细胞水平上考察铁代谢相关基因的变异型/野生型与HbF的超表达/SiRNA，观察相关基因变异型产物的表达对HbF表达的修饰作用，以阐明铁代谢相关基因变异与β中间型地贫贫血程度差异的机理。

The anemia level of intermediate beta thalassemia is between moderate and serious, and the phenotypes is various, but the mechanism to these characters is still unclear. In the former studies, we found that in addition to the HbF level, the mutation of iron metabolism related gene also affect the phenotype of intermediate beta thalassemia patients. In this application, we assumed that iron relative regulator gene is a kind of modifier gene which lead to the variety of intermediate beta thalassemia phenotypes. Therefore, we will design with case-only method and careful use our big population thalassemia samples and genetic resource, to detect their HbF and Hepicidin level, TF-FE saturation, iron concentration and CBC, and analyze the mutation of TMPRSS6, BMP6 and HFE genes using DNA sequencing. By genotyping targeted gene and analyzing the genotype-phenotype with bioinformatics, so we could find the evidences of relationship between intermediate thalassemia and iron metabolism relative genes. Where after the over expression of siRNA of the iron metabolism relative gene of mutation/wild type and HbF are invested in cells, and the mutation genes expression level affecting on HbF level was observed, so as to illuminate the mechanism of iron metabolism relative genes mutation affect the intermediate thalassemia anemia level variety, and its potential value in clinical application.