云南地区β-地中海贫血患者中胎儿血红蛋白的修饰机制研究

Various studies have showed that increase of the HbF level resulted from the reactivation of γ-globin gene expression could reduce the clinical severity of β-thalassemia. Many genetic modifying factors could increase the HbF level, but different genotypes of these factors have different contribution for the reactivation of the γ-globin gene expression in different populations. At present, little is known about the association between the genetic modifying factors and the HbF level in Yunnan population. Our previous studies have showed that β-thalassemia is prevalent in Yunnan population, and the mutations in globin genes exhibit high genetic diversity and regional specificity. Therefore, in this study, the genetic modifying factors of γ-globin gene expression in Yunnan population will be detected to elucidate the effects of different modifying factors on the HbF level in β- thalassemia patients in Yunnan Province. At the same time, whole-genome sequencing of some β-thalassemia patients with mild symptoms or effective treatment will be carried out, with the aim to explore other potential genetic modifying factors of HbF expression. Moreover, the relationship of HbF level with different miRNA expression will be further analyzed by using the cell models derived from the β-thalassemia patients. Based on the results, the reactivation mechanisms of γ-globin gene expression in β-thalassemia patients in Yunnan Province will be uncovered, and the potential genetic modifying factors and their reactivation mechanisms will also be explored. This study will provide theoretic basis for the establishment of accurate and comprehensive diagnosis system of β-thalassemia and the seeking of therapeutic approaches for the β-thalassemia patients in Yunnan Province.

研究表明β-地贫患者中γ-珠蛋白基因表达的重激活导致胎儿血红蛋白（HbF）含量增加并可缓解患者临床症状，而且不同人群中修饰因子的基因型对γ-珠蛋白基因重激活表达的影响不同，但在云南人群中未见类似研究报道。我们前期的研究表明，β-地贫在云南人群中发病率高，珠蛋白突变类型呈明显的多样性和独特性。本项目拟通过检测与γ-珠蛋白基因表达相关的修饰因子，明确不同修饰因子对云南β-地贫患者HbF表达的影响。同时我们将对部分临床症状轻或治疗效果好的β-地贫患者采用全基因组测序来探寻是否存在其它调节HbF表达的潜在修饰因子。进一步利用β-地贫患者细胞模型检测分析HbF表达水平和不同miRNA表达之间的关系。通过这些研究将揭示云南β-地贫患者中γ-珠蛋白的修饰激活机制，探讨潜在的HbF修饰因子及其修饰激活机制，为建立β-地贫的精准全面诊断体系和探寻云南β-地贫患者的治疗途径提供理论基础。

β-地贫患者中γ-珠蛋白基因表达的重激活导致胎儿血红蛋白（HbF）含量增加并可缓解患者临床症状，而且不同人群中修饰因子的基因型对γ-珠蛋白基因重激活表达的影响不同，但在云南人群中未见类似研究报道。该研究通过检测与γ-珠蛋白基因表达相关的修饰因子，明确不同修饰因子对云南β-地贫患者HbF表达的影响。研究中我们检测了云南地贫患者的HBG、BCL11A、MYB基因的rs7482144、rs1188686、rs766432、rs9399137、rs66650371位点多态性和KLF1基因突变。结果表明rs7482144、rs766432、rs9399137、rs66650371位点和KLF1基因与Hb F升高有关，rs11886868位点的多态性与Hb F升高无关。研究中检出KLF1基因的c.544 T>C、c.901 C>T、c.902 G>A位点3种突变类型，这3种突变在印度和东南亚国家见报道。为了明确HBG1基因上的rs368698783位点和HBG2基因上rs7482144位点多态性调节HbF表达，改善β-地贫患者的临床症状的相关性，我们检测了Gγ/Aγ珠蛋白基因相对表达量。研究证实rs368698783的A等位基因与rs7482144位点的T等位基因可以调控γ-珠蛋白基因表达, 但rs368698783位点调控γ-珠蛋白基因表达的作用更强。同时对76例中重型β-地贫患者采用二代测序来探寻是否存在其它调节HbF表达的潜在修饰因子。通过测序数据的分析与解读，发现15个SNPs与高HbF水平相关。上述研究结果丰富了β-地贫的遗传修饰位点，为探讨HbF的修饰激活机制、建立β-地贫的精准全面诊断体系和探寻云南β-地贫患者的治疗途径提供理论基础。同时，项目研究过程中，地贫防控技术得到了很好的推广，获得较好的应用效果，社会效益显著。

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