影响HbH-CS病表型多样性的甲基化基因位点的研究

Hemoglobin H (HbH) disease is a common form of α-thalassemia. It has two forms, non-deletional and deletional. The former, which is more clinically severe than the latter, usually results from point mutation, insertion, or small deletion, while the latter has large deletion in the α-globin genes. HbH-Constant Spring(HbH-CS) disease is the most common form of non-deletional HbH disease in the South of China. It has long been noted that a great phenotypic heterogeneity exists among patients with the same HbH-CS genotype, which cannot be fully interpreted by classical genetics at present. Recent data have shown that human globin genes were regulated by epigenetic changes. That the human β-globin gene cluster sequentially open and close during developmental processes was closely associated with DNA methylation. It is also reported that, Histone deacetylase 3 (HDAC3) gene was hypermethylated in β-thalassemia patients. Therefore, we assume that epigenetics may play a role in modifying the phenotypic heterogeneity in patients with HbH-CS disease. In the current study, we aim to explore HbH-CS related hyper/hypomethylation genes by using commercially available whole-genome DNA methylation screening kit (Infinium HumanMethylation450K BeadChip) and AmiGO Gene Ontology analysis, in an attempt to improve the accuracy of genetic counseling and to seek potential therapeutic targets for HbH-CS patients.

HbH-CS病是α地中海贫血的一种，是我国南方最为常见的非缺失型HbH病，其临床表现往往比缺失型HbH病重。同时，HbH-CS病的表型具有明显的遗传异质性，目前经典的遗传学不能解释其机制。有研究表明，珠蛋白基因的表达受表观遗传学的调节,人类β珠蛋白基因簇在发育过程中的次序开启和关闭与DNA甲基化有关，组蛋白甲基转移酶3( HDAC3)基因在β地中海贫血呈高度甲基化。因此，我们推测，HbH-CS病的遗传异质性与表观遗传学有关。本研究拟通过DNA甲基化筛查芯片结合AmiGO数据库进行基因功能学分析，探索与HbH-CS病遗传异质性相关的甲基化基因位点，对筛查的靶点进行验证，并进一步探讨DNA甲基化抑制剂或DNA甲基化诱导剂对HbH-CS病的治疗作用和安全性，不仅从表观遗传学的角度解释HbH-CS病的遗传异质性，提高HbH-CS病遗传咨询的准确性，更为HbH-CS病寻找新的治疗靶点。

HbH-CS 病的表型具有明显的遗传异质性，珠蛋白基因受表观遗传学的影响，我们推测，HbH-CS 病的遗传异质性与表观遗传学有关。本研究通过DNA甲基化筛查芯片结合AmiGO数据库进行基因功能学分析，发现差异甲基化基因 251个，其中高甲基化基因 148 个，低甲基化基因103个，HbH-CS 组存在较多高甲基化基因，而对照组存在较多低甲基化基因，GO富集分析发现基因功能主要涉及免疫反应、离子平衡、细胞因子分泌、生物大分子合成等几个方面。通过STRING数据库分析构建这些差异甲基化基因相互作用通路，并通过NCBI数据库对节点基因进行分析。通过荧光定量PCR验证血红蛋白生成相关基因AHSP、SMARCA4及PIP4 KⅡα的表达。为揭示HbH-CS病遗传异质性的发生机制奠定了研究基础。

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