基因拷贝数变异在新疆不同民族变应性鼻炎分子遗传学机制中作用的相关性研究

Allergic Rhinitis,AR has become a worldwide common disease with its incidence increased year by year. The pathogenesis is remain unclear, but closely related to the environment and genetic factors.Xinjiang due to its unique geographical environmental factors, incidence of AR remains high. Xinjiang as a multi-ethnic area, differences in AR incidence and molecular genetic mechanisms may exist among different ethnic group populations. According to foreign research reports: the incidence of Asthma and other genetic characteristic related diseases (obesity, autism, schizophrenia, etc.) are closely related to Copy Number Variations，CNVs.Therefore, we proposed this scientific hypothesis: genomic CNVs may associated with the pathogenesis and genetic factors of AR among different ethnic group populations.Firstly, this study intends to use whole genome sequencing to detect allergic rhinitis-related genes CNVs in the Xinjiang Uygur and Han families, screened positive CNVs; Followed by using RT-PCR technology to verify the co-relationship between CNVs positive AR individuals and allergic rhinitis population.Finally, through the expression of Westing blot, molecular biology techniques such as liquid-chip , to test positive CNVs in the case group and the control group in the nasal mucosa, in order to validate the molecular mechanisms leading to differential gene expression in AR.The completion of this study can further clarify the molecular genetic mechanisms of AR patients among different ethnic group populations(Uygur, Han) in Xinjiang, to provide brand-new perspectives in finding new intervention targets in treatments of Allergic Rhinitis.

变应性鼻炎(allergic rhinitis,AR)发病率逐年递增已成为世界性的常见疾病，其发病机制尚不明确，但与环境及遗传密切相关。新疆是多民族聚居地因其特殊的地域环境导致AR高发，不同民族在AR发病及分子遗传机制中可能存在差异。根据国外研究报道：基因拷贝数变异 (copy number variations，CNVs)与哮喘及具有遗传特征（自闭症等）疾病的发病相关。因此我们推测基因CNVs可能与不同民族AR的发病及遗传相关。本课题拟首先应用全基因测序技术检测新疆维吾尔族和汉族AR家系中与AR发病相关的基因CNVs；其次采用RT-PCR技术验证散发AR患者阳性CNVs与AR群体的相关性；通过液相芯片等分子生物学技术验证阳性CNVs在病例组及对照组鼻黏膜组织中的表达差异从而导致AR发生的分子机制。本研究可进一步阐明新疆不同民族AR发病的遗传机制的新解释，为寻找到AR新的干预靶点提供思路。

变应性鼻炎(allergic rhinitis,AR)发病率呈逐年递增趋势，是世界性的常见疾病之一，其发病机制尚不明确，但与环境及遗传密切相关。而新疆因其特殊的地域环境又是多民族聚居地导致AR高发，不同民族在AR发病及分子遗传机制中可能存在差异。多项研究发现基因拷贝数变异 ( copy number variations，CNVs)与哮喘及具有遗传特征（自闭症等）疾病的发病相关。首先参照变应性鼻炎诊断和治疗指南(2015年,天津)收集维、汉族AR患者2个家系、AR诊断汉族AR患者400例，维族患者300例，健康对照组汉族400例，维族300例。应用全基因测序技术检测结果分析基因组DGV， 7个CNV被选作AR候选致病CNV。进一步生物信息学分析，筛选MUC5AC和MUC5B，MIR8054，MIR548AD，MIR4454,SERPINA1，NME7，ORMDL3，IL1RL1等候选CNV。我们在验证队列中采用Accucopy技术对候选CNV进行了检测，探讨了这些CNV的CNV及其AR关联。在我们的验证队列中，没有发现MIR8054和MIR548AD的拷贝数变异。然而，在汉族病例组中，有40.12％的个体具有MIR4454基因的duplication CNV，并且鉴定出33.42％的对照组具有MIR4454的duplication CNV（χ2= 9.123； P = 0.0025），而在维族病例组中不具有MIR4454的duplication CNV。在多变量logistic回归中，关联仍然显著（Padj = 0.045）。功能验证结果显示，和汉族健康个体相比，汉族AR患者鼻腔粘膜组织中MUC5AC mRNA、miR548AD和miR4454的表达量均显著提高（p<0.05），miR8054表达量在两组之间差异不显著（p>0.05）。而在维吾尔族中，AR患者鼻腔粘膜组织中MUC5AC mRNA、miR548AD和miR8054的表达量均显著高于健康个体（p<0.05），但miR4454表达量在两组之间差异不显著（p>0.05）。这表明汉族和维吾尔族AR疾病发生存在民族异质性，不同的CNV会导致基因表达量发生改变，最终影响AR的发生发展。这进一步提示我们需要对疾病的CNV致病机制进行深入的研究。......