广西壮族哮喘人群5-HTT基因rs3794808位点多态性与CD4+T辅助淋巴细胞因子表达谱关系研究

About 300 million people around the world suffer from asthma, which seriously affect human health. Currently,there is no unified view about the relationship between polymorphism of 5-HTT gene and asthma. Our previous study found that rs3794808 locus of 5-HTT gene in Guangxi Zhuang population may be a potential genetic susceptibility loci, the asthma risk of CC genotype individual is 2.83 times the risk of TT genotype individual,However, the relationship between target rs3794808 polymorphism and the development of asthma are still not clear. As we know, the pathogenesis of asthma involves a network about many cytokines secreted by the Th1/Th2 cells and Th17/Treg cells. In order to find differential expression of cytokines, the sample of this study is the CC genotype asthma patients of Guangxi Zhuang population and TT genotype patients as the research control group, which we will study serum cytokines in Th1/Th2/Th17/Treg cell expression porifile.These will initially revealed the cytokine network pathways of high asthma risk CC genotypes may be involved, and provide scientific basis for the study of asthma pathogenesis related to polymorphisms and individualized treatment.

全球约3 亿人罹患哮喘，严重影响人类健康。5-羟色胺转运体（5-HTT）基因多态性与哮喘关系各方报道不一。我们前期研究发现5-HTT 基因的rs140700、rs2020936、rs3794808 位点多态性可能是广西壮族人群潜在的遗传易感位点，其中rs3794808位点的CC 基因型个体的哮喘发生风险较之TT基因型个体达2.83 倍，而大量研究证实5-羟色胺（5-HT）涉及的哮喘发病机制与Th1/Th2 和Th17/Treg免疫细胞群分泌的多种细胞因子所构成的复杂网络关系密切。本项目以广西壮族哮喘人群5-HTT 基因的CC 基因型患者与TT 基因型患者为研究对象，研究其血清中Th1/Th2/Th17/Treg 细胞群的细胞因子表达谱情况，寻找差异化表达的细胞因子，初步揭示5-HTT 基因的CC 基因型高风险哮喘发病可能通过的细胞因子网络途径，为哮喘异质性个体防治和明确其多态性机制提供依据。

5-羟色胺转运体（5-HTT）作为一种跨膜蛋白，通过运转5-羟色胺（5-HT）而参与哮喘炎症反应。为了探讨5-HTT基因rs3794808位点与哮喘的关系是否通过调节Th细胞因子网络发挥免疫调节作用进行了病例对照研究，研究结果表明广西壮族人群5-HTT基因rs3794808位点CC基因型患哮喘的风险高于TT基因型，进而比较CC 基因型患者与TT 基因型患者Th1/Th2/Th17/Treg信号通路的细胞因子的水平，发现与携带TT基因型哮喘患者相比，CC基因型哮喘患者血清中IFN-γ、IL-2和IL-10浓度较低，而IL-4 、IL-5和IL-17浓度较高，IFN-γ/IL-4比值降低及IL-17/IL-10比值增高。CC基因型哮喘患者的T-bet mRNA表达量低于TT基因型，而GATA3 mRNA表达量高于TT基因型， T-bet/GATA3比值与IL-2浓度呈正相关，与IL-5浓度呈负相关。说明广西壮族哮喘人群5-HTT 基因rs3794808位点CC 基因型与TT 基因型患者Th1/Th2/Th17/Treg 细胞群的细胞因子存在差异化表达，5-HTT基因有可能通过影响Th1/Th2/Th17/Treg平衡从而影响哮喘的发病，且5-HTT基因的多态性可作为遗传易感背景影响T-bet / GATA3转录因子的表达，从而造成Th1/Th2失衡来参与哮喘的发病过程。从另一个角度为哮喘机制研究提供了切入点和线索，这或许能成为哮喘治疗的途径之一。此外，还发现了5-HTT基因rs3813034位点的GG基因型和rs2054847位点的TT基因型是壮族人群哮喘的遗传危险因素，且这两种风险基因型患者外周血小板水平高于非风险基因型。而血小板是5-HT的主要储存体，表明这两种风险基因型患者可能具有更高的外周血 5-HT 储存能力从而增加了哮喘发病的风险。