PRDM1-ATG5与中国汉族人群结核发生风险性的关联研究

发布时间：2018-05-09 22:11

本文选题：肺结核(TB) + PRDM1-ATG5　；参考：《第三军医大学》2014年硕士论文

【摘要】：结核病是一种可致死的严重传染病，是人体感染结核分枝杆菌引起的，在人类历史上曾导致重大疾病疫情。目前，据WHO最新报告统计的数据，全世界约有1/3人口、近20亿人感染了结核菌，成为结核病菌的携带者。同时，每年至少新增800万结核病患者，其中约1/3死于结核病，近45万人发展为耐多药结核病(MDR-TB)，17万人死于MDR-TB。研究发现，大部分个体受到结核分枝杆菌感染后都将演变成潜伏性感染，在一定时间内并不发病，其中除了个体营养水平及环境因素差异以外，遗传因素在决定结核发病与否中起到了关键作用。 PRDM1(又名Blimp-1，位于人第6号染色体)，是一种在成熟B淋巴细胞发育为浆细胞时发挥重要作用转录因子，并能够分泌一种抗体来增强机体的免疫应答功能。巨噬细胞自噬及凋亡是结核分枝杆菌体内清除的重要途径，自噬相关基因ATG5，作为细胞自噬和凋亡的转换开关，在自噬与凋亡的发生和发展过程中起重要的调控作用。ATG5直接参与了自噬泡的磷脂双分子层延伸和封闭的2个重要环节，而自噬泡的形成是自噬现象发生的核心过程，也是到目前为止对自噬现象检测和评价的重要指标。近来有文献报道，PRDM1-ATG5基因间的变异会影响PRDM1及ATG5的表达，进而影响机体免疫应答。因此，我们推测PRDM1-ATG5间基因多态性可能与结核感染存在相关性。本研究试图通过在中国西南汉族人群中搜集大量相关血液样本，，开展结核易感性研究，验证位于基因PRDM1-ATG5之间rs548234位点及rs6937876位点的多态性与结核易感之间的关联性，目的是在提高结核病预防、诊断、风险预测上取得进展，为个体化医疗打下一定基础。该研究获得以下主要实验结果： 1.搜集了251例结核组和294例对照组人群的外周血，提取基因组DNA后，通过PCR测序鉴定，其基因分型率为100%； 2.在整个研究人群中，rs548234位点、rs6937876位点在结核组和对照组中的基因型分布上均符合HWE平衡定律。rs548234位点及rs6937876位点单独及联合分析表明其与结核病的发生风险无遗传学关联； 3.在原发性肺结核组与对照组研究发现：rs6937876位点与原发性肺结核发生无显著关联；而rs548234位点与原发性肺结核发生显著关联，其中CC基因型频率高于健康对照人群(CC vs. TT：OR=3.37，95%CI=1.498-7.579，p=0.003；CC vsCT+TT： OR=3.59，95%CI=1.642-7.848， p=0.001)；经吸烟和城镇差异校正后的Logistic回归分析差异存在统计学意义(OR=1.532,95%CI=1.238-2.076，P=0.03)。 4.危险因素分析表明：吸烟及城市化为结核发生的危险因素(吸烟vs.不吸烟：OR=1.741,95%CI=1.189-2.547， p=0.004；城市vs.非城市： OR=1.638,95%CI=1.166-2.301，p=0.004)，而其他因素如年龄、饮酒及职业与结核发病无关联。综上所述，在结核组和对照组中PRDM1-ATG5基因间rs548234位点和rs6937876位点的基因型分布均符合HWE平衡。在本研究所关注的人群中，rs548234及rs6937876多态性位点与结核病发生风险无显著遗传学关联。然而，其中一项数据显示，在原发性肺结核病患者中，rs548234位点的CC基因型的频率明显高于健康对照人群，这提示rs548234C等位基因存在增加原发性肺结核病发生风险的可能性。因此，有理由推测，rs548234T/C多态性位点与中国西南地区汉族人群原发性肺结核病发病有关。
[Abstract]:Tuberculosis (TB) is a fatal and serious infectious disease, caused by Mycobacterium tuberculosis, which has caused major diseases in human history. At present, according to the data of the latest WHO report, there are about 1/3 population around the world, nearly 2 billion people are infected with TB bacteria and become carriers of tuberculosis bacteria. At the same time, at least 8 million new tuberculosis is added. About 1/3 of the patients, about 1/3 died of tuberculosis, nearly 450 thousand people developed to multidrug resistant tuberculosis (MDR-TB), and 170 thousand people died from MDR-TB. research. Most individuals will become latent infection after infection with Mycobacterium tuberculosis and are not ill for a certain period of time, in addition to the individual nutritional level and environmental factors, genetic factors It plays a key role in determining the incidence of tuberculosis.
PRDM1 (also known as Blimp-1, located on human chromosome sixth), is an important transcription factor in the development of a mature B lymphocyte as a plasma cell and can secrete an antibody to enhance the immune response function of the body. Macrophage autophagy and apoptosis are an important pathway for the clearance of Mycobacterium tuberculosis, as autophagy related gene ATG5. The conversion switch of autophagy and apoptosis plays an important role in the development and development of autophagy and apoptosis..ATG5 directly participates in the 2 important links of the phospholipid bimolecular layer extension and closure of autophagic vesicles, and the formation of autophagic bubbles is the core process of autophagy, and is also the test and evaluation of autophagy so far. It has been reported recently that the variation of PRDM1-ATG5 gene may affect the expression of PRDM1 and ATG5 and then affect the immune response of the body. Therefore, we speculate that the polymorphism of PRDM1-ATG5 gene may be associated with tuberculosis infection.
The purpose of this study is to verify the association between the polymorphism of the rs548234 and rs6937876 loci between PRDM1-ATG5 and the susceptibility to tuberculosis by collecting a large number of related blood samples in the Han population of Southwest China to verify the association between the polymorphism of the loci and rs6937876 loci between the gene and the susceptibility to tuberculosis. The purpose is to make progress in the prevention, diagnosis and risk prediction of tuberculosis. Physical medical treatment lays a foundation for it.
The study obtained the following main experimental results:
1. the peripheral blood of 251 cases of tuberculosis group and 294 cases of control group was collected. Genomic DNA was extracted and identified by PCR sequencing. The genotyping rate was 100%.
2. in the whole study population, the genotype distribution of rs548234 loci and rs6937876 loci in the tuberculosis group and the control group all conformed to the HWE equilibrium law.Rs548234 locus and the rs6937876 locus alone and in combination analysis showed that there was no genetic association with the risk of tuberculosis.
3. in the primary pulmonary tuberculosis group and the control group, there was no significant association between the rs6937876 locus and the primary pulmonary tuberculosis; the rs548234 locus was significantly associated with the primary pulmonary tuberculosis, and the CC genotype frequency was higher than that of the healthy controls (CC vs. TT:OR=3.37,95%CI= 1.498-7.579, p=0.003; CC vsCT+TT:OR=3.59,95%CI=1.642. -7.848, p=0.001); there was statistical significance in Logistic regression analysis after smoking and town difference correction (OR=1.532,95%CI=1.238-2.076, P=0.03).
4. analysis of risk factors showed that smoking and urbanization were risk factors for tuberculosis (smoking vs. non smoking: OR=1.741,95%CI=1.189-2.547, p=0.004; urban vs. non City: OR=1.638,95%CI=1.166-2.301, p=0.004), while other factors such as age, drinking and occupation were not associated with tuberculosis.
To sum up, the genotype distribution of the rs548234 and rs6937876 loci between the PRDM1-ATG5 gene and the rs6937876 loci in the tuberculosis group and the control group were all conformed to the HWE balance. There was no significant genetic association between the rs548234 and rs6937876 polymorphic loci and the risk of tuberculosis in the population of this study.
However, one of the data shows that in patients with primary pulmonary tuberculosis, the frequency of the CC genotype at the rs548234 site is significantly higher than that in healthy controls, suggesting the possibility of increasing the risk of primary pulmonary tuberculosis by rs548234C alleles. Therefore, there is reason to speculate that the rs548234T/C polymorphic loci are associated with the Han nationality in the southwest of China. The incidence of primary pulmonary tuberculosis in the population is related.

【学位授予单位】：第三军医大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R52

【参考文献】