结核免疫应答相关基因多态性与肺结核易感性的关联研究
发布时间：2018-08-08 17:28
【摘要】：背景：结核病（Tuberculosis，TB）是由结核分支杆菌（Mycobacteriumtuberculosis，M.TB）感染引起的人类较早和最具影响力的传染病疾病之一。到目前为止，结核病仍然是由单一病原菌导致死亡人数最多的疾病，并且近年来呈现死灰复燃之势。目前，全国结核菌感染人数超过5亿，结核病患者达500万之多，年发病人数约为130万。根据2010年世界卫生组织（World Health Organization，WHO）的统计，我国结核病病人总数居全球第二位，是全球22个结核病高负担国家之一。研究表明，暴露于结核杆菌，三分之一的人群会被感染，在感染人群中，不到10%的感染者发展为结核病。提示个体对于结核病具有遗传易感性。 结核病是慢性细胞内感染的典型病症，机体抵抗结核杆菌的感染的天然和适应性免疫应答主要是通过表达于T淋巴细胞和巨噬细胞以及树突细胞表面的模式识别受体与结核杆菌的识别触发天然免疫应答，进而激活参与抗原提呈和疾病进程相关的下游的信号通路及其调节基因的如细胞因子和趋化因子等分子的级联反应，清除或者控制病原体的感染。由于参与结核病免疫应答的基因存在遗传变异，可能会影响个体的免疫状态或能力，而个体间的免疫状态或能力的差异也就可能增加了个体肺结核的危险度，从而影响对结核病的易感性以及疾病的发生与发展。 目的：为了探讨基因多态性与肺结核易感性的关系，我们假设参与结核病免疫应答的细胞因子及其受体、趋化因子和模式识别受体类等重要功能基因的单核苷酸多态性位点（Single nucleotide polymorphism，SNP）单独或联合与肺结核易感性有关，且可能存在基因-基因交互作用；肺结核严重程度的表型是由其重要基因的遗传变异决定的，个体之间疾病严重程度的差异可能与其功能基因的SNPs息息相关。 方法：为验证上述假设，本研究采用病例-对照研究方法，综合运用“以序列为基础”和“以图谱为基础”的SNPs选点策略，采用聚合酶链式反应-限制性片段长度多态性（Polymerase chain reaction-restriction fragment lengthpolymorphism，PCR-RFLP）、扩增阻滞突变系统（Amplification refractory mutationsystem，ARMS）PCR、MassARRAY和SNPstream技术对参与结核免疫应答相关基因的包括细胞因子及其受体、趋化因子和模式识别受体（Pattern recognitionreceptors，PRRs）在内的20个具有明确功能的代表性基因，包括肿瘤坏死因子α（Tumor necrosis factor α，TNF-α），干扰素γ（Interferon gamma，IFN-γ）、白介素10（Interleukin10，IL-10）、IL-1β、IL-12β、IL-12β1、IL-17、IL-23受体（Interleukin-23receptor，IL-23R）、IL-6R、IL-6、C-C趋化因子配体1（ChemokineC-C motif ligand1，CCL1）、树突状细胞特异性细胞间粘附分子-3-结合非整合素(Dendritic cell-specific ICAM-3grabbing nonintergrin，DC-SIGN)、单核细胞吸附蛋白1（Monocyte chemotactic protein-1，MCP-1）、调节正常T细胞表达和分泌因子（Regulated upon activation normal T cell expressed and secreted，RANTES）、SP110、维生素D受体（Vitamin D receptor，VDR）、Toll样受体（Toll like receptor，TLR）2、TLR4、肝X受体（Liver X receptors，LXRs）、带有胶原结构的巨噬细胞受体（Macrophage receptor with a collagenous structure，MARCO）和干扰素调节因子5（Interferon regulatory factor5，IRF5）基因的115个SNPs位点进行分型，研究基因多态性单独或联合与肺结核易感性的关系。本研究病例来源于3级甲等医院均经临床或实验室确诊新发肺结核病人923例。正常人群来自于相应医院同时期体检的健康正常人群1033例。对照人群按地区（城乡）和民族与病例匹配。使用统一设计的健康状况调查表进行流行病学调查获取相关信息。实验过程中采用设立内对照和盲法复测等多种方法进行质量控制。所有实验数据和编码的调查表资料经过反复检查、核对，用Microsoft excel建立数据库。运用SPSS17.0、SNPstats、Haploview和MDR软件进行数据整理与分析。 结果：（1）细胞因子及其受体基因多态性的关联分析：位于TNF-α基因启动子区域的-857CT和-863AC位点与肺结核的发生显著相关，与-857CT位点携带CC基因型者相比较，携带TT基因型者肺结核的风险降低了32%（OR=0.68，95%CI：0.53-0.86）；与-863A/C位点携带CC基因型者比较，携带AA基因型者肺结核的风险度会增加了142%（OR=2.42，95%CI：1.28-4.59），并且基因型也与病情严重的肺结核相关（OR=3.59，95%CI：1.41-9.11）。此外，携带有-863A/C位点A等位基因者血清中TNF-α含量显著低于C等位基因者。因此，我们认为TNF-α基因启动子区域-857CT和-863AC位点多态性可能与中国汉族人群肺结核遗传易感性有关。（2）趋化因子基因多态性的关联分析：CCL1基因的rs159291、rs159294和rs210837三个SNP位点以及RANTES基因的rs2107538位点与肺结核显著相关，其中与rs159291位点携带AA基因型者比较，GG基因型携带者肺结核的风险会降低71%（OR=0.71，95%CI：0.56-0.92）；而与rs159294、rs210837位点携带TT或GG基因型者相比较，携带AA基因型者肺结核的风险度分别增加了17%和59%（OR=1.17，95%CI：1.01-1.35；OR=1.59，95%CI：1.07-2.36）。而RANTES基因rs2107538位点与肺结核的易感性负相关（OR=0.79，95%CI：0.66-0.94）。进一步对CCL1基因构建了单倍型，结果表明由rs159291和rs159294位点构成的AT单倍型携带者与GT单倍型携带者相比，与肺结核易感性显著相关（OR=1.16，95%CI：1.00-1.35）。（3）受体类基因多态性的关联分析：在53个SNPs位点中，IRF5基因的rs729302、MARCO基因的rs17009726、rs6761637和VDR基因的rs7975232位点与肺结核易感性显著相关。显性模型研究结果显示，对于IRF5基因的rs729302位点，与携带A等位基因的AA和CA基因型相比，CC基因型能够降低人群对结核杆菌的易感性（OR=0.71，95%CI：0.54-0.93），通过进一步连锁不平衡（Linkage disequilibrium，LD）和单倍型作图分析，结果显示CG单倍型（rs729302和rs4728142）明显与肺结核易感性呈负相关（OR=0.83，95%CI：0.72-0.96）；而MARCO基因rs17009726和rs6761637位点携带“G”或“C”等位基因携带者与肺结核易感性呈正相关（OR=1.24，95%CI：1.02-1.52；OR=1.65，95%CI：1.32-2.05）。单倍型分析发现包含rs17009726位点“G”等位基因的GC单倍型和包含rs6761637位点“C”等位基因的TGCC单倍型（OR=1.62，95%CI：1.31-2.00；OR=1.31，95%CI：1.06-1.60）也与肺结核的易感性呈正相关。同时，VDR基因的rs797523（ApaΙ）位点携带A等位基因者与肺结核显著关联（OR=0.82，95%CI：0.69-0.98），且A等位基因与血清中高浓度25羟维生素D（25-hydroxyvitamin D，25-OHD）相关，证明该位点对肺结核的保护作用主要可能是通过对维生素D的正调控发挥作用。（4）基因-基因交互作用分析：通过基因-基因交互作用分析，发现趋化因子基因RANTES的rs2107538和CCL1的rs3091324位点存在交互作用，对最佳模型的两个变量根据MDR软件进行两分类化（即分为危险层和非危险层），处在相对危险层的个体患肺结核的风险显著增加了0.4倍（OR=1.40，95%CI：1.17-1.67）。同时，VDR基因的rs7975232、MARCO基因的rs2077344、TLR2基因的rs7656411和IRF5基因的rs729302位点存在交互作用，，两分类化后处在相对危险层的个体患肺结核的风险显著增加了1.36倍（OR=2.36，95%CI：1.95-2.84）。 结论：本研究通过采用大样本量的病例-对照研究，在中国人群中开展了参与结核病免疫应答基因多态性与肺结核易感性关系的研究，发现了TNF-α、CCL1、RANTES、IRF5、MARCO和VDR基因多态性单位点或联合其他基因位点的交互作用与肺结核易感性显著相关，且TNF-α和VDR多态性位点与其血清中的表达水平密切相关。本研究结果对于进一步评价和识别遗传因素对肺结核发生发展的危险性，阐明肺结核发生、发展的分子遗传学机制及可能存在的基因-基因等具有重要的理论和现实意义。方法学部分将对其他疾病的分子流行病学研究具有一定的借鉴价值。通过本研究发现的与我国人群肺结核易感性相关的危险基因型、单倍型，验证后有望为分子标志物用于筛选高危人群，对肺结核实施有效和目标明确的个体预防、早期诊断和预后判断等均具有重要的意义。
[Abstract]:Background: Tuberculosis (TB) is one of the early and most influential infectious diseases caused by Mycobacteriumtuberculosis (M.TB) infection. Up to now, tuberculosis is still the most fatal disease caused by a single pathogen, and it has shown the trend of resurgence in recent years. The number of tuberculosis infections in the country is over 500 million, and the number of TB patients is over 5 million. The number of patients in the year is about 1 million 300 thousand. According to the statistics of the WHO (World Health Organization, WHO) in 2010, the total number of TB patients in China ranks second in the world, and is one of the 22 TB countries in the world. The study shows that the tuberculosis is exposed to three points. One of the population will be infected, in the infected population, less than 10% of the infected people develop tuberculosis. Individuals have a genetic susceptibility to tuberculosis.
Tuberculosis is a typical disease of chronic intracellular infection. The natural and adaptive immune response of the body against Mycobacterium tuberculosis is mainly through the recognition of the pattern recognition receptors expressed on the surface of T lymphocytes and macrophages and dendritic cells and the identification of Mycobacterium tuberculosis to trigger natural immune response, and then activate the antigen presentation and disease. The cascade of signaling pathways related to the downstream process and the cascade of molecules that regulate genes, such as cytokines and chemokines, to clear or control the infection of pathogens. Genetic variation in genes involved in the immune response to tuberculosis may affect the individual's immune state or ability, and the immune state or ability of individuals. Differences may also increase the risk of individual tuberculosis, thereby affecting susceptibility to tuberculosis and the occurrence and development of the disease.
Objective: To explore the relationship between genetic polymorphisms and susceptibility to tuberculosis, we hypothesized that the single nucleotide polymorphisms (Single nucleotide polymorphism, SNP), which are important functional genes such as chemokines and pattern recognition receptors (SNP), are involved in the susceptibility to tuberculosis in the immune response of tuberculosis. And there may be gene gene interaction; the phenotype of the severity of tuberculosis is determined by the genetic variation of its important genes, and the difference in the severity of the disease among individuals may be closely related to the SNPs of the functional genes.
Methods: to verify the hypothesis, a case control study was used in this study. The SNPs selection strategy based on "sequence based" and "Atlas Based" was used in this study. The polymerase chain reaction restriction fragment length polymorphism (Polymerase chain reaction-restriction fragment lengthpolymorphism, PCR-RFLP) was used to amplify the resistance. The Amplification refractory mutationsystem (ARMS) PCR, MassARRAY, and SNPstream techniques include 20 representative genes, including cytokine and its receptors, chemokines, and pattern recognition receptors (Pattern recognitionreceptors, PRRs) involved in the immune response related genes of tuberculosis, including tumor damage. Death factor alpha (Tumor necrosis factor alpha, TNF- alpha), interferon gamma (Interferon gamma, IFN- gamma), interleukin 10 (Interleukin10, IL-10), IL-1 beta, IL-12 beta, IL-12 beta 1, dendritic cell specific intercellular adhesion -3- combined with non integrin (Dendritic cell-specific ICAM-3grabbing nonintergrin, DC-SIGN), mononuclear cell adsorption protein 1 (Monocyte chemotactic protein-1, MCP-1), regulating normal T cell expression and secretory factor. Ptor, VDR), the Toll like receptor (Toll like receptor, TLR) 2, TLR4, the liver X receptor (Liver X receptors), the macrophage receptor with the collagen structure, and the 115 locus of the interferon regulatory factor 5 gene. In this study, 923 cases of new pulmonary tuberculosis were confirmed by clinical or laboratory diagnosis in grade 3 first class hospitals. The normal population was from 1033 healthy people in the corresponding hospital at the same time. The control population was matched by the region (Town township) and the national and case. A variety of methods, such as internal control and blind retesting, were used for quality control. All experimental data and coded questionnaire data were checked repeatedly, checked with Microsoft excel and used SPSS17.0, SNPstats, Haploview and MDR soft. The data is arranged and analyzed.
Results: (1) association analysis of the polymorphism of cytokine and its receptor gene: the -857CT and -863AC loci located in the promoter region of the TNF- alpha gene were significantly related to the occurrence of tuberculosis. Compared with those with the CC genotype at the -857CT locus, the risk of pulmonary tuberculosis carrying TT genotypes decreased by 32% (OR=0.68,95%CI:0.53-0.86); and with -863A/C position. Compared with those with CC genotype, the risk of pulmonary tuberculosis with AA genotype increased by 142% (OR=2.42,95%CI:1.28-4.59), and the genotype was also associated with severe pulmonary tuberculosis (OR=3.59,95%CI:1.41-9.11). In addition, the serum TNF- alpha content in the serum carrying -863A/C loci A alleles was significantly lower than that of C alleles. Therefore, I have found that the level of TNF- alpha in serum with -863A/C locus A allele is significantly lower than that of the C allele. We believe that the polymorphism of -857CT and -863AC loci in the promoter region of TNF- alpha gene may be related to the genetic susceptibility to tuberculosis in Chinese Han population. (2) the association analysis of the chemokine gene polymorphism: the three SNP loci of the CCL1 gene and the rs2107538 loci of the RANTES gene are significantly related to the pulmonary tuberculosis, including R. Compared with those with the AA genotype at the s159291 locus, the risk of tuberculosis in GG genotype carriers decreased by 71% (OR=0.71,95%CI:0.56-0.92); compared with those with rs159294 and rs210837 loci with TT or GG genotypes, the risk of tuberculosis with AA genotype increased by 17% and 59% respectively (OR=1.17,95%CI:1.01-1.35; OR=1.59,95%CI:1.07-). 2.36). The rs2107538 locus of the RANTES gene was negatively correlated with the susceptibility to tuberculosis (OR=0.79,95%CI:0.66-0.94). The haplotype of the CCL1 gene was further constructed. The results showed that the AT haplotype carriers composed of rs159291 and rs159294 loci were significantly related to the susceptibility of the GT haplotype carriers (OR=1.16,95%CI:1.00-1.35). 3) association analysis of the receptor gene polymorphism: in the 53 SNPs loci, the rs729302 of the IRF5 gene, the rs17009726 of the MARCO gene, the rs7975232 loci of the rs6761637 and VDR genes are significantly related to the susceptibility to tuberculosis. The results of the dominant model study show that the rs729302 loci of the IRF5 gene are compared with the AA and genotype of the A allele, The CC genotype could reduce the population susceptibility to tuberculosis (OR=0.71,95%CI:0.54-0.93), and by further linkage disequilibrium (Linkage disequilibrium, LD) and haplotype analysis, the results showed that the CG haplotype (rs729302 and rs4728142) was significantly negatively correlated with the susceptibility to tuberculosis (OR=0.83,95%CI:0.72-0.96), while MARCO gene rs170. 09726 and rs6761637 loci carrying "G" or "C" allele carriers were positively correlated with the susceptibility to tuberculosis (OR=1.24,95%CI:1.02-1.52; OR=1.65,95%CI:1.32-2.05). Haplotype analysis found GC haplotypes containing the rs17009726 locus "G" alleles and TGCC haplotypes containing the rs6761637 point "C" allele (OR=1.62). 95%CI:1.31-2.00; OR=1.31,95%CI:1.06-1.60) was also positively correlated with the susceptibility to tuberculosis. At the same time, the rs797523 (Apa) locus of the VDR gene was associated with the pulmonary tuberculosis (OR=0.82,95%CI:0.69-0.98), and the A allele was associated with the high concentration of 25 hydroxyvitamin D (25-hydroxyvitamin D, 25-OHD) in the serum. The protective effect of loci on tuberculosis may be mainly through the positive regulation of vitamin D. (4) gene gene interaction analysis: through gene gene interaction analysis, it is found that the rs3091324 loci of rs2107538 and CCL1 of chemokine gene RANTES are interacted, and the two variables of the best model are based on MDR software. The risk of pulmonary tuberculosis in the relative risk layer was significantly increased by 0.4 times (OR=1.40,95%CI:1.17-1.67). At the same time, the rs7975232 of the VDR gene, the rs2077344 of the MARCO gene, the rs7656411 of the TLR2 gene, and the rs729302 loci of the IRF5 base were interacted upon, and then were divided into two categories. The risk of TB in the relative risk layer increased significantly by 1.36 times (OR=2.36,95%CI:1.95-2.84).
Conclusion: in this study, a large sample case control study was used to study the relationship between the polymorphism of the immune response gene and the susceptibility to tuberculosis in the Chinese population. The interaction of TNF- alpha, CCL1, RANTES, IRF5, MARCO and VDR gene polymorphisms or combined with other gene loci was found to be susceptible to the susceptibility to tuberculosis. The TNF- alpha and VDR polymorphic loci are closely related to the level of expression in the serum. The results of this study have important theories and realities to further evaluate and identify the risk of genetic factors for the development of tuberculosis, to elucidate the pathogenesis of tuberculosis, the molecular genetic mechanism of development and the gene gene gene that may exist. The methodological part will be of reference to the molecular epidemiology of other diseases. Through this study, the risk genotypes associated with susceptibility to tuberculosis in our population, haplotype, are expected to be used to screen high risk groups for the molecular markers, and to carry out effective and targeted individual prevention of tuberculosis. Early diagnosis and prognosis are of great significance.
【学位授予单位】：中国人民解放军军事医学科学院
【学位级别】：博士
【学位授予年份】：2012
【分类号】：R521
[Abstract]:Background: Tuberculosis (TB) is one of the early and most influential infectious diseases caused by Mycobacteriumtuberculosis (M.TB) infection. Up to now, tuberculosis is still the most fatal disease caused by a single pathogen, and it has shown the trend of resurgence in recent years. The number of tuberculosis infections in the country is over 500 million, and the number of TB patients is over 5 million. The number of patients in the year is about 1 million 300 thousand. According to the statistics of the WHO (World Health Organization, WHO) in 2010, the total number of TB patients in China ranks second in the world, and is one of the 22 TB countries in the world. The study shows that the tuberculosis is exposed to three points. One of the population will be infected, in the infected population, less than 10% of the infected people develop tuberculosis. Individuals have a genetic susceptibility to tuberculosis.
Tuberculosis is a typical disease of chronic intracellular infection. The natural and adaptive immune response of the body against Mycobacterium tuberculosis is mainly through the recognition of the pattern recognition receptors expressed on the surface of T lymphocytes and macrophages and dendritic cells and the identification of Mycobacterium tuberculosis to trigger natural immune response, and then activate the antigen presentation and disease. The cascade of signaling pathways related to the downstream process and the cascade of molecules that regulate genes, such as cytokines and chemokines, to clear or control the infection of pathogens. Genetic variation in genes involved in the immune response to tuberculosis may affect the individual's immune state or ability, and the immune state or ability of individuals. Differences may also increase the risk of individual tuberculosis, thereby affecting susceptibility to tuberculosis and the occurrence and development of the disease.
Objective: To explore the relationship between genetic polymorphisms and susceptibility to tuberculosis, we hypothesized that the single nucleotide polymorphisms (Single nucleotide polymorphism, SNP), which are important functional genes such as chemokines and pattern recognition receptors (SNP), are involved in the susceptibility to tuberculosis in the immune response of tuberculosis. And there may be gene gene interaction; the phenotype of the severity of tuberculosis is determined by the genetic variation of its important genes, and the difference in the severity of the disease among individuals may be closely related to the SNPs of the functional genes.
Methods: to verify the hypothesis, a case control study was used in this study. The SNPs selection strategy based on "sequence based" and "Atlas Based" was used in this study. The polymerase chain reaction restriction fragment length polymorphism (Polymerase chain reaction-restriction fragment lengthpolymorphism, PCR-RFLP) was used to amplify the resistance. The Amplification refractory mutationsystem (ARMS) PCR, MassARRAY, and SNPstream techniques include 20 representative genes, including cytokine and its receptors, chemokines, and pattern recognition receptors (Pattern recognitionreceptors, PRRs) involved in the immune response related genes of tuberculosis, including tumor damage. Death factor alpha (Tumor necrosis factor alpha, TNF- alpha), interferon gamma (Interferon gamma, IFN- gamma), interleukin 10 (Interleukin10, IL-10), IL-1 beta, IL-12 beta, IL-12 beta 1, dendritic cell specific intercellular adhesion -3- combined with non integrin (Dendritic cell-specific ICAM-3grabbing nonintergrin, DC-SIGN), mononuclear cell adsorption protein 1 (Monocyte chemotactic protein-1, MCP-1), regulating normal T cell expression and secretory factor. Ptor, VDR), the Toll like receptor (Toll like receptor, TLR) 2, TLR4, the liver X receptor (Liver X receptors), the macrophage receptor with the collagen structure, and the 115 locus of the interferon regulatory factor 5 gene. In this study, 923 cases of new pulmonary tuberculosis were confirmed by clinical or laboratory diagnosis in grade 3 first class hospitals. The normal population was from 1033 healthy people in the corresponding hospital at the same time. The control population was matched by the region (Town township) and the national and case. A variety of methods, such as internal control and blind retesting, were used for quality control. All experimental data and coded questionnaire data were checked repeatedly, checked with Microsoft excel and used SPSS17.0, SNPstats, Haploview and MDR soft. The data is arranged and analyzed.
Results: (1) association analysis of the polymorphism of cytokine and its receptor gene: the -857CT and -863AC loci located in the promoter region of the TNF- alpha gene were significantly related to the occurrence of tuberculosis. Compared with those with the CC genotype at the -857CT locus, the risk of pulmonary tuberculosis carrying TT genotypes decreased by 32% (OR=0.68,95%CI:0.53-0.86); and with -863A/C position. Compared with those with CC genotype, the risk of pulmonary tuberculosis with AA genotype increased by 142% (OR=2.42,95%CI:1.28-4.59), and the genotype was also associated with severe pulmonary tuberculosis (OR=3.59,95%CI:1.41-9.11). In addition, the serum TNF- alpha content in the serum carrying -863A/C loci A alleles was significantly lower than that of C alleles. Therefore, I have found that the level of TNF- alpha in serum with -863A/C locus A allele is significantly lower than that of the C allele. We believe that the polymorphism of -857CT and -863AC loci in the promoter region of TNF- alpha gene may be related to the genetic susceptibility to tuberculosis in Chinese Han population. (2) the association analysis of the chemokine gene polymorphism: the three SNP loci of the CCL1 gene and the rs2107538 loci of the RANTES gene are significantly related to the pulmonary tuberculosis, including R. Compared with those with the AA genotype at the s159291 locus, the risk of tuberculosis in GG genotype carriers decreased by 71% (OR=0.71,95%CI:0.56-0.92); compared with those with rs159294 and rs210837 loci with TT or GG genotypes, the risk of tuberculosis with AA genotype increased by 17% and 59% respectively (OR=1.17,95%CI:1.01-1.35; OR=1.59,95%CI:1.07-). 2.36). The rs2107538 locus of the RANTES gene was negatively correlated with the susceptibility to tuberculosis (OR=0.79,95%CI:0.66-0.94). The haplotype of the CCL1 gene was further constructed. The results showed that the AT haplotype carriers composed of rs159291 and rs159294 loci were significantly related to the susceptibility of the GT haplotype carriers (OR=1.16,95%CI:1.00-1.35). 3) association analysis of the receptor gene polymorphism: in the 53 SNPs loci, the rs729302 of the IRF5 gene, the rs17009726 of the MARCO gene, the rs7975232 loci of the rs6761637 and VDR genes are significantly related to the susceptibility to tuberculosis. The results of the dominant model study show that the rs729302 loci of the IRF5 gene are compared with the AA and genotype of the A allele, The CC genotype could reduce the population susceptibility to tuberculosis (OR=0.71,95%CI:0.54-0.93), and by further linkage disequilibrium (Linkage disequilibrium, LD) and haplotype analysis, the results showed that the CG haplotype (rs729302 and rs4728142) was significantly negatively correlated with the susceptibility to tuberculosis (OR=0.83,95%CI:0.72-0.96), while MARCO gene rs170. 09726 and rs6761637 loci carrying "G" or "C" allele carriers were positively correlated with the susceptibility to tuberculosis (OR=1.24,95%CI:1.02-1.52; OR=1.65,95%CI:1.32-2.05). Haplotype analysis found GC haplotypes containing the rs17009726 locus "G" alleles and TGCC haplotypes containing the rs6761637 point "C" allele (OR=1.62). 95%CI:1.31-2.00; OR=1.31,95%CI:1.06-1.60) was also positively correlated with the susceptibility to tuberculosis. At the same time, the rs797523 (Apa) locus of the VDR gene was associated with the pulmonary tuberculosis (OR=0.82,95%CI:0.69-0.98), and the A allele was associated with the high concentration of 25 hydroxyvitamin D (25-hydroxyvitamin D, 25-OHD) in the serum. The protective effect of loci on tuberculosis may be mainly through the positive regulation of vitamin D. (4) gene gene interaction analysis: through gene gene interaction analysis, it is found that the rs3091324 loci of rs2107538 and CCL1 of chemokine gene RANTES are interacted, and the two variables of the best model are based on MDR software. The risk of pulmonary tuberculosis in the relative risk layer was significantly increased by 0.4 times (OR=1.40,95%CI:1.17-1.67). At the same time, the rs7975232 of the VDR gene, the rs2077344 of the MARCO gene, the rs7656411 of the TLR2 gene, and the rs729302 loci of the IRF5 base were interacted upon, and then were divided into two categories. The risk of TB in the relative risk layer increased significantly by 1.36 times (OR=2.36,95%CI:1.95-2.84).
Conclusion: in this study, a large sample case control study was used to study the relationship between the polymorphism of the immune response gene and the susceptibility to tuberculosis in the Chinese population. The interaction of TNF- alpha, CCL1, RANTES, IRF5, MARCO and VDR gene polymorphisms or combined with other gene loci was found to be susceptible to the susceptibility to tuberculosis. The TNF- alpha and VDR polymorphic loci are closely related to the level of expression in the serum. The results of this study have important theories and realities to further evaluate and identify the risk of genetic factors for the development of tuberculosis, to elucidate the pathogenesis of tuberculosis, the molecular genetic mechanism of development and the gene gene gene that may exist. The methodological part will be of reference to the molecular epidemiology of other diseases. Through this study, the risk genotypes associated with susceptibility to tuberculosis in our population, haplotype, are expected to be used to screen high risk groups for the molecular markers, and to carry out effective and targeted individual prevention of tuberculosis. Early diagnosis and prognosis are of great significance.
【学位授予单位】：中国人民解放军军事医学科学院
【学位级别】：博士
【学位授予年份】：2012
【分类号】：R521
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