【摘要】：背景：結(jié)核�。═uberculosis，TB）是由結(jié)核分支桿菌（Mycobacteriumtuberculosis，M.TB）感染引起的人類較早和最具影響力的傳染病疾病之一。到目前為止，結(jié)核病仍然是由單一病原菌導(dǎo)致死亡人數(shù)最多的疾病，并且近年來呈現(xiàn)死灰復(fù)燃之勢。目前，全國結(jié)核菌感染人數(shù)超過5億，結(jié)核病患者達(dá)500萬之多，年發(fā)病人數(shù)約為130萬。根據(jù)2010年世界衛(wèi)生組織（World Health Organization，WHO）的統(tǒng)計(jì)，我國結(jié)核病病人總數(shù)居全球第二位，是全球22個結(jié)核病高負(fù)擔(dān)國家之一。研究表明，暴露于結(jié)核桿菌，三分之一的人群會被感染，在感染人群中，不到10%的感染者發(fā)展為結(jié)核病。提示個體對于結(jié)核病具有遺傳易感性。 結(jié)核病是慢性細(xì)胞內(nèi)感染的典型病癥，機(jī)體抵抗結(jié)核桿菌的感染的天然和適應(yīng)性免疫應(yīng)答主要是通過表達(dá)于T淋巴細(xì)胞和巨噬細(xì)胞以及樹突細(xì)胞表面的模式識別受體與結(jié)核桿菌的識別觸發(fā)天然免疫應(yīng)答，進(jìn)而激活參與抗原提呈和疾病進(jìn)程相關(guān)的下游的信號通路及其調(diào)節(jié)基因的如細(xì)胞因子和趨化因子等分子的級聯(lián)反應(yīng)，清除或者控制病原體的感染。由于參與結(jié)核病免疫應(yīng)答的基因存在遺傳變異，可能會影響個體的免疫狀態(tài)或能力，而個體間的免疫狀態(tài)或能力的差異也就可能增加了個體肺結(jié)核的危險度，從而影響對結(jié)核病的易感性以及疾病的發(fā)生與發(fā)展。 目的：為了探討基因多態(tài)性與肺結(jié)核易感性的關(guān)系，我們假設(shè)參與結(jié)核病免疫應(yīng)答的細(xì)胞因子及其受體、趨化因子和模式識別受體類等重要功能基因的單核苷酸多態(tài)性位點(diǎn)（Single nucleotide polymorphism，SNP）單獨(dú)或聯(lián)合與肺結(jié)核易感性有關(guān)，且可能存在基因-基因交互作用；肺結(jié)核嚴(yán)重程度的表型是由其重要基因的遺傳變異決定的，個體之間疾病嚴(yán)重程度的差異可能與其功能基因的SNPs息息相關(guān)。 方法：為驗(yàn)證上述假設(shè)，本研究采用病例-對照研究方法，綜合運(yùn)用“以序列為基礎(chǔ)”和“以圖譜為基礎(chǔ)”的SNPs選點(diǎn)策略，采用聚合酶鏈?zhǔn)椒磻?yīng)-限制性片段長度多態(tài)性（Polymerase chain reaction-restriction fragment lengthpolymorphism，PCR-RFLP）、擴(kuò)增阻滯突變系統(tǒng)（Amplification refractory mutationsystem，ARMS）PCR、MassARRAY和SNPstream技術(shù)對參與結(jié)核免疫應(yīng)答相關(guān)基因的包括細(xì)胞因子及其受體、趨化因子和模式識別受體（Pattern recognitionreceptors，PRRs）在內(nèi)的20個具有明確功能的代表性基因，包括腫瘤壞死因子α（Tumor necrosis factor α，TNF-α），干擾素γ（Interferon gamma，IFN-γ）、白介素10（Interleukin10，IL-10）、IL-1β、IL-12β、IL-12β1、IL-17、IL-23受體（Interleukin-23receptor，IL-23R）、IL-6R、IL-6、C-C趨化因子配體1（ChemokineC-C motif ligand1，CCL1）、樹突狀細(xì)胞特異性細(xì)胞間粘附分子-3-結(jié)合非整合素(Dendritic cell-specific ICAM-3grabbing nonintergrin，DC-SIGN)、單核細(xì)胞吸附蛋白1（Monocyte chemotactic protein-1，MCP-1）、調(diào)節(jié)正常T細(xì)胞表達(dá)和分泌因子（Regulated upon activation normal T cell expressed and secreted，RANTES）、SP110、維生素D受體（Vitamin D receptor，VDR）、Toll樣受體（Toll like receptor，TLR）2、TLR4、肝X受體（Liver X receptors，LXRs）、帶有膠原結(jié)構(gòu)的巨噬細(xì)胞受體（Macrophage receptor with a collagenous structure，MARCO）和干擾素調(diào)節(jié)因子5（Interferon regulatory factor5，IRF5）基因的115個SNPs位點(diǎn)進(jìn)行分型，研究基因多態(tài)性單獨(dú)或聯(lián)合與肺結(jié)核易感性的關(guān)系。本研究病例來源于3級甲等醫(yī)院均經(jīng)臨床或?qū)嶒?yàn)室確診新發(fā)肺結(jié)核病人923例。正常人群來自于相應(yīng)醫(yī)院同時期體檢的健康正常人群1033例。對照人群按地區(qū)（城鄉(xiāng)）和民族與病例匹配。使用統(tǒng)一設(shè)計(jì)的健康狀況調(diào)查表進(jìn)行流行病學(xué)調(diào)查獲取相關(guān)信息。實(shí)驗(yàn)過程中采用設(shè)立內(nèi)對照和盲法復(fù)測等多種方法進(jìn)行質(zhì)量控制。所有實(shí)驗(yàn)數(shù)據(jù)和編碼的調(diào)查表資料經(jīng)過反復(fù)檢查、核對，用Microsoft excel建立數(shù)據(jù)庫。運(yùn)用SPSS17.0、SNPstats、Haploview和MDR軟件進(jìn)行數(shù)據(jù)整理與分析。 結(jié)果：（1）細(xì)胞因子及其受體基因多態(tài)性的關(guān)聯(lián)分析：位于TNF-α基因啟動子區(qū)域的-857CT和-863AC位點(diǎn)與肺結(jié)核的發(fā)生顯著相關(guān)，與-857CT位點(diǎn)攜帶CC基因型者相比較，攜帶TT基因型者肺結(jié)核的風(fēng)險降低了32%（OR=0.68，95%CI：0.53-0.86）；與-863A/C位點(diǎn)攜帶CC基因型者比較，攜帶AA基因型者肺結(jié)核的風(fēng)險度會增加了142%（OR=2.42，95%CI：1.28-4.59），并且基因型也與病情嚴(yán)重的肺結(jié)核相關(guān)（OR=3.59，95%CI：1.41-9.11）。此外，攜帶有-863A/C位點(diǎn)A等位基因者血清中TNF-α含量顯著低于C等位基因者。因此，我們認(rèn)為TNF-α基因啟動子區(qū)域-857CT和-863AC位點(diǎn)多態(tài)性可能與中國漢族人群肺結(jié)核遺傳易感性有關(guān)。（2）趨化因子基因多態(tài)性的關(guān)聯(lián)分析：CCL1基因的rs159291、rs159294和rs210837三個SNP位點(diǎn)以及RANTES基因的rs2107538位點(diǎn)與肺結(jié)核顯著相關(guān)，其中與rs159291位點(diǎn)攜帶AA基因型者比較，GG基因型攜帶者肺結(jié)核的風(fēng)險會降低71%（OR=0.71，95%CI：0.56-0.92）；而與rs159294、rs210837位點(diǎn)攜帶TT或GG基因型者相比較，攜帶AA基因型者肺結(jié)核的風(fēng)險度分別增加了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位點(diǎn)與肺結(jié)核的易感性負(fù)相關(guān)（OR=0.79，95%CI：0.66-0.94）。進(jìn)一步對CCL1基因構(gòu)建了單倍型，結(jié)果表明由rs159291和rs159294位點(diǎn)構(gòu)成的AT單倍型攜帶者與GT單倍型攜帶者相比，與肺結(jié)核易感性顯著相關(guān)（OR=1.16，95%CI：1.00-1.35）。（3）受體類基因多態(tài)性的關(guān)聯(lián)分析：在53個SNPs位點(diǎn)中，IRF5基因的rs729302、MARCO基因的rs17009726、rs6761637和VDR基因的rs7975232位點(diǎn)與肺結(jié)核易感性顯著相關(guān)。顯性模型研究結(jié)果顯示，對于IRF5基因的rs729302位點(diǎn)，與攜帶A等位基因的AA和CA基因型相比，CC基因型能夠降低人群對結(jié)核桿菌的易感性（OR=0.71，95%CI：0.54-0.93），通過進(jìn)一步連鎖不平衡（Linkage disequilibrium，LD）和單倍型作圖分析，結(jié)果顯示CG單倍型（rs729302和rs4728142）明顯與肺結(jié)核易感性呈負(fù)相關(guān)（OR=0.83，95%CI：0.72-0.96）；而MARCO基因rs17009726和rs6761637位點(diǎn)攜帶“G”或“C”等位基因攜帶者與肺結(jié)核易感性呈正相關(guān)（OR=1.24，95%CI：1.02-1.52；OR=1.65，95%CI：1.32-2.05）。單倍型分析發(fā)現(xiàn)包含rs17009726位點(diǎn)“G”等位基因的GC單倍型和包含rs6761637位點(diǎn)“C”等位基因的TGCC單倍型（OR=1.62，95%CI：1.31-2.00；OR=1.31，95%CI：1.06-1.60）也與肺結(jié)核的易感性呈正相關(guān)。同時，VDR基因的rs797523（ApaΙ）位點(diǎn)攜帶A等位基因者與肺結(jié)核顯著關(guān)聯(lián)（OR=0.82，95%CI：0.69-0.98），且A等位基因與血清中高濃度25羥維生素D（25-hydroxyvitamin D，25-OHD）相關(guān)，證明該位點(diǎn)對肺結(jié)核的保護(hù)作用主要可能是通過對維生素D的正調(diào)控發(fā)揮作用。（4）基因-基因交互作用分析：通過基因-基因交互作用分析，發(fā)現(xiàn)趨化因子基因RANTES的rs2107538和CCL1的rs3091324位點(diǎn)存在交互作用，對最佳模型的兩個變量根據(jù)MDR軟件進(jìn)行兩分類化（即分為危險層和非危險層），處在相對危險層的個體患肺結(jié)核的風(fēng)險顯著增加了0.4倍（OR=1.40，95%CI：1.17-1.67）。同時，VDR基因的rs7975232、MARCO基因的rs2077344、TLR2基因的rs7656411和IRF5基因的rs729302位點(diǎn)存在交互作用，，兩分類化后處在相對危險層的個體患肺結(jié)核的風(fēng)險顯著增加了1.36倍（OR=2.36，95%CI：1.95-2.84）。 結(jié)論：本研究通過采用大樣本量的病例-對照研究，在中國人群中開展了參與結(jié)核病免疫應(yīng)答基因多態(tài)性與肺結(jié)核易感性關(guān)系的研究，發(fā)現(xiàn)了TNF-α、CCL1、RANTES、IRF5、MARCO和VDR基因多態(tài)性單位點(diǎn)或聯(lián)合其他基因位點(diǎn)的交互作用與肺結(jié)核易感性顯著相關(guān)，且TNF-α和VDR多態(tài)性位點(diǎn)與其血清中的表達(dá)水平密切相關(guān)。本研究結(jié)果對于進(jìn)一步評價和識別遺傳因素對肺結(jié)核發(fā)生發(fā)展的危險性，闡明肺結(jié)核發(fā)生、發(fā)展的分子遺傳學(xué)機(jī)制及可能存在的基因-基因等具有重要的理論和現(xiàn)實(shí)意義。方法學(xué)部分將對其他疾病的分子流行病學(xué)研究具有一定的借鑒價值。通過本研究發(fā)現(xiàn)的與我國人群肺結(jié)核易感性相關(guān)的危險基因型、單倍型，驗(yàn)證后有望為分子標(biāo)志物用于篩選高危人群，對肺結(jié)核實(shí)施有效和目標(biāo)明確的個體預(yù)防、早期診斷和預(yù)后判斷等均具有重要的意義。
[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.
【學(xué)位授予單位】：中國人民解放軍軍事醫(yī)學(xué)科學(xué)院
【學(xué)位級別】：博士
【學(xué)位授予年份】：2012
【分類號】：R521

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7 李s

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