2010-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/645528摘要：近年來有關結核病之易感性(susceptibility)基因之研究愈來愈受重視。在小鼠實驗模式，已發現sst1 基因座 (locus)與對結核菌的易感性有關，且已發現sst1susceptible 小鼠在感染結核菌之後，肺部會出現壞死性病灶，與人類結核病患者肺部之空洞性病灶相似。現在已知在sst1 基因座內，與結核病之易感性有關之基因是Ipr1 基因。而在人類，與Ipr1 基因同質性最高者為SP110 基因。SP110基因有單核苷酸多型性(single nucleotide polymorphism)，其中有些單核苷酸多型性最近被發現與結核病之易感性有關。除了SP110 基因之外，與結核病之易感性有關之基因還包括: 1)丙種干擾素(interferon-gamma, IFN-γ)，丙種干擾素可說是宿主對抗結核病最重要的細胞素(cytokine)。2) 腫瘤壞死因子(tumor necrosis factor-alpha, TNF-α)，此為與肉芽腫之形成有關的細胞素，也是宿主對抗結核病很重要的細胞素。3) 介白質-10(interleukin-10, IL-10)，它的作用與上述兩種細胞素相反，介白質-10 的量增加時會促進結核病之再活化(reactivation)。上述三種與細胞素有關之基因都有單核苷酸多型性，且其中有些單核苷酸多型性曾被發現與結核病之易感性有關。我們提出的計畫，是以三年的時間，作上述四種基因(SP110, IFN-γ, TNF-α及 IL-10)之單核苷酸多型性研究，對象是肺結核、肺外結核病人、病人的接觸者及健康且無結核病接觸史之成年人，探討是否有某些單核苷酸多型性:1. 在結核病病人出現之百分比高於接觸者或高於健康對照組，或2. 在肺結核與肺外結核病人出現之百分比不同，或3. 在有空洞之肺結核病人出現之百分比高於無空洞之肺結核病人，或4. 與結核病之嚴重性或預後有關我們將使用PCR 及DNA 定序法分析，預定研究之單核苷酸多型性位置為:1. SP110 基因: 共研究20 個單核苷酸多型性位置2. IFN-γ 基因: +874T/A3. IL-10 基因: -1082G/A， -819C/T，-592A/C4. TNF-α 基因: -1030T/C， -862C/A， -856C/T， -308G/A， -238G/A在第一年，我們將分析SP110 基因之20 個單核苷酸多型性，在第二年，將分析IFN-γ 基因之1 個及IL-10 基因之3 個單核苷酸多型性，在第三年，將分析TNF-α 基因之5 個單核苷酸多型性。我們希望藉著這些研究，能發現與結核病之易感性有關之單核苷酸多型性，能分辨出哪些接觸者將來較可能發生結核病，哪些接觸者較需要預防性給藥，為何有些肺結核病人肺部容易產生空洞? 為何有些病人容易發生肺外或散播性結核? 哪些結核病病人可能病情會較嚴重、需要較長時間之intensive phasetreatment? 也希望因而對結核病之免疫機轉有較多瞭解。<br> Abstract: Several susceptibility-associated genetic polymorphisms have beenproposed to explain different susceptibility to tuberculosis (TB) among infectedindividuals. The sst1 locus has been identified in a mouse model to controlsusceptibility to M. tuberculosis infection. sst1 susceptible mice developednecrotic pulmonary lesions resembling cavities in human TB patients.Subsequent studies have identified Ipr1 (intracellular pathogen resistance 1) tobe the gene in sst1 locus which is responsible for the susceptibility. The closesthuman homologue of Ipr1 gene, the SP110 gene, has been found to havesingle nucleotide polymorphism (SNP) which was associated withsusceptibility to TB.Susceptibility to TB is also related to efficient activation of cellular immuneresponse that interferon-gamma (IFN-γ) plays a key role. Anotherimmunological gene, tumor necrosis factor- alpha (TNF-α), which is a centralmediator of granuloma formation, also controls the spread of M. tuberculosisbacilli. On the contrary, interleukin-10 (IL-10) gene has an antagonistic role,with increased production of IL-10 promoting reactivation of pulmonary TB.SNPs of these three cytokine genes have been found to be associated withsusceptibility or resistance to TB, although the results were inconsistent.We plan to conduct a 3 year study, in which we’ll investigate the SNPs ofSP110, IFN-γ, TNF-α and IL-10 gene, in patients with pulmonary andextrapulmonary TB, their household contacts, and healthy control subjects.We’ll perform PCR and sequencing to analyze these SNPs:1. SP110 gene: We’ll study 20 SNP sites (the first year)2. IFN-γ gene: +874T/A (the second year)3. IL-10 gene: -1082G/A, -819C/T, -592A/C (the second year)4. TNF-α gene: -1030T/C, -862C/A, -856C/T, -308G/A, -238G/A (the 3rd y)We want to observe if any SNP(s):1. is more common in TB patients than in contacts or controls, or2. is more common in pulm TB than in extrapulmonary TB patients, or3. is more common in patients with cavitary disease, or4. is associated with the severity or poorer outcome of tuberculosisWe hope we may identify genes that are associated with susceptibility to TB,identify contacts of TB patients who have high risk of developing TB and mayneed chemoprevention, identify TB patients who may need longer anti-TBtherapy, and understand the protective mechanisms against TB.