慢性阻塞性肺疾病患者调节性T细胞核转录因子Foxp3的表达及单核苷酸多态性的研究
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摘要
第一章Foxp3+调节性T细胞在肺功能正常吸烟者及慢性阻塞性肺疾病患者肺部组织中的表达及意义
目的：本研究旨在观察Foxp3+调节性T细胞(regulatory T cell, Treg细胞)在肺功能正常的吸烟者和吸烟的稳定期慢性阻塞性肺疾病(chronic obstructive pulmonary disease, COPD)患者肺组织中的表达,并探讨Foxp3+调节性T细胞在COPD肺部炎症反应及获得性免疫反应发生机制中的作用。
方法：将需手术治疗的周围型肺癌患者分为肺功能正常非吸烟组(N组,10例)、肺功能正常吸烟组(S组,10例)、吸烟稳定期COPD组(COPD组,10例)。于手术切除标本中选取距肺癌病灶5cm以上的新鲜正常肺组织,苏木精-伊红(hematoxylin and eosin, HE)染色观察各组平均肺泡面积,免疫组化法检测CD4+T细胞、Foxp3+T细胞在肺泡壁的表达,荧光定量PCR法和Western blot法检测肺组织匀浆中Foxp3mRNA和蛋白表达水平,分析Foxp3+T细胞与肺泡肺气肿破坏和肺功能降低的相关关系。
结果：COPD组平均肺泡面积(152345±24497μ m2)明显大于S组(106551±15815μ m2)和N组(50708±14125μ m2),S组与N组对比也有明显差异(P值均<0.05)。肺泡壁CD4+T细胞数在COPD组(22±8个/m)明显高于S组(16±6个/mm)和N组(6±2个/mm)；Foxp3+T细胞在COPD组(3±1个/mm)明显低于S组(4±1个/mm)和N组(5±1个/mm),并且S组明显低于N组(P值均<0.05)。肺组织匀浆中Foxp3的mRNA表达水平在COPD组(0.431±0.109)明显降低,其次是S组(0.930±0.413),在N组为1.391±0.312(P值均<0.05)。肺组织匀浆Foxp3蛋白表达水平与mRNA表达结果一致,在N组为0.824±0.180,S组0.504±0.218,COPD组0.307±0.051(P值均<0.05)。肺泡壁上表达的Foxp3+细胞与CD4+细胞表达呈负相关(R=-0.681,P<0.001),与平均肺泡面积呈负相关(R=-0.797,P<0.001)。肺组织匀浆中Foxp3mRNA和蛋白含量分别与FEV1%pred呈正相关(R=0.601,P<0.001；R=0.573,P=0.001)。
结论：Foxp3+T细胞在肺功能正常吸烟者和稳定期COPD患者肺部表达明显减少,与肺泡壁肺气肿破坏程度和肺功能降低密切相关,提示Foxp3+T细胞减少参与了COPD肺部炎症和获得性免疫失调。
第二章调节性T细胞核转录因子Foxp3在肺功能正常吸烟者和
不同分级慢性阻塞性肺疾病患者外周血的表达及意义
目的：本研究旨在观察调节性T细胞(regulatory T cell,Treg细胞)核转录因子Foxp3在肺功能正常吸烟者和不同分级慢性阻塞性肺疾病(chronic obstructive pulmonary disease, COPD)患者外周血中的表达,并探讨其意义。
方法：以病人外周血为研究对象,分为4组即肺功能正常非吸烟组(N组,20例)、肺功能正常吸烟组(S组,20例)、吸烟稳定期COPD1-2级组(COPD1-2级组,20例),吸烟稳定期COPD3-4级组(COPD3-4级组,20例)。收集病人外周血做荧光定量PCR,检测Foxp3mRNA表达水平,分析其与COPD分级、肺功能降低的关系。
结果：外周血Foxp3的mRNA表达水平在COPD3-4组(0.498±0.235)和COPD1-2组0.931±0.237)明显降低,其次是S组(1.215±0.258),在N组表达最高(1.452±0.254),四组间两两比较均有差别(P值均<0.05),并且Foxp3mRNA表达水平与FEV1%pred呈正相关关系(R=0.758,P<0.001)。
结论：Foxp3mRNA表达水平在吸烟肺功能正常者和COPD病人体内表达明显降低,并且随着COPD病情分级加重而降低更明显,提示Foxp3+Treg细胞减少很可能与COPD病情严重程度密切相关。
第三章调节性T细胞核转录因子Foxp3单核苷酸多态性与慢性阻塞性肺疾病关联的研究
目的：探讨调节性T细胞(regulatory T cell,Treg细胞)核转录因子Foxp3单核苷酸多态性(single nucleotide polymorphism, SNP)与慢性阻塞性肺疾病(chronic obstructive pulmonary disease, COPD)的关系,以及SNP出现的相关危险因素。
方法：以病人外周血为研究对象,分为4组即肺功能正常非吸烟组(N组,61例)、肺功能正常吸烟组(S组,81例)、吸烟稳定期COPD1-2级组(COPD1-2级组,65例),吸烟稳定期COPD3-4级组(COPD3-4级组,117例),采用Taqman探针法荧光定量PCR对Foxp3基因四个位点rs2280883. rs3761548、rs3761549、rs5902434进行基因分型。
结果：FOXP3基因四个SNP位点均符合哈迪-温伯格(Hardy-Weinberg)遗传平衡定律。SNP位点rs5902434在COPD3-4级组,COPD1-2级组,S组,N组中分布有差异(P<0.05)。logistic多因素回归分析发现携带-/-基因型个体罹患COPD1-2级和3-4级风险均降低(COPD1-2级：OR=0.278,95%CI=0.079-0.974;COPD3-4级：OR=0.235,95%CI=0.074-0.747)。-／-基因型对FEVl%pred=30-50的病人有保护作用(OR=0.222,95%CI=0.094-0.525);对FEV1/FVC<50和FEV1/FVC=50-70的病人均有保护作用(FEV1/FVC<50:OR=0.295,95%CI=0.130-0.666; FEV1/FVC=50-70:OR=0.337,95%CI=0.131-0.866).-/ATT基因型对FEV1%pred=30-50的病人有保护作用(OR=0.359,95%CI=0.150-0.863)。单倍体分析发现-单倍体对吸烟的非COPD者易感(OR=1.746,95%CI=1.048-2.914);-单倍体对FEV1%pred=30-50和FEV1/FVC<50的病人均有保护作用(FEV1%pred=30-50:OR=0.582,95%CI=0.358-0.946; FEV1/FVC<50:OR=0.622,95%CI=0.403-0.961).对吸烟史、年龄、BMI、民族因素综合分析发现,非汉族人群较汉族人群更容易出现-/ATT基因型(OR=2.277,95%CI=1.022-5.072)。
结论：FOXP3基因位点rs5902434与男性罹患COPD有关,并且-/-基因型和-单倍体型对COPD病人及肺功能降低有保护作用；但吸烟和年龄因素并非该位点突变的影响因素。该结果提示Foxp3+Treg细胞单核苷酸多态性可能是COPD发病的上游危险因素,其多态性不受吸烟和年龄等COPD危险因素的影响。
CHAPTER I
Foxp3+regulatory T cell in lung tissues of smokers with normal lung function and patients with chronic obstructive pulmonary disease
Objective:This study aimed to observe the expression of Foxp3+regulatory T cell (Treg cell) in the lung tissues of smokers with normal lung function and patients with COPD, and dicusse the role of Foxp3+Treg cell in the lung inflammation and acquired immune response.
Methods:The patients with peripheral lung cancer who performed surgery were divided into non-somking group with normal lung function (N group,10cases), smoking group with normal lung function (S group,10cases) and smoking with stable COPD group (COPD group,10cases). The fresh normal lung tissues from the surgical specimens were selected, which is over5cm from the lung cancer resection. The average alveolar area was detected by HE, Foxp3+cells in alveolar walls were analysed by immunohistochemistry. The level of Foxp3mRNA in lung tissues was analyzed by quantitative real-time polymerase chain reaction (PCR). The levels of Foxp3protein in lung tissues was analyzed by Western blot.
Results:The average alveolar area in COPD group(152345±24497μm2) was significantly larger than that in the S group (106551±15815μm2) and in N group (50708±14125μm2)(P<0.05). The CD4+T cells in alveolar wall in the COPD group (22±8/mm) were more than that in S group (16±6/mm) and in N group (6±2/mm). Foxp3+Treg cells in the COPD group (3±1/mm) were less than that in S group (4±1/mm) and N group (5±1/mm), and that in S group was less than in N group. The Foxp3mRNA expression in lung tissues was decreased in the COPD group (0.431±0.109) followed by that in S group (0.930±0.413), compared with that in N group (1.391±0.312)(P values were all<0.05). The Foxp3protein expression in lung tusses was decreased in COPD group (0.307±0.051) followed by that in S group (0.504±0.218), compared with that in N group (0.824±0.180)(P values<0.05). There was a negative correlation between the numbers of Foxp3+cells and CD4+cells (R=-0.681, P<0.001). And the Foxp3+cell number was negatively correlated with mean alveolar area (R=-0.797, P<0.001). The levels of Foxp3mRNA and protein in lung tissues were both positively correlated with FEV1%pred (R=0.601, P <0.001; R=0.573, P=0.001).
Conclusions:The expression of Foxp3+T cell was decreased in the lung tissues of smokers with normal lung function and COPD patients, which was correlated with alveolar mean area and reduced lung function, suggesting decreased Foxp3+T cell may participate lung inflammation and acquired immune response in COPD patients.
CHAPTER II
Transcription factor Foxp3of regulatory T cell in the peripheral blood of chronic obstructive pulmonary disease patients at different stages
Objective:This study aim to observe the expression of transcription factor Foxp3of regulatory T cell (Treg cell) in the peripheral blood of somkers with normal lung function and patients with chronic obstructive pulmonary disease (COPD) at differernt stages.
Methods:Subjects received treatment or physical examination in our hospital were selected and devided into non-somking group with normal lung function (N group,20cases), smoking group with normal lung function (S group,20cases), smoking with COPD in the Global initiative for Chronic Obstructive Lung Disease (GOLD)1and2(COPD1-2group,20cases) and smoking with COPD in GOLD3and4(COPD3-4group,20cases). The Foxp3mRNA expression in peripheral blood was analysed by quantitative real-time polymerase chain reaction (PCR).
Results:The Foxp3mRNA levels in peripheral blood were decreased in COPD3-4group (0.498±0.235)and COPD1-2group (0.931±0.237) followed by that in S group (1.215±0.258), compared with that in N group (1.452±0.254)(P values were all<0.05). The expression of Foxp3mRNA was positively correlated with FEV1%pred (R=0.758, P<0.001).
Conclusion:The expressions of Foxp3mRNA in smokers with normal lung function and COPD patients were decreased, especially in COPD patients at3-4stages, suggesting the decrease of Foxp3+Treg cell is invovled in the severity of COPD and the activation of acquired immune response in COPD patients.
CHAPTER III
Single nucleotide polymorphisms of Transcription Factor Foxp3in regulatory T cell and chronic obstructive pulmonatory disease
Obsjective:To investigate the single nucleotide polymorphisms (SNPs) of transcription factor Foxp3of regulatory T cell (Treg cell) in patients with chronic obstructive pulmonatory disease (COPD) at different stages, and discusse the risk factors of the SNPs.
Methods:Subjects received treatment or physical examination in our hospital were selected and devided into non-somking group with normal lung function (N group,61cases), smoking group with normal lung function (S group,81cases), smoking with COPD in the Global initiative for chronic Obstructive Lung Disease (GOLD)1and2(COPD1-2group,65cases) and smoking with COPD in GOLD3and4(COPD3-4group,117cases). Samples of peripheral blood were collected. The Foxp3SNPs rs2280883, rs3761548, rs3761549and rs5902434were analyzed by Tanman quantitative real-time polymerase chain reaction (PCR). The susceptibility of COPD in people with differernt genotypes, and the risk factors for genetic mutations were both analyzed by logistic regression model.
Results:All four SNPs comply with Hardy-Weinberg genetic equilibrium. The genotypes and haplotypes of Foxp3SNP rs5902434were differently expressed in COPD3-4group, COPD1-2group, S group and N group (P<0.05). The-/-genotype was protective for COPD patients both at stage1-2and at stage3-4(COPD1-2group:OR=0.278,95%CI=0.079-0.974,; COPD3-4group:OR=0.235,95%CI=0.074-0.747). The genotype-/-of rs5902434was protective for patients with FEV1%pred=30-50(OR=0.222, 95%CI=0.094-0.525), as well as patients with FEV1/FVC<50and FEV1/FVC=50-70(FEV1/FVC<50:OR=0.295,95%CI=0.130-0.666; FEV1/FVC=50-70:OR=0.337,95%CI=0.131-0.866). The genotype-/ATT of rs5902434also could be protective for patients with FEV1%pred=30-50(OR=0.359,95%CI=0.150-0.863). The analysis of rs5902434haplotypes showed that-haplotype was susceptible to smokers with normal lung function (OR=1.746,95%CI=1.048-2.914). Furthermore,-haplotype was found to be protective for patients with FEV1%pred=30-50and FEV1/FVC<50, respectively (FEV1%pred=30-50:OR=0.582,95%CI=0.358-0.946; FEV1/FVC<50:OR=0.622,95%CI=0.403-0.961). The comprehensive analysis with smoking history, age, BMI and nation showed that non-Han people are more likely to have-/ATT genotype than Han people (OR=2.277,95%CI=1.022-5.072).
Conclusions:The Foxp3SNP rs5902434was risk for COPD in males, and-/-genotype was protective for COPD and the decline of lung function. But smoking history and age didn't influence this SNP. These foundings suggested that SNPs may be a up-stream factor of COPD. But risk factors of COPD including smoking and age maynot be associated with this SNP of Foxp3.
目的：本研究旨在观察Foxp3+调节性T细胞(regulatory T cell, Treg细胞)在肺功能正常的吸烟者和吸烟的稳定期慢性阻塞性肺疾病(chronic obstructive pulmonary disease, COPD)患者肺组织中的表达,并探讨Foxp3+调节性T细胞在COPD肺部炎症反应及获得性免疫反应发生机制中的作用。
方法：将需手术治疗的周围型肺癌患者分为肺功能正常非吸烟组(N组,10例)、肺功能正常吸烟组(S组,10例)、吸烟稳定期COPD组(COPD组,10例)。于手术切除标本中选取距肺癌病灶5cm以上的新鲜正常肺组织,苏木精-伊红(hematoxylin and eosin, HE)染色观察各组平均肺泡面积,免疫组化法检测CD4+T细胞、Foxp3+T细胞在肺泡壁的表达,荧光定量PCR法和Western blot法检测肺组织匀浆中Foxp3mRNA和蛋白表达水平,分析Foxp3+T细胞与肺泡肺气肿破坏和肺功能降低的相关关系。
结果：COPD组平均肺泡面积(152345±24497μ m2)明显大于S组(106551±15815μ m2)和N组(50708±14125μ m2),S组与N组对比也有明显差异(P值均<0.05)。肺泡壁CD4+T细胞数在COPD组(22±8个/m)明显高于S组(16±6个/mm)和N组(6±2个/mm)；Foxp3+T细胞在COPD组(3±1个/mm)明显低于S组(4±1个/mm)和N组(5±1个/mm),并且S组明显低于N组(P值均<0.05)。肺组织匀浆中Foxp3的mRNA表达水平在COPD组(0.431±0.109)明显降低,其次是S组(0.930±0.413),在N组为1.391±0.312(P值均<0.05)。肺组织匀浆Foxp3蛋白表达水平与mRNA表达结果一致,在N组为0.824±0.180,S组0.504±0.218,COPD组0.307±0.051(P值均<0.05)。肺泡壁上表达的Foxp3+细胞与CD4+细胞表达呈负相关(R=-0.681,P<0.001),与平均肺泡面积呈负相关(R=-0.797,P<0.001)。肺组织匀浆中Foxp3mRNA和蛋白含量分别与FEV1%pred呈正相关(R=0.601,P<0.001；R=0.573,P=0.001)。
结论：Foxp3+T细胞在肺功能正常吸烟者和稳定期COPD患者肺部表达明显减少,与肺泡壁肺气肿破坏程度和肺功能降低密切相关,提示Foxp3+T细胞减少参与了COPD肺部炎症和获得性免疫失调。
第二章调节性T细胞核转录因子Foxp3在肺功能正常吸烟者和
不同分级慢性阻塞性肺疾病患者外周血的表达及意义
目的：本研究旨在观察调节性T细胞(regulatory T cell,Treg细胞)核转录因子Foxp3在肺功能正常吸烟者和不同分级慢性阻塞性肺疾病(chronic obstructive pulmonary disease, COPD)患者外周血中的表达,并探讨其意义。
方法：以病人外周血为研究对象,分为4组即肺功能正常非吸烟组(N组,20例)、肺功能正常吸烟组(S组,20例)、吸烟稳定期COPD1-2级组(COPD1-2级组,20例),吸烟稳定期COPD3-4级组(COPD3-4级组,20例)。收集病人外周血做荧光定量PCR,检测Foxp3mRNA表达水平,分析其与COPD分级、肺功能降低的关系。
结果：外周血Foxp3的mRNA表达水平在COPD3-4组(0.498±0.235)和COPD1-2组0.931±0.237)明显降低,其次是S组(1.215±0.258),在N组表达最高(1.452±0.254),四组间两两比较均有差别(P值均<0.05),并且Foxp3mRNA表达水平与FEV1%pred呈正相关关系(R=0.758,P<0.001)。
结论：Foxp3mRNA表达水平在吸烟肺功能正常者和COPD病人体内表达明显降低,并且随着COPD病情分级加重而降低更明显,提示Foxp3+Treg细胞减少很可能与COPD病情严重程度密切相关。
第三章调节性T细胞核转录因子Foxp3单核苷酸多态性与慢性阻塞性肺疾病关联的研究
目的：探讨调节性T细胞(regulatory T cell,Treg细胞)核转录因子Foxp3单核苷酸多态性(single nucleotide polymorphism, SNP)与慢性阻塞性肺疾病(chronic obstructive pulmonary disease, COPD)的关系,以及SNP出现的相关危险因素。
方法：以病人外周血为研究对象,分为4组即肺功能正常非吸烟组(N组,61例)、肺功能正常吸烟组(S组,81例)、吸烟稳定期COPD1-2级组(COPD1-2级组,65例),吸烟稳定期COPD3-4级组(COPD3-4级组,117例),采用Taqman探针法荧光定量PCR对Foxp3基因四个位点rs2280883. rs3761548、rs3761549、rs5902434进行基因分型。
结果：FOXP3基因四个SNP位点均符合哈迪-温伯格(Hardy-Weinberg)遗传平衡定律。SNP位点rs5902434在COPD3-4级组,COPD1-2级组,S组,N组中分布有差异(P<0.05)。logistic多因素回归分析发现携带-/-基因型个体罹患COPD1-2级和3-4级风险均降低(COPD1-2级：OR=0.278,95%CI=0.079-0.974;COPD3-4级：OR=0.235,95%CI=0.074-0.747)。-／-基因型对FEVl%pred=30-50的病人有保护作用(OR=0.222,95%CI=0.094-0.525);对FEV1/FVC<50和FEV1/FVC=50-70的病人均有保护作用(FEV1/FVC<50:OR=0.295,95%CI=0.130-0.666; FEV1/FVC=50-70:OR=0.337,95%CI=0.131-0.866).-/ATT基因型对FEV1%pred=30-50的病人有保护作用(OR=0.359,95%CI=0.150-0.863)。单倍体分析发现-单倍体对吸烟的非COPD者易感(OR=1.746,95%CI=1.048-2.914);-单倍体对FEV1%pred=30-50和FEV1/FVC<50的病人均有保护作用(FEV1%pred=30-50:OR=0.582,95%CI=0.358-0.946; FEV1/FVC<50:OR=0.622,95%CI=0.403-0.961).对吸烟史、年龄、BMI、民族因素综合分析发现,非汉族人群较汉族人群更容易出现-/ATT基因型(OR=2.277,95%CI=1.022-5.072)。
结论：FOXP3基因位点rs5902434与男性罹患COPD有关,并且-/-基因型和-单倍体型对COPD病人及肺功能降低有保护作用；但吸烟和年龄因素并非该位点突变的影响因素。该结果提示Foxp3+Treg细胞单核苷酸多态性可能是COPD发病的上游危险因素,其多态性不受吸烟和年龄等COPD危险因素的影响。
CHAPTER I
Foxp3+regulatory T cell in lung tissues of smokers with normal lung function and patients with chronic obstructive pulmonary disease
Objective:This study aimed to observe the expression of Foxp3+regulatory T cell (Treg cell) in the lung tissues of smokers with normal lung function and patients with COPD, and dicusse the role of Foxp3+Treg cell in the lung inflammation and acquired immune response.
Methods:The patients with peripheral lung cancer who performed surgery were divided into non-somking group with normal lung function (N group,10cases), smoking group with normal lung function (S group,10cases) and smoking with stable COPD group (COPD group,10cases). The fresh normal lung tissues from the surgical specimens were selected, which is over5cm from the lung cancer resection. The average alveolar area was detected by HE, Foxp3+cells in alveolar walls were analysed by immunohistochemistry. The level of Foxp3mRNA in lung tissues was analyzed by quantitative real-time polymerase chain reaction (PCR). The levels of Foxp3protein in lung tissues was analyzed by Western blot.
Results:The average alveolar area in COPD group(152345±24497μm2) was significantly larger than that in the S group (106551±15815μm2) and in N group (50708±14125μm2)(P<0.05). The CD4+T cells in alveolar wall in the COPD group (22±8/mm) were more than that in S group (16±6/mm) and in N group (6±2/mm). Foxp3+Treg cells in the COPD group (3±1/mm) were less than that in S group (4±1/mm) and N group (5±1/mm), and that in S group was less than in N group. The Foxp3mRNA expression in lung tissues was decreased in the COPD group (0.431±0.109) followed by that in S group (0.930±0.413), compared with that in N group (1.391±0.312)(P values were all<0.05). The Foxp3protein expression in lung tusses was decreased in COPD group (0.307±0.051) followed by that in S group (0.504±0.218), compared with that in N group (0.824±0.180)(P values<0.05). There was a negative correlation between the numbers of Foxp3+cells and CD4+cells (R=-0.681, P<0.001). And the Foxp3+cell number was negatively correlated with mean alveolar area (R=-0.797, P<0.001). The levels of Foxp3mRNA and protein in lung tissues were both positively correlated with FEV1%pred (R=0.601, P <0.001; R=0.573, P=0.001).
Conclusions:The expression of Foxp3+T cell was decreased in the lung tissues of smokers with normal lung function and COPD patients, which was correlated with alveolar mean area and reduced lung function, suggesting decreased Foxp3+T cell may participate lung inflammation and acquired immune response in COPD patients.
CHAPTER II
Transcription factor Foxp3of regulatory T cell in the peripheral blood of chronic obstructive pulmonary disease patients at different stages
Objective:This study aim to observe the expression of transcription factor Foxp3of regulatory T cell (Treg cell) in the peripheral blood of somkers with normal lung function and patients with chronic obstructive pulmonary disease (COPD) at differernt stages.
Methods:Subjects received treatment or physical examination in our hospital were selected and devided into non-somking group with normal lung function (N group,20cases), smoking group with normal lung function (S group,20cases), smoking with COPD in the Global initiative for Chronic Obstructive Lung Disease (GOLD)1and2(COPD1-2group,20cases) and smoking with COPD in GOLD3and4(COPD3-4group,20cases). The Foxp3mRNA expression in peripheral blood was analysed by quantitative real-time polymerase chain reaction (PCR).
Results:The Foxp3mRNA levels in peripheral blood were decreased in COPD3-4group (0.498±0.235)and COPD1-2group (0.931±0.237) followed by that in S group (1.215±0.258), compared with that in N group (1.452±0.254)(P values were all<0.05). The expression of Foxp3mRNA was positively correlated with FEV1%pred (R=0.758, P<0.001).
Conclusion:The expressions of Foxp3mRNA in smokers with normal lung function and COPD patients were decreased, especially in COPD patients at3-4stages, suggesting the decrease of Foxp3+Treg cell is invovled in the severity of COPD and the activation of acquired immune response in COPD patients.
CHAPTER III
Single nucleotide polymorphisms of Transcription Factor Foxp3in regulatory T cell and chronic obstructive pulmonatory disease
Obsjective:To investigate the single nucleotide polymorphisms (SNPs) of transcription factor Foxp3of regulatory T cell (Treg cell) in patients with chronic obstructive pulmonatory disease (COPD) at different stages, and discusse the risk factors of the SNPs.
Methods:Subjects received treatment or physical examination in our hospital were selected and devided into non-somking group with normal lung function (N group,61cases), smoking group with normal lung function (S group,81cases), smoking with COPD in the Global initiative for chronic Obstructive Lung Disease (GOLD)1and2(COPD1-2group,65cases) and smoking with COPD in GOLD3and4(COPD3-4group,117cases). Samples of peripheral blood were collected. The Foxp3SNPs rs2280883, rs3761548, rs3761549and rs5902434were analyzed by Tanman quantitative real-time polymerase chain reaction (PCR). The susceptibility of COPD in people with differernt genotypes, and the risk factors for genetic mutations were both analyzed by logistic regression model.
Results:All four SNPs comply with Hardy-Weinberg genetic equilibrium. The genotypes and haplotypes of Foxp3SNP rs5902434were differently expressed in COPD3-4group, COPD1-2group, S group and N group (P<0.05). The-/-genotype was protective for COPD patients both at stage1-2and at stage3-4(COPD1-2group:OR=0.278,95%CI=0.079-0.974,; COPD3-4group:OR=0.235,95%CI=0.074-0.747). The genotype-/-of rs5902434was protective for patients with FEV1%pred=30-50(OR=0.222, 95%CI=0.094-0.525), as well as patients with FEV1/FVC<50and FEV1/FVC=50-70(FEV1/FVC<50:OR=0.295,95%CI=0.130-0.666; FEV1/FVC=50-70:OR=0.337,95%CI=0.131-0.866). The genotype-/ATT of rs5902434also could be protective for patients with FEV1%pred=30-50(OR=0.359,95%CI=0.150-0.863). The analysis of rs5902434haplotypes showed that-haplotype was susceptible to smokers with normal lung function (OR=1.746,95%CI=1.048-2.914). Furthermore,-haplotype was found to be protective for patients with FEV1%pred=30-50and FEV1/FVC<50, respectively (FEV1%pred=30-50:OR=0.582,95%CI=0.358-0.946; FEV1/FVC<50:OR=0.622,95%CI=0.403-0.961). The comprehensive analysis with smoking history, age, BMI and nation showed that non-Han people are more likely to have-/ATT genotype than Han people (OR=2.277,95%CI=1.022-5.072).
Conclusions:The Foxp3SNP rs5902434was risk for COPD in males, and-/-genotype was protective for COPD and the decline of lung function. But smoking history and age didn't influence this SNP. These foundings suggested that SNPs may be a up-stream factor of COPD. But risk factors of COPD including smoking and age maynot be associated with this SNP of Foxp3.
引文
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6. Cosio MG, Majo J, Cosio MG. Inflammation of the airways and lung parenchyma in COPD:role of T cells. Chest 2002,121(5 Suppl):160S-165S.
7. Barnes PJ. Small airways in COPD. N Engl J Med 2004,350(26):2635-2637.
8. Bluestone JA, Tang Q. How do CD4+CD25+ regulatory T cells control autoimmunity? Curr Opin Immunol 2005; 17:638-42.
9. Jiang H, Chess L. Regulation of immune responses by T cells. N Engl J Med 2006;354:1166-76.
10. Sakaguchi S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol. 2005;6(4):345-52.
11. Mottonen M, Heikkinen J, Mustonen L, Isomaki P, Luukkainen R, Lassila O. CD4+CD25+T cells with the phenotypic and functional characteristics of regulatory T cells are enriched in the synovial fluid of patients with rheumatoid arthritis. Clin Exp Immunol 2005; 140:360-7.
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13. Smyth LJ, Starkey C, Vestbo J, Singh D. CD4-regulatory cells in COPD patients. Chest 2007;132(1):156-63.
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15. Isajevs S, Taivans I, Strazda G, Kopeika U, Bukouskis M, Gordjusina V, et al. Decreased FOXP3 expression in small airways of smokers with COPD. Eur Respir J 2009;33(1):61-7.
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