肿瘤坏死因子-α基因多态性与黑龙江省东部地区慢性阻塞性肺疾病人群易感性的研究
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摘要
目的探讨肿瘤坏死因子(TNF)-α基因多态性与黑龙江省东部地区慢性阻塞性肺疾病(简称慢阻肺)人群易感性的相关性。方法选取2016年1月至2017年1月在佳木斯大学附属第一医院呼吸内科住院、门诊确诊的慢阻肺患者347例为病例组,同期本院体检中心的健康体检人群338例作为对照组。提取全血DNA,通过高分辨熔解曲线突变检测系统HRM及基因测序的方法检测基因型,比较两组基因表型及等位基因概率并进行SHEsis遗传不平衡单倍型分析。结果 TNF-α–308G/A共显性模型和隐性模型在两组间差异有统计学意义(共显性P=0.036,OR 1.512,95%CI 1.023～2.234);隐性P=0.027,OR 1.202,95%CI 1.024～1.741)。–850G/A共显性模型、显性模型和超显性模型在两组间差异均有统计学意义(共显性P=0.000,OR 1.781,95%CI 1.363～2.329;显性P=0.000,OR 0.391 7,95%CI 1.363～2.329;超显性P=0.000,OR 2.680,95%CI 1.728～4.156)]。单倍体分析及单倍体基因型分析结果显示+489、–308、–850位点分别为A、G、A时有统计学意义(P<0.05,OR>1,95%CI>1)。病例组中按照肺功能分级相比较,–308G/A、–863C/A位点突变基因组与野生型基因组肺功能差异有统计学意义(P=0.038,P=0.020)。结论在黑龙江省东部地区人群中,TNF-α–308位点上A、–850位点上G等位基因可能是慢阻肺的危险因素,且纯合子发病风险较高。当+489、–308、–850分别为A、G、A时可能是慢阻肺的危险因素,此三位点基因型为AGA的患者发病风险较高。TNF-α–308中A等位基因、–863中A等位基因与慢阻肺肺功能恶化有关,此二位点含A等位基因的慢阻肺患者肺功能下降速率更高、更易恶化。
Objective To investigate the association between tumor necrosis factor(TNF)-α gene polymorphism and susceptibility to chronic obstructive pulmonary disease(COPD) in eastern Heilongjiang province. Methods A total of 347 COPD patients in the Department of Respiratory Medicine, the First Affiliated Hospital of Jiamusi University, were enrolled from January 2016 to January 2017. In the same period, 338 healthy subjects in the hospital physical examination center were selected as controls. The genotype of the two groups was analyzed by high resolution melting(HRM) and gene sequencing. The genotype and allele probability of the two groups were compared and analyzed by the SHEsis genetic imbalance haplotype analysis. Results Both TNF-a –308 G/A co-dominant model and recessive model have significant differences between COPD patients and healthy subjects(P=0.036, OR 1.512, 95%CI 1.023 – 2.234; P=0.027, OR 1.202,95%CI 1.024 – 1.741). –850 G/A co-dominant model(P=0.000, OR 1.781, 95%CI 1.363 – 2.329), dominant model(P=0.000, OR 0.391 7, 95%CI 1.363 – 2.329) and hyper-dominant model(P=0.000, OR 2.680, 95%CI 1.728 – 4.156) in the two groups were statistically different. The haploid analysis and haploid genotype analysis showed statistically significant differences(all P<0.05, OR>1, 95%CI>1) at +489, –308, –850 sites by allele A, G, A, respectively between the two groups. There was a significant difference in the lung function between the –308 G/A, –863 C/A mutant genome and the wild type(P=0.038, P=0.02) in COPD patients according to the classification of lung function. Conclusions A allele in TNF-α –308 and G allele in TNF-α –850 locus may be risk factors for COPD in the eastern Heilongjiang Province, and the risk of homozygous genotype is higher. +489 A, –308 G and –850 A respectively may be the predisposing factor of COPD while the three genotypes of AGA patients were at higher risk. TNF-α –308 A allele and–863 A allele are related to lung function deterioration, and the two sites with A allele in patients with COPD indicate poor lung function.
Objective To investigate the association between tumor necrosis factor(TNF)-α gene polymorphism and susceptibility to chronic obstructive pulmonary disease(COPD) in eastern Heilongjiang province. Methods A total of 347 COPD patients in the Department of Respiratory Medicine, the First Affiliated Hospital of Jiamusi University, were enrolled from January 2016 to January 2017. In the same period, 338 healthy subjects in the hospital physical examination center were selected as controls. The genotype of the two groups was analyzed by high resolution melting(HRM) and gene sequencing. The genotype and allele probability of the two groups were compared and analyzed by the SHEsis genetic imbalance haplotype analysis. Results Both TNF-a –308 G/A co-dominant model and recessive model have significant differences between COPD patients and healthy subjects(P=0.036, OR 1.512, 95%CI 1.023 – 2.234; P=0.027, OR 1.202,95%CI 1.024 – 1.741). –850 G/A co-dominant model(P=0.000, OR 1.781, 95%CI 1.363 – 2.329), dominant model(P=0.000, OR 0.391 7, 95%CI 1.363 – 2.329) and hyper-dominant model(P=0.000, OR 2.680, 95%CI 1.728 – 4.156) in the two groups were statistically different. The haploid analysis and haploid genotype analysis showed statistically significant differences(all P<0.05, OR>1, 95%CI>1) at +489, –308, –850 sites by allele A, G, A, respectively between the two groups. There was a significant difference in the lung function between the –308 G/A, –863 C/A mutant genome and the wild type(P=0.038, P=0.02) in COPD patients according to the classification of lung function. Conclusions A allele in TNF-α –308 and G allele in TNF-α –850 locus may be risk factors for COPD in the eastern Heilongjiang Province, and the risk of homozygous genotype is higher. +489 A, –308 G and –850 A respectively may be the predisposing factor of COPD while the three genotypes of AGA patients were at higher risk. TNF-α –308 A allele and–863 A allele are related to lung function deterioration, and the two sites with A allele in patients with COPD indicate poor lung function.
引文
1中华医学会呼吸病学分会慢性阻塞性肺疾病学组.慢性阻塞性肺疾病诊治指南.中华结核和呼吸杂志,2007, 30(1):8-17.
2 Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease(GOLD); 2017. Available at:http://www.goldcopd.org/. Accessed June 5, 2017.
3 Zhang S, Wang C, Xi B, et al. Association between the tumour necrosis factor-alpha-308G/A polymorphism and chronic obstructive pulmonary disease:an update. Respirology, 2011, 16(1):107-115.
4 Lamprecht B, McBurnie MA, Vollmer WM, et al. COPD in never smokers:results from the population-based burden of obstructive lung disease study. Chest, 2011, 139(4):752-763.
5 Marciniak SJ, Lomas DA. What can naturally occurring mutations tell us about the pathogenesis of COPD?. Thorax, 2009, 64(4):359-364.
6 Wei L, Xu D, Qian Y, et al. Comprehensive analysis of gene expression profile in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis, 2015,10:1103-1109.
7 Hobbs BD, Hersh CP. Integrative genomics of chronic obstructive pulmonary disease. Biochem Biophys Res Commun, 2014, 452(2):276-286.
8 Lee PN, Fry JS. Systematic review of the evidence relating FEV1decline to giving up smoking. BMC Med, 2010, 8:84.
9 Klimentidis YC, Vazquez AI, de Los Campos G, et al. Heritability of pulmonary function estimated from pedigree and wholegenome markers. Front Genet, 2013, 4:174.
10 Henderson J, Harrison C. Management of COPD in general practice. Aust Fam Physician C, 2012, 41(11):841.
11 Wouters EF, Reynaert NL, Dentener MA, et al. Systemic and local inflammation in asthma and chronic obstructive pulmonary disease:is there a connection?. Proc Am Thorac Soc, 2009, 6(8):638-647.
12 Ji J, von Scheele I, Bergstrom J, et al. Compartment differences of inflammatory activity in chronic obstructive pulmonary disease.Respir Res, 2014, 15:104.
13 Keatings VM, Collins PD, Scott DM, et al. Differences in interleukin-8 and tumor necrosis factor-alpha in induced sputumfrom patients with chronic obstructive pulmonary disease or asthma. Am J Respir Crit Care Med, 1996,153(2):530-534.
14 Takabatake N, Arao T, Sata M, et al. Circulating levels of soluble Fas ligand in cachexic patients with COPD are higher than those in non-cachexic patients with COPD. Intern Med, 2005, 44(11):1137-1143.
15 Eurlings IM, Dentener MA, Mercken EM, et al. A comparative study of matrix remodeling in chronic models for COPD;mechanistic insights into the role of TNF-a. Am J Physiol Lung Cell Mol Physiol, 2014. 307(7):L557-L565.
16 Zhang L, Gu H, Gu Y, et al. Association between TNF-α-308 G/A polymorphism and COPD susceptibility:a meta-analysis update.Int J Chron Obstruct Pulmon Dis, 2016, 11:1367-1179.
17 Cui K, Ge XY, Ma HL. Association of the TNF-α+489 G/A polymorphism with chronic obstructive pulmonary disease risk in Asians:meta-analysis. Genet Mol Res, 2015, 14(2):5210-5220.
18 Cui K, Ge XY, Ma HL. Association of-238G/A and-863C/A polymorphisms in the TNF-a gene with chronic obstructive pulmonary disease based on a meta-analysis. Genet Mol Res, 2013,12(4):4981-4989.
19中华医学会呼吸病学分会慢性阻塞性肺疾病学组.慢性阻塞性肺疾病诊治指南(2013年修订版).中华结核和呼吸杂志.2013,36(1):1-10.
20慢性阻塞性肺疾.病急性加重(AECOPD)诊治组专家.慢性阻塞性肺疾病急性加重(AECOPD)诊治中国专家共识(草案).中华哮喘杂志电子版,2013, 7(1):1-13.
21 Sakao S, Tatusumi K, Igari H, et al. Association of tumor necrosis factor-alpha gene promoter polymorphism with the presence of chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 2001, 163(2):420-422.
22 Huang SL, Su CH, Chang SC, et al. Tumor necrosis factor-alpha gene polymorphism in chronic bronchitis. Am J Respir Crit Care Med, 1997, 156(5):1436-1439.
23 Ozdogan N, Tutar N, Demir R, et al. Is TNF-a gene polymorphism related to pulmonary functions and prognosis as determined by FEV1, BMI, COPD exacerbation and hospitalization in patients with smoking-related COPD in a Turkish population?. Rev Port Pneumol, 2014, 20(6):305-310.
24 Teramoto S, Ishii T, Ishii M, et al. Variation in the tumour necrosis factor-alpha gene is not associated with susceptibility to Asian COPD. Eur Respir J, 2008, 31(3):682-683.
25 Gingo MR, Silveira LJ, Miller YE, et al. Tumour necrosis factor gene polymorphisms are associated with COPD. Eur Respir J, 2008,31(5):1005-1012.
26 Chiang CH, Chuang CH, Liu SL, et al. Transforming growth factor-β1 and tumor necrosis factor-a are associated with clinical severity and airflow limitation of COPD in an additive manner.Lung, 2014,192(1):95-102.
27 Kucukaycan M, Van Krugten M, Pennings HJ, et al. Tumor necrosis factor-a+489G/A gene polymorphism is associated with chronic obstructive pulmonary disease. Respir Res, 2002, 3:29.
2 Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease(GOLD); 2017. Available at:http://www.goldcopd.org/. Accessed June 5, 2017.
3 Zhang S, Wang C, Xi B, et al. Association between the tumour necrosis factor-alpha-308G/A polymorphism and chronic obstructive pulmonary disease:an update. Respirology, 2011, 16(1):107-115.
4 Lamprecht B, McBurnie MA, Vollmer WM, et al. COPD in never smokers:results from the population-based burden of obstructive lung disease study. Chest, 2011, 139(4):752-763.
5 Marciniak SJ, Lomas DA. What can naturally occurring mutations tell us about the pathogenesis of COPD?. Thorax, 2009, 64(4):359-364.
6 Wei L, Xu D, Qian Y, et al. Comprehensive analysis of gene expression profile in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis, 2015,10:1103-1109.
7 Hobbs BD, Hersh CP. Integrative genomics of chronic obstructive pulmonary disease. Biochem Biophys Res Commun, 2014, 452(2):276-286.
8 Lee PN, Fry JS. Systematic review of the evidence relating FEV1decline to giving up smoking. BMC Med, 2010, 8:84.
9 Klimentidis YC, Vazquez AI, de Los Campos G, et al. Heritability of pulmonary function estimated from pedigree and wholegenome markers. Front Genet, 2013, 4:174.
10 Henderson J, Harrison C. Management of COPD in general practice. Aust Fam Physician C, 2012, 41(11):841.
11 Wouters EF, Reynaert NL, Dentener MA, et al. Systemic and local inflammation in asthma and chronic obstructive pulmonary disease:is there a connection?. Proc Am Thorac Soc, 2009, 6(8):638-647.
12 Ji J, von Scheele I, Bergstrom J, et al. Compartment differences of inflammatory activity in chronic obstructive pulmonary disease.Respir Res, 2014, 15:104.
13 Keatings VM, Collins PD, Scott DM, et al. Differences in interleukin-8 and tumor necrosis factor-alpha in induced sputumfrom patients with chronic obstructive pulmonary disease or asthma. Am J Respir Crit Care Med, 1996,153(2):530-534.
14 Takabatake N, Arao T, Sata M, et al. Circulating levels of soluble Fas ligand in cachexic patients with COPD are higher than those in non-cachexic patients with COPD. Intern Med, 2005, 44(11):1137-1143.
15 Eurlings IM, Dentener MA, Mercken EM, et al. A comparative study of matrix remodeling in chronic models for COPD;mechanistic insights into the role of TNF-a. Am J Physiol Lung Cell Mol Physiol, 2014. 307(7):L557-L565.
16 Zhang L, Gu H, Gu Y, et al. Association between TNF-α-308 G/A polymorphism and COPD susceptibility:a meta-analysis update.Int J Chron Obstruct Pulmon Dis, 2016, 11:1367-1179.
17 Cui K, Ge XY, Ma HL. Association of the TNF-α+489 G/A polymorphism with chronic obstructive pulmonary disease risk in Asians:meta-analysis. Genet Mol Res, 2015, 14(2):5210-5220.
18 Cui K, Ge XY, Ma HL. Association of-238G/A and-863C/A polymorphisms in the TNF-a gene with chronic obstructive pulmonary disease based on a meta-analysis. Genet Mol Res, 2013,12(4):4981-4989.
19中华医学会呼吸病学分会慢性阻塞性肺疾病学组.慢性阻塞性肺疾病诊治指南(2013年修订版).中华结核和呼吸杂志.2013,36(1):1-10.
20慢性阻塞性肺疾.病急性加重(AECOPD)诊治组专家.慢性阻塞性肺疾病急性加重(AECOPD)诊治中国专家共识(草案).中华哮喘杂志电子版,2013, 7(1):1-13.
21 Sakao S, Tatusumi K, Igari H, et al. Association of tumor necrosis factor-alpha gene promoter polymorphism with the presence of chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 2001, 163(2):420-422.
22 Huang SL, Su CH, Chang SC, et al. Tumor necrosis factor-alpha gene polymorphism in chronic bronchitis. Am J Respir Crit Care Med, 1997, 156(5):1436-1439.
23 Ozdogan N, Tutar N, Demir R, et al. Is TNF-a gene polymorphism related to pulmonary functions and prognosis as determined by FEV1, BMI, COPD exacerbation and hospitalization in patients with smoking-related COPD in a Turkish population?. Rev Port Pneumol, 2014, 20(6):305-310.
24 Teramoto S, Ishii T, Ishii M, et al. Variation in the tumour necrosis factor-alpha gene is not associated with susceptibility to Asian COPD. Eur Respir J, 2008, 31(3):682-683.
25 Gingo MR, Silveira LJ, Miller YE, et al. Tumour necrosis factor gene polymorphisms are associated with COPD. Eur Respir J, 2008,31(5):1005-1012.
26 Chiang CH, Chuang CH, Liu SL, et al. Transforming growth factor-β1 and tumor necrosis factor-a are associated with clinical severity and airflow limitation of COPD in an additive manner.Lung, 2014,192(1):95-102.
27 Kucukaycan M, Van Krugten M, Pennings HJ, et al. Tumor necrosis factor-a+489G/A gene polymorphism is associated with chronic obstructive pulmonary disease. Respir Res, 2002, 3:29.