CYP2A6基因多态性与个人吸烟行为及慢性阻塞性肺疾病相关性研究
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摘要
研究目的：探讨人细胞色素P450酶2A6(CYP2A6)基因*1(即CYP2A6wt)、*2、*3、*4(即CYP2A6del)型基因多态性与个人吸烟行为及慢性阻塞性肺疾病(COPD)遗传易感性的关系,同时与吸烟环境危险因素进行交互作用分析,寻找COPD的易感基因,为COPD高危人群的筛选、早期防治提供可能性依据。
材料和方法：采用病例-对照研究,收集COPD患者90例、健康对照者90例的晨空腹静脉血,提取全血细胞基因组DNA,采用直接测序法,检测CYP2A6基因外显子3位点碱基排列序列以确定CYP2A6*1、*2、*3、*4基因型在两组人群中的分布频率,并收集各种检查指标。年龄均数的比较采用两独立样本t检验,两组的性别、吸烟史、吸烟指数构成比及各基因型频率的比较采用x2检验,,并对有统计学意义者计算其比值比(OR)和95%可信区间(CI),以评估特殊基因型及在疾病中的危险度；并用相加模型判断吸烟和基因多态性之间的交互作用。
结果：
1、COPD组CYP2A6wt和CYP2A6del基因型频率分别为95.56%和4.44%,而对照组分别为85.56%和14.44%；两组间比较有显著性差异(P=0.023)；携带CYP2A6wt基因型者较携带CYP2A6del基因型者患COPD风险增加3.63倍(95%Cl=1.14-11.60,P=0.023)。
2、吸烟组CYP2A6wt和CYP2A6del基因型频率分别为94.29%和5.71%,而不吸烟组分别为85.33%和14.67%；两组间比较有显著性差异(P=0.043)。
3、吸烟史及吸烟指数在两组中差异有统计学意义(P=0.000)；有吸烟史与无吸烟史相比,患COPD的危险性增加6.909倍(OR=6.91,95%CI=3.35-13.52;P=0.000),且随吸烟指数的增高,患COPD的危险性显著增加(OR值逐渐增大,P=0.000)。
4、吸烟并携带CYP2A6wt基因型者较吸烟但携带CYP2A6del基因型者患COPD的风险性增加12.68倍(95%Cl=1.42-113.41,P=0.011)。
5、携带CYP2A6wt基因型的吸烟者较携带CYP2A6wt基因型的不吸烟者患COPD的风险性增加8.28倍(95%Cl=4.01-17.11,P=0.000)。
6、吸烟指数PY≥20包年并携带CYP2A6wt基因型者较吸烟指数PY≥20包年但携带CYP2A6del基因型者患COPD的风险性增加13.68倍(95%Cl=1.44-129.85,P=0.015)。
结论：
1、CYP2A6基因多态性可能是COPD发病的遗传危险因素。
2、CYP2A6基因多态性可能影响个人吸烟行为。
3、吸烟是COPD发病的危险因素,且与CYP2A6wt基因型在COPD发生学中可能有交互作用。
Object To investigate whether polymorphisms in gene for CYP 2A6 have any relations on individual smoking habit and the susceptibility to the development of COPD in order to find out the "susceptible" gene in COPD.Through the gene-smoking environment interactions analysis, we can select the high dangerous population to prevent and treat the COPD.
Materials and Methods The research design was a case-control study.After collecting the peripheral blood of 90 COPD patients and 90 control subjects in Han nationality of Changsha, Hunan province in China, we extracted their genomic DNA.Direct sequencing was performed to detect CYP2A6 gene polymorphisms. We also collected the clinical and laboratorial items for the research. The data of age were analyzed by t-test, the data of sex, cigarette smoking history, smoking index, frequency of genotype between groups were analyzed by Chi-square. The statistical OR and 95%CI were calculated to evaluate the risk of the special genotype. Additive model of interaction were performed to investigate the relationship between risk factors and COPD.
Results (1) The frequency of CYP2A6wt and CYP2A6del genotype was 95.56% and4.44% in COPD group and 85.56% and 14.44% in control group respectively. A highly significant difference was found between the two groups (P=0.023). And that the people who carried with CYP2A6wt genotype had a 3.63 fold increased risk of COPD than those who carried with CYP2A6del genotype (95%Cl=1.14-11.60, P=0.023). (2) The frequency of CYP2A6wt and CYP2A6del genotype was94.29% and 5.71% in smoke group and 85.33% and 14.67% in non-smoke group respectively. A significant difference was found between the two groups (P=0.043). (3) There were significant differences between two groups about cigarette smoking history and smoking index (P=0.000); Smoker had a higher risk of COPD compared with non-smoker (OR=6.91,95% Cl=3.35-13.52, P=0.000). Furthermore a significant increased risk of COPD were found in patients with higher smoke index (OR=19.4> 3.59,1.00,P=0.000).(4) The smokers who carried with CYP2A6wt genotype had a 12.68 fold increased risk of COPD than that those who carried with CYP2A6del genotype (95%Cl= 1.42-113.41, P=0.011). (5) The smokers who carried with CYP2A6wt genotype had a 8.28 fold increased risk of COPD than that nonsmokers who carried with CYP2A6wt genotype (95%Cl=4.01-17.11, P=0.000). (6) The heavy smokers (PY≥20) who carried with CYP2A6wt genotype had a 13.68fold increased risk of COPD than those who carried with CYP2A6del genotype (95%CI=1.44-129.85, P=0.015). Conclusion:(1) CYP2A6 gene polymorphisms possibly was a genetic risk factor in the incidence of COPD. (2) CYP2A6 gene polymorphisms may influence smoking habit. (3) Smoking is a important risk factor in the incidence of COPD, furthermore, smoking and CYP2A6 gene polymorphisms played a positive interactive role in the development of COPD.
材料和方法：采用病例-对照研究,收集COPD患者90例、健康对照者90例的晨空腹静脉血,提取全血细胞基因组DNA,采用直接测序法,检测CYP2A6基因外显子3位点碱基排列序列以确定CYP2A6*1、*2、*3、*4基因型在两组人群中的分布频率,并收集各种检查指标。年龄均数的比较采用两独立样本t检验,两组的性别、吸烟史、吸烟指数构成比及各基因型频率的比较采用x2检验,,并对有统计学意义者计算其比值比(OR)和95%可信区间(CI),以评估特殊基因型及在疾病中的危险度；并用相加模型判断吸烟和基因多态性之间的交互作用。
结果：
1、COPD组CYP2A6wt和CYP2A6del基因型频率分别为95.56%和4.44%,而对照组分别为85.56%和14.44%；两组间比较有显著性差异(P=0.023)；携带CYP2A6wt基因型者较携带CYP2A6del基因型者患COPD风险增加3.63倍(95%Cl=1.14-11.60,P=0.023)。
2、吸烟组CYP2A6wt和CYP2A6del基因型频率分别为94.29%和5.71%,而不吸烟组分别为85.33%和14.67%；两组间比较有显著性差异(P=0.043)。
3、吸烟史及吸烟指数在两组中差异有统计学意义(P=0.000)；有吸烟史与无吸烟史相比,患COPD的危险性增加6.909倍(OR=6.91,95%CI=3.35-13.52;P=0.000),且随吸烟指数的增高,患COPD的危险性显著增加(OR值逐渐增大,P=0.000)。
4、吸烟并携带CYP2A6wt基因型者较吸烟但携带CYP2A6del基因型者患COPD的风险性增加12.68倍(95%Cl=1.42-113.41,P=0.011)。
5、携带CYP2A6wt基因型的吸烟者较携带CYP2A6wt基因型的不吸烟者患COPD的风险性增加8.28倍(95%Cl=4.01-17.11,P=0.000)。
6、吸烟指数PY≥20包年并携带CYP2A6wt基因型者较吸烟指数PY≥20包年但携带CYP2A6del基因型者患COPD的风险性增加13.68倍(95%Cl=1.44-129.85,P=0.015)。
结论：
1、CYP2A6基因多态性可能是COPD发病的遗传危险因素。
2、CYP2A6基因多态性可能影响个人吸烟行为。
3、吸烟是COPD发病的危险因素,且与CYP2A6wt基因型在COPD发生学中可能有交互作用。
Object To investigate whether polymorphisms in gene for CYP 2A6 have any relations on individual smoking habit and the susceptibility to the development of COPD in order to find out the "susceptible" gene in COPD.Through the gene-smoking environment interactions analysis, we can select the high dangerous population to prevent and treat the COPD.
Materials and Methods The research design was a case-control study.After collecting the peripheral blood of 90 COPD patients and 90 control subjects in Han nationality of Changsha, Hunan province in China, we extracted their genomic DNA.Direct sequencing was performed to detect CYP2A6 gene polymorphisms. We also collected the clinical and laboratorial items for the research. The data of age were analyzed by t-test, the data of sex, cigarette smoking history, smoking index, frequency of genotype between groups were analyzed by Chi-square. The statistical OR and 95%CI were calculated to evaluate the risk of the special genotype. Additive model of interaction were performed to investigate the relationship between risk factors and COPD.
Results (1) The frequency of CYP2A6wt and CYP2A6del genotype was 95.56% and4.44% in COPD group and 85.56% and 14.44% in control group respectively. A highly significant difference was found between the two groups (P=0.023). And that the people who carried with CYP2A6wt genotype had a 3.63 fold increased risk of COPD than those who carried with CYP2A6del genotype (95%Cl=1.14-11.60, P=0.023). (2) The frequency of CYP2A6wt and CYP2A6del genotype was94.29% and 5.71% in smoke group and 85.33% and 14.67% in non-smoke group respectively. A significant difference was found between the two groups (P=0.043). (3) There were significant differences between two groups about cigarette smoking history and smoking index (P=0.000); Smoker had a higher risk of COPD compared with non-smoker (OR=6.91,95% Cl=3.35-13.52, P=0.000). Furthermore a significant increased risk of COPD were found in patients with higher smoke index (OR=19.4> 3.59,1.00,P=0.000).(4) The smokers who carried with CYP2A6wt genotype had a 12.68 fold increased risk of COPD than that those who carried with CYP2A6del genotype (95%Cl= 1.42-113.41, P=0.011). (5) The smokers who carried with CYP2A6wt genotype had a 8.28 fold increased risk of COPD than that nonsmokers who carried with CYP2A6wt genotype (95%Cl=4.01-17.11, P=0.000). (6) The heavy smokers (PY≥20) who carried with CYP2A6wt genotype had a 13.68fold increased risk of COPD than those who carried with CYP2A6del genotype (95%CI=1.44-129.85, P=0.015). Conclusion:(1) CYP2A6 gene polymorphisms possibly was a genetic risk factor in the incidence of COPD. (2) CYP2A6 gene polymorphisms may influence smoking habit. (3) Smoking is a important risk factor in the incidence of COPD, furthermore, smoking and CYP2A6 gene polymorphisms played a positive interactive role in the development of COPD.
引文
[1]Barnes PJ.Chronic Obstructive Pulmonary Disease.N EngI J Med,2000, 343(4):269-280.
[2]LoPez AD, Murray CC.The global burden of disease,1990-2020.Nat Med, 1998,4(11):1241-1243.
[3]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(2007年修订版).中华内科杂志.2007：46(3)：254.
[4]刘生明,王小平,王大礼等.广东部分地区慢性阻塞性肺疾病发病状况调查.中华医学杂志,2005,85(11)：747-752.
[5]C Fletcher, R Peto. The natural history of chronic airflow obstruction. Br Med J, 1977,1(6077):1645-1648.
[6]张少卿,汤彦.影响慢性阻塞性肺疾病肺功能下降的易感性[J].实用医学杂志,2008,24(10)：1846-1847.
[7]Anto.J.M, Vermeire. P, Vestbo.J, Sunyer.Eur.Resp.2001,17:982-994.
[8]Khoury MJ, Beaty TH, Newili CA, et al. Genetie-environmental interactions in chronic airways obstruction.Int.EPidemiol 1986,15(1):65-72.
[9]Ladina Foos, Peter D.Pare, Andrew F.Sandford.Genetic risk factors for chronic obstructive pulmonary disease.Swiss Med Wkly 2002:132:27-37.
[10]Minematsu N, Nakamura H, Iwata M, et al. Association of CYP2A6 deletion polymorphism with smoking habit and development of pulmonary emphysema. Thorax,2003,58:623-628.
[11]Ariyoshi N.Miyamoto M, Umetsu Y, et al. Genetic Polymorphism of CYP2A6 Gene and Tobacco-induced Lung Cancer Risk in Male Smokers. Cancer Epidemiology, Bio & Pre,2002,11:890-894.
[12]Malaiyandi V, Shari D.Goodz, Edward M. CYP2A6 Genotype, Phenotype, and the Use of Nicotine Metabolites as Biomarkers during Ad libitum Smoking.Cancer Epidemiol Biomarkers Prev.2006; 15(10):1812-1819.
[13]Nakajima M. Yoshida R Fukami T, Novel human CYP2A6 alleles confound gene deletion analysis. FEBS Letters,2004; 12(569):75-81.
[14]Tan W, Chen GF, Xing DY, et al. Frequency of CYP2A6 gene deletion and it's relation to risk of lung and esophageal cancer in the Chinese population.Int J Cancer,2001,95(2):96-101.
[15]顾艳斐,张树才,赖百塘,湛秀萍,张毅CYP2A6基因多态性与肺癌易感性 关系的研究.中国肺癌杂志,2005,8(4)：297-299
[16]袁天柱,周清华等.CYP2A6、CYP1B1和GSTT1基因多态性与人肺癌遗传易感性关系研究：[博士学位论文].成都：四川大学,2005.
[17]邓彦超,张晨,张艳等。CYP2A6基因多态性与食管癌易感性的关系.新疆医科大学学报,2009,32(5)：536-542.
[18]袁晓,王晓春等.CYP2A6基因多态性与烟草代谢物相关性冠心病的关系：[硕士学位论文].长沙：中南大学,2008.
[19]Kyoko K, Naoki K, Takahiko K, et al. The significance of the Homozygous CYP2A6 deletion on Nicotine Metabolism:A New Genotyping Method ofCYP2A6 Using a Single PCR-RFLP. Biochemical and Biophysical Research Communications,1999,262:146-151.
[20]Xia Xueyan, Peng Renxiu. Role of cytochrome P450 2A6 polymorphism in nicotine metabolism and tobacco-dependent behavior. Acta Pharmaceutica Sinica 2004,39(9):758-763.
[21]Krate F.Coumarin-7-hydroxylase activity in microsomes from needle biopsies of normal and diseased human liver.Eur J Clin Pharmacol,1976,10(2):133-137.
[22]Kapitulnik J, Popper PJ, Conney AH. Comparative metabolism of benzo[a]pyrene arid drugs in human liver. Clin Pharmacol Ther,1977,21(2):166-176.
[23]Pelkonen O, Sotaniemi EA, Ahokas JT.Coumarin7-hydroxylase Activity in human liver microsomes. ProPerties of the enzyme and interspecies comparisons. Br J Clin Pharmacol,1985,19(1):59-66.
[24]童紫莺,诸葛坚,余应年.细胞色素P4502A6的多态性研究,中华医学遗传学杂志,2002,19(5)：424-427.
[25]胡春松,JUN-Yan Hong,YU-Jing Zhao,CENG-Jun Dend.CYP2A6基因多态性的一步PCR-RFLR分析法,江西医学院学报,2002,42(5)：24-27.
[26]胡春松,朱文玲,程晓曙,苏海,罗伟,洪均言.检测CYP2A6基因多态性的PCR技术的基因型方法,中国药理学与毒理学杂志,2004,18(3)：233-236.
[27]Kitagawa K, Kunugita N, Katoh T, et al.Significance of theHomozygous CYP2A6deletion on nicotine metabolism:a new genotyping method of CYP2A6 using a single PCR-RFLP. Biochem Biophys Res Commun,1999 262(1):146-151.
[28]Mikael O, Roman A, Mclellana H, et al. Characterisation and PCR-based detection of a CYP2A6 gene deletion found at a high Frequency in a Chinese population. FEBS Letters,1999,448:105-110.
[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(2007年修订版).中华内科杂志.2007：46(3)：254.
[2]张少卿,汤彦.影响慢性阻塞性肺疾病肺功能下降的易感性.实用医学杂志,2008,24(10)：1846-1847.
[3]Anto. J. M., Vermeire. P, Vestbo. J, Sunyer.Eur.Resp,2001,17:982-994.
[4]Khoury MJ, Beaty TH, Newill CA, et al. Genetic-environmental interactions in chronic airways obstruction. Int.Epidemiol 1986,15(1):65-72.
[5]Sandford AJ, Spinelli JJ, Weir TD, et al. Mutation in the 3region of the alpha-1-antitrysin gene and chronic obstructive pulmonary disease.Med Genet, 1997,34(10):874-875.
[6]Black LF, Kueppers F.α1-antitrypsin deficiency detected by screening in nonsmokers. Am Rev Respir Dis 1978; 117:421-428.
[7]MacNee W. Oxidant/antioxidants and COPD. Chest 2000; 17:303S-317S.
[8]Rvberg D, Skaug V, Hewer A, et al. Genotypes of glutathione transferaseM1 and P1 and their significance for lung DNA adduct levels and cancer risk. Carcinogenesis,1997,18:1285-289.
[9]Kawajiri K, Nakachi K, Imai K, et al. Identification of genetically high risk individuals to lung cancer by DNA polymorphisms of the cytochrome P4501A1 gene.FEBSLett,1990,263:131-133.
[10]Hayashi S, Watanabe J, Nakachi K, et al. Genetic linkage of lung cancer associated Msp1 polymorphisms with amino acid replacement in the heme binding region of the human cytochrome P4501 A1 gene J Bioehem,1991,110: 407-411.
[11]Taioli E, Ford J, Trachman J, et al. Lung cancer risk and CYP1 A1 genotype in African Americans.Carcinogenesis,1998,19:813-817.
[12]Cascorbi I, Brockmoller J, Rootsl.A C4887A polymorphism in exon7 of human CYP1A1 population frequency, mutation linkages, and impact on lung cancers susceptibility. Cancer Res,1996,56:4965-4969.
[13]Canilay.AM, Lamb D, Giliooly M, et al. Association between the CYP 1A1 gene polymorphism and susceptibility to emphysema and lung cancer. Clin Mol pathol,1995,48(4):M210-214.
[14]Budhi A, Hiyama K,Isobe T, et al. Genetic susceptibility for emphysematous changes of the lung in Japanese. Int. Mol Med,2003, 1(3):321-329.
[15]王晓珍,杨小东等.细胞色素氧化酶P4501A1基因多态性与中国西南地区汉族人群慢性阻塞性肺疾病易感相关性的研究.WEST CHINA MEDICAL JOURNAL 2008,23 (16):1316-1318.
[16]李淑勤,刘学军等.CYP1A1及IL-8基因多态性与COPD发病的相关性研究：[硕士学位论文].太原：山西医科大学,2009.
[17]Rendic S.D., Carlo F.J., et al. Human cytochrome P-450 enzymes:a status report summarizing their reaction substrates, inducers and inhibitors. Drug Meta. Rev. 1997:29:413-580.
[18]Liang H.C.L, Li H.et al. CYP1A2 (-/-) null mutating mice develop normally but show deficient drug metabolism.Proc.Natl.Acad.US,1993,1671-1676.
[19]Mace K, Bowman E.D.Vautravers P. et al. Characterisation of xenobiotic-metabolizing enzyme expression in human bronchial mucosa and peripheral lung tissues. Eur. J. Cancer,1998,34:914-920.
[20]Kaur-Knudsen D,Nordestgaard BG.et al. CYP1B1 genotype and risk of cardiovascular disease, pulmonary disease, and cancer in 50,000 individuals. Pharmacogenet Genomics.2009 Sep; 19(9):685-94.
[21]Bourian M., Gullsten H., Legrum W.et al. Genetic polymorphism of CYP2A6 in the German population. Toxicology,2000,144:129-137.
[22]Osearson M., Gullsten Ⅱ., Rautio A., et al.Genotyping of human cytochromeP450 2A6 (CYP2A6), a nicotine C-oxidase. Letters,1998:438: 201-205.
[23]Minematsu N, Nakamura H, Iwata M, et al. Association of CYP2A6 deletion polymorphism with smoking habit and development of pulmonary emphysema.Thorax,2003,58:623-628.
[24]袁晓,王晓春等CYP2A6基因多态性与烟草代谢物相关性冠心病的关系：[硕士学位论文].长沙：中南大学,2008.
[25]Li ShaHan, Yuan Zhang, et al. Study on relationship between polymorphism of CYP2A6 and chronic obstructive pulmonary disease in Innermongolia Hans.Cell Biology International.2008,32:S1-S67.
[26]Tsutsumi M, Takada A, Wang JS. Genetic polymorphisms of cytochromeP450 2E1 related to the development of alcoholic liver disease. Gastroenterology,1994, 107(13):1430-1435.
[27]Ali-Osman F, Akande O, Antoun G,et al.Molecular cloning, characterization, and expression in Escherichia coli of full-length cDNAs of three human glutathione S-transferaseP1 gene variants:evidence for differential catalytic activity of the encoded proteins. J Biol Chem,1997,272 (8):10004-10012.
[28]Harries LW, Stubbins MJ, Forman D, et al. Identification of genetic polymorphisms at the glutathione S-transferaseP1 locus and association with susceptibility to bladder, testicular and prostate cancer. Carcinogenesis,1997, 18(4):641-644.
[29]Spurdle AB, Webb PM, Purdie DM, et al. Polymorphisms at the glutathione S-transferaseGSTM1, GSTT1 and GSTP1 loci:risk of ovarian cancer by histological subtype. Carcinogenesis,2001,22(1):67-72.
[30]Tan W, Song N, Wang GQ, et al. Impact of genetic polymorphism in cytochromeP450 2E1 and glutathione S-transferaseMl, T1 and P1 on susceptibility to esophageal cancer among high risk individuals in China. Cancer Epidemiol Biomarkers Pre,2000,9(7):551-556.
[31]Ishii T, Matsuse T,Teramoto S, et al. Glutathione S-transferaseP1 (GSTP1) polymorphism in patients with chronic obstructive pulmonary disease. Thorax, 1999,54(7):683-696.
[32]张杰,吴亚梅,刘兴,等.谷胱甘肽S转移酶P1基因多态性与中国汉族慢性阻塞性肺疾病关系探讨.中华结核和呼吸杂志,2003,26(5)：310-311.
[33]Yim JJ, Park GY, Lee CT, et al.Genetic Susceptibility to chronic obstructive pulmonary disease in Koreans:combined analysis of polymorphic genotypes for microsomal epoxide hydrolase and glutathione S-transferaseM1 and T1. Thorax, 2000,55(2):121-125.
[34]Baranova H, Perriot J, Albuisson E, et al.Peculiarities of the GSTM10/0 genotype in French heavy smokers with various types of chronic bronchitis. Hum Genet,997,99(10):822-826.
[35]Xiao D, Wang C, Du MJ, et al. Relationship between polymorphisms of genes encoding microsomal epoxide hydrolase and glutathione S-transferasePl and chronic obstructive pulmonary disease. Chin Med J,2004,117(5):661-667.
[36]胡远贵,沈云峰等.谷胱甘肽S转移酶P1基因多态性与慢性阻塞性肺疾病关系的研究.江汉大学学报(自然科学版)2005,33(2)：28-30.
[37]Cheng SL, Yu CJ, Chen CJ, et al. Genetic polymorphism of epoxide hydrolase and glutathione S-transferaseMl in COPD. Eur Respir J,2004,23(10):818-824.
[38]马志明,张珍祥等GSTM1和GSTT1基因多态性与COPD易感性的研究.中国医师杂志,2004,6(6)：721-724.
[39]Tomaki M, Sugiura H, Koarai A, et al. Decreased expression of antioxidant enzymes and increased expression of chemokines in COPD lung.Pulmonary Pharmacology&Therapeutics,2007,20(5):596-605.
[40]Hu GuoPing, Shi Zhe, Hu Jinxing, et al. Association between polymorphisms of microsomal epoxide hydrolase and COPD:results from meta-analyses. Respirology,2008,13(6):837-850.
[2]LoPez AD, Murray CC.The global burden of disease,1990-2020.Nat Med, 1998,4(11):1241-1243.
[3]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(2007年修订版).中华内科杂志.2007：46(3)：254.
[4]刘生明,王小平,王大礼等.广东部分地区慢性阻塞性肺疾病发病状况调查.中华医学杂志,2005,85(11)：747-752.
[5]C Fletcher, R Peto. The natural history of chronic airflow obstruction. Br Med J, 1977,1(6077):1645-1648.
[6]张少卿,汤彦.影响慢性阻塞性肺疾病肺功能下降的易感性[J].实用医学杂志,2008,24(10)：1846-1847.
[7]Anto.J.M, Vermeire. P, Vestbo.J, Sunyer.Eur.Resp.2001,17:982-994.
[8]Khoury MJ, Beaty TH, Newili CA, et al. Genetie-environmental interactions in chronic airways obstruction.Int.EPidemiol 1986,15(1):65-72.
[9]Ladina Foos, Peter D.Pare, Andrew F.Sandford.Genetic risk factors for chronic obstructive pulmonary disease.Swiss Med Wkly 2002:132:27-37.
[10]Minematsu N, Nakamura H, Iwata M, et al. Association of CYP2A6 deletion polymorphism with smoking habit and development of pulmonary emphysema. Thorax,2003,58:623-628.
[11]Ariyoshi N.Miyamoto M, Umetsu Y, et al. Genetic Polymorphism of CYP2A6 Gene and Tobacco-induced Lung Cancer Risk in Male Smokers. Cancer Epidemiology, Bio & Pre,2002,11:890-894.
[12]Malaiyandi V, Shari D.Goodz, Edward M. CYP2A6 Genotype, Phenotype, and the Use of Nicotine Metabolites as Biomarkers during Ad libitum Smoking.Cancer Epidemiol Biomarkers Prev.2006; 15(10):1812-1819.
[13]Nakajima M. Yoshida R Fukami T, Novel human CYP2A6 alleles confound gene deletion analysis. FEBS Letters,2004; 12(569):75-81.
[14]Tan W, Chen GF, Xing DY, et al. Frequency of CYP2A6 gene deletion and it's relation to risk of lung and esophageal cancer in the Chinese population.Int J Cancer,2001,95(2):96-101.
[15]顾艳斐,张树才,赖百塘,湛秀萍,张毅CYP2A6基因多态性与肺癌易感性 关系的研究.中国肺癌杂志,2005,8(4)：297-299
[16]袁天柱,周清华等.CYP2A6、CYP1B1和GSTT1基因多态性与人肺癌遗传易感性关系研究：[博士学位论文].成都：四川大学,2005.
[17]邓彦超,张晨,张艳等。CYP2A6基因多态性与食管癌易感性的关系.新疆医科大学学报,2009,32(5)：536-542.
[18]袁晓,王晓春等.CYP2A6基因多态性与烟草代谢物相关性冠心病的关系：[硕士学位论文].长沙：中南大学,2008.
[19]Kyoko K, Naoki K, Takahiko K, et al. The significance of the Homozygous CYP2A6 deletion on Nicotine Metabolism:A New Genotyping Method ofCYP2A6 Using a Single PCR-RFLP. Biochemical and Biophysical Research Communications,1999,262:146-151.
[20]Xia Xueyan, Peng Renxiu. Role of cytochrome P450 2A6 polymorphism in nicotine metabolism and tobacco-dependent behavior. Acta Pharmaceutica Sinica 2004,39(9):758-763.
[21]Krate F.Coumarin-7-hydroxylase activity in microsomes from needle biopsies of normal and diseased human liver.Eur J Clin Pharmacol,1976,10(2):133-137.
[22]Kapitulnik J, Popper PJ, Conney AH. Comparative metabolism of benzo[a]pyrene arid drugs in human liver. Clin Pharmacol Ther,1977,21(2):166-176.
[23]Pelkonen O, Sotaniemi EA, Ahokas JT.Coumarin7-hydroxylase Activity in human liver microsomes. ProPerties of the enzyme and interspecies comparisons. Br J Clin Pharmacol,1985,19(1):59-66.
[24]童紫莺,诸葛坚,余应年.细胞色素P4502A6的多态性研究,中华医学遗传学杂志,2002,19(5)：424-427.
[25]胡春松,JUN-Yan Hong,YU-Jing Zhao,CENG-Jun Dend.CYP2A6基因多态性的一步PCR-RFLR分析法,江西医学院学报,2002,42(5)：24-27.
[26]胡春松,朱文玲,程晓曙,苏海,罗伟,洪均言.检测CYP2A6基因多态性的PCR技术的基因型方法,中国药理学与毒理学杂志,2004,18(3)：233-236.
[27]Kitagawa K, Kunugita N, Katoh T, et al.Significance of theHomozygous CYP2A6deletion on nicotine metabolism:a new genotyping method of CYP2A6 using a single PCR-RFLP. Biochem Biophys Res Commun,1999 262(1):146-151.
[28]Mikael O, Roman A, Mclellana H, et al. Characterisation and PCR-based detection of a CYP2A6 gene deletion found at a high Frequency in a Chinese population. FEBS Letters,1999,448:105-110.
[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(2007年修订版).中华内科杂志.2007：46(3)：254.
[2]张少卿,汤彦.影响慢性阻塞性肺疾病肺功能下降的易感性.实用医学杂志,2008,24(10)：1846-1847.
[3]Anto. J. M., Vermeire. P, Vestbo. J, Sunyer.Eur.Resp,2001,17:982-994.
[4]Khoury MJ, Beaty TH, Newill CA, et al. Genetic-environmental interactions in chronic airways obstruction. Int.Epidemiol 1986,15(1):65-72.
[5]Sandford AJ, Spinelli JJ, Weir TD, et al. Mutation in the 3region of the alpha-1-antitrysin gene and chronic obstructive pulmonary disease.Med Genet, 1997,34(10):874-875.
[6]Black LF, Kueppers F.α1-antitrypsin deficiency detected by screening in nonsmokers. Am Rev Respir Dis 1978; 117:421-428.
[7]MacNee W. Oxidant/antioxidants and COPD. Chest 2000; 17:303S-317S.
[8]Rvberg D, Skaug V, Hewer A, et al. Genotypes of glutathione transferaseM1 and P1 and their significance for lung DNA adduct levels and cancer risk. Carcinogenesis,1997,18:1285-289.
[9]Kawajiri K, Nakachi K, Imai K, et al. Identification of genetically high risk individuals to lung cancer by DNA polymorphisms of the cytochrome P4501A1 gene.FEBSLett,1990,263:131-133.
[10]Hayashi S, Watanabe J, Nakachi K, et al. Genetic linkage of lung cancer associated Msp1 polymorphisms with amino acid replacement in the heme binding region of the human cytochrome P4501 A1 gene J Bioehem,1991,110: 407-411.
[11]Taioli E, Ford J, Trachman J, et al. Lung cancer risk and CYP1 A1 genotype in African Americans.Carcinogenesis,1998,19:813-817.
[12]Cascorbi I, Brockmoller J, Rootsl.A C4887A polymorphism in exon7 of human CYP1A1 population frequency, mutation linkages, and impact on lung cancers susceptibility. Cancer Res,1996,56:4965-4969.
[13]Canilay.AM, Lamb D, Giliooly M, et al. Association between the CYP 1A1 gene polymorphism and susceptibility to emphysema and lung cancer. Clin Mol pathol,1995,48(4):M210-214.
[14]Budhi A, Hiyama K,Isobe T, et al. Genetic susceptibility for emphysematous changes of the lung in Japanese. Int. Mol Med,2003, 1(3):321-329.
[15]王晓珍,杨小东等.细胞色素氧化酶P4501A1基因多态性与中国西南地区汉族人群慢性阻塞性肺疾病易感相关性的研究.WEST CHINA MEDICAL JOURNAL 2008,23 (16):1316-1318.
[16]李淑勤,刘学军等.CYP1A1及IL-8基因多态性与COPD发病的相关性研究：[硕士学位论文].太原：山西医科大学,2009.
[17]Rendic S.D., Carlo F.J., et al. Human cytochrome P-450 enzymes:a status report summarizing their reaction substrates, inducers and inhibitors. Drug Meta. Rev. 1997:29:413-580.
[18]Liang H.C.L, Li H.et al. CYP1A2 (-/-) null mutating mice develop normally but show deficient drug metabolism.Proc.Natl.Acad.US,1993,1671-1676.
[19]Mace K, Bowman E.D.Vautravers P. et al. Characterisation of xenobiotic-metabolizing enzyme expression in human bronchial mucosa and peripheral lung tissues. Eur. J. Cancer,1998,34:914-920.
[20]Kaur-Knudsen D,Nordestgaard BG.et al. CYP1B1 genotype and risk of cardiovascular disease, pulmonary disease, and cancer in 50,000 individuals. Pharmacogenet Genomics.2009 Sep; 19(9):685-94.
[21]Bourian M., Gullsten H., Legrum W.et al. Genetic polymorphism of CYP2A6 in the German population. Toxicology,2000,144:129-137.
[22]Osearson M., Gullsten Ⅱ., Rautio A., et al.Genotyping of human cytochromeP450 2A6 (CYP2A6), a nicotine C-oxidase. Letters,1998:438: 201-205.
[23]Minematsu N, Nakamura H, Iwata M, et al. Association of CYP2A6 deletion polymorphism with smoking habit and development of pulmonary emphysema.Thorax,2003,58:623-628.
[24]袁晓,王晓春等CYP2A6基因多态性与烟草代谢物相关性冠心病的关系：[硕士学位论文].长沙：中南大学,2008.
[25]Li ShaHan, Yuan Zhang, et al. Study on relationship between polymorphism of CYP2A6 and chronic obstructive pulmonary disease in Innermongolia Hans.Cell Biology International.2008,32:S1-S67.
[26]Tsutsumi M, Takada A, Wang JS. Genetic polymorphisms of cytochromeP450 2E1 related to the development of alcoholic liver disease. Gastroenterology,1994, 107(13):1430-1435.
[27]Ali-Osman F, Akande O, Antoun G,et al.Molecular cloning, characterization, and expression in Escherichia coli of full-length cDNAs of three human glutathione S-transferaseP1 gene variants:evidence for differential catalytic activity of the encoded proteins. J Biol Chem,1997,272 (8):10004-10012.
[28]Harries LW, Stubbins MJ, Forman D, et al. Identification of genetic polymorphisms at the glutathione S-transferaseP1 locus and association with susceptibility to bladder, testicular and prostate cancer. Carcinogenesis,1997, 18(4):641-644.
[29]Spurdle AB, Webb PM, Purdie DM, et al. Polymorphisms at the glutathione S-transferaseGSTM1, GSTT1 and GSTP1 loci:risk of ovarian cancer by histological subtype. Carcinogenesis,2001,22(1):67-72.
[30]Tan W, Song N, Wang GQ, et al. Impact of genetic polymorphism in cytochromeP450 2E1 and glutathione S-transferaseMl, T1 and P1 on susceptibility to esophageal cancer among high risk individuals in China. Cancer Epidemiol Biomarkers Pre,2000,9(7):551-556.
[31]Ishii T, Matsuse T,Teramoto S, et al. Glutathione S-transferaseP1 (GSTP1) polymorphism in patients with chronic obstructive pulmonary disease. Thorax, 1999,54(7):683-696.
[32]张杰,吴亚梅,刘兴,等.谷胱甘肽S转移酶P1基因多态性与中国汉族慢性阻塞性肺疾病关系探讨.中华结核和呼吸杂志,2003,26(5)：310-311.
[33]Yim JJ, Park GY, Lee CT, et al.Genetic Susceptibility to chronic obstructive pulmonary disease in Koreans:combined analysis of polymorphic genotypes for microsomal epoxide hydrolase and glutathione S-transferaseM1 and T1. Thorax, 2000,55(2):121-125.
[34]Baranova H, Perriot J, Albuisson E, et al.Peculiarities of the GSTM10/0 genotype in French heavy smokers with various types of chronic bronchitis. Hum Genet,997,99(10):822-826.
[35]Xiao D, Wang C, Du MJ, et al. Relationship between polymorphisms of genes encoding microsomal epoxide hydrolase and glutathione S-transferasePl and chronic obstructive pulmonary disease. Chin Med J,2004,117(5):661-667.
[36]胡远贵,沈云峰等.谷胱甘肽S转移酶P1基因多态性与慢性阻塞性肺疾病关系的研究.江汉大学学报(自然科学版)2005,33(2)：28-30.
[37]Cheng SL, Yu CJ, Chen CJ, et al. Genetic polymorphism of epoxide hydrolase and glutathione S-transferaseMl in COPD. Eur Respir J,2004,23(10):818-824.
[38]马志明,张珍祥等GSTM1和GSTT1基因多态性与COPD易感性的研究.中国医师杂志,2004,6(6)：721-724.
[39]Tomaki M, Sugiura H, Koarai A, et al. Decreased expression of antioxidant enzymes and increased expression of chemokines in COPD lung.Pulmonary Pharmacology&Therapeutics,2007,20(5):596-605.
[40]Hu GuoPing, Shi Zhe, Hu Jinxing, et al. Association between polymorphisms of microsomal epoxide hydrolase and COPD:results from meta-analyses. Respirology,2008,13(6):837-850.