新疆维吾尔族白细胞介素13基因多态性与慢性阻塞性肺疾病易感性关联研究
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摘要
目的：探讨IL-13基因启动子-1055C/T、外显子+2044A/G、内含子+1923C/T 3个位点的SNPs与新疆维吾尔族人群COPD易感性的关系。方法：采用病例-对照研究方法,以新疆和田地区确诊为COPD的220例60岁以上维吾尔族稳定期患者为病例组,对照组为220例年龄、性别与病例组相匹配的、无血缘关系的该地区维吾尔族无COPD者。采集静脉血并收集各项检查指标。用全血DNA提取试剂盒提取静脉血中基因组DNA,应用聚合酶链反应(PCR)法扩增目的片段,DNA测序法进行单核苷酸多态性(SNPs)鉴定。用SPSS17.0软件进行统计学分析。用SHEsis软件进行连锁不平衡及单倍型分析。结果：(1)IL-13基因启动子-1055C/T位点,病例组和对照组CC、CT、TT基因型的频率分布比较χ2=14.185,P<0.05；C、T等位基因的频率分布比较χ2=16.055,P<0.05。Logistic回归分析,CT基因型对CC基因型的优势比OR值为2.155(95%Cl：1.286-3.614),TT基因型对CC基因型的优势比OR值为2.705(95%Cl：1.103-6.634)。(2)IL-13基因外显子+2044G/A位点,病例组和对照组GG、GA、AA基因型的频率分布比较χ2=1.518,P>0.05；G、A等位基因的频率分布比较χ2=0.880,P>0.05。(3)IL-13基因内含子+1923C/T位点,病例组和对照组CC、CT. TT基因型的频率分布比较χ2=3.191,P>0.05；C、T等位基因的频率分布比较χ2=1.410,P>0.05。(4)IL-13基因启动子-1055C/T、外显子+2044A/G、内含子+1923C/T3个SNPs两两之间不存在连锁不平衡。(5)3个SNPs位点构成8种单倍型,其中3种单倍型的频率分布在病例组与对照组中有统计学差异。结论：IL-13基因启动子-1055C/T位点SNPs与维吾尔族COPD发生有关；外显子+2044G/A位点SNPs与维吾尔族COPD发生不相关；内含子+1923C/T位点SNPs与维吾尔族COPD发生不相关。3个SNPs两两之间不存在连锁不平衡。3种单倍型可能与新疆维吾尔族人群COPD相关。
Objective:To study the association between polymorphism of IL-13 gene promoter-1055C/T, exon+2044A/G, intron+1923C/T and susceptibility to chronic obstructive pulmonary disease in Xinjiang Uyger population. Methods:220 stable COPD patients (the case group) and healthy controls (the control group) of 220 age-and-sex matched with the case group, unrelated individuals were recruited in a case-control study to the Uygur of Hetian region. The venous blood and the check index were collected. Whole blood genomic DNA were extracted, DNA fragment was amplified by Polymerase chain reaction (PCR), DNA sequencing were identified by single nucleotide polymorphism (SNPs) cation. Data were analysised by SPSS 17.0 software. LD and haplotype were analysised by SHEsis software. Results:(1) For IL-13 gene promoter-1055C/T locus, comparison of genotype frequency distribution of CC, CT and TT isχ2=14.185 and P<0.05 in case group and control groups; Comparison of allele frequency distribution of C and T isχ2=16.055, P＜0.05; In Logistic regression analysis, OR of CT genotype vs CC genotype is 2.155(95%CI:1.286-3.614), OR of TT genotypes vs CC genotype is 2.705(95%CI:1.103-6.634). (2) For IL-13 exon+2044G/A locus, comparison of genotype frequency distribution of GG, GA and AA isχ2=1.518 and P>0.05 in case group and control groups; Comparison of allele frequency distribution of G and A isχ2=0.880 and P >0.05. (3) For IL-13 gene intron+1923C/T locus, comparison of genotype frequency distribution of CC, CT and TT isχ2=3.191and P>0.05 in case group and control groups; Comparison of allele frequency distribution of C and T isχ2=1.410 and P>0.05. (4) Pairwise LD analysis found there were no linkage disequilibrium in three SNPs. (5) Three SNPs loci constitute 8 haplotypes, and three haplotypes frequency distribution in the case group and control group were significantly different. Conclusion:The genetic polymorphism in promoter-1055C/T locus of IL-13 was associated with the susceptibility to COPD in Xinjiang Uyger population. The genetic polymorphism in Exon +2044G/A locus of IL-13 was not associated with the susceptibility to COPD in Xinjiang Uyger population. The genetic polymorphism in Intron+1923C/T locus of IL-13 was not associated with the susceptibility to COPD in Xinjiang Uyger population. There were no linkage disequilibrium in three SNPs. Three haplotypes may be associated with COPD in Xinjiang Uygur population.
Objective:To study the association between polymorphism of IL-13 gene promoter-1055C/T, exon+2044A/G, intron+1923C/T and susceptibility to chronic obstructive pulmonary disease in Xinjiang Uyger population. Methods:220 stable COPD patients (the case group) and healthy controls (the control group) of 220 age-and-sex matched with the case group, unrelated individuals were recruited in a case-control study to the Uygur of Hetian region. The venous blood and the check index were collected. Whole blood genomic DNA were extracted, DNA fragment was amplified by Polymerase chain reaction (PCR), DNA sequencing were identified by single nucleotide polymorphism (SNPs) cation. Data were analysised by SPSS 17.0 software. LD and haplotype were analysised by SHEsis software. Results:(1) For IL-13 gene promoter-1055C/T locus, comparison of genotype frequency distribution of CC, CT and TT isχ2=14.185 and P<0.05 in case group and control groups; Comparison of allele frequency distribution of C and T isχ2=16.055, P＜0.05; In Logistic regression analysis, OR of CT genotype vs CC genotype is 2.155(95%CI:1.286-3.614), OR of TT genotypes vs CC genotype is 2.705(95%CI:1.103-6.634). (2) For IL-13 exon+2044G/A locus, comparison of genotype frequency distribution of GG, GA and AA isχ2=1.518 and P>0.05 in case group and control groups; Comparison of allele frequency distribution of G and A isχ2=0.880 and P >0.05. (3) For IL-13 gene intron+1923C/T locus, comparison of genotype frequency distribution of CC, CT and TT isχ2=3.191and P>0.05 in case group and control groups; Comparison of allele frequency distribution of C and T isχ2=1.410 and P>0.05. (4) Pairwise LD analysis found there were no linkage disequilibrium in three SNPs. (5) Three SNPs loci constitute 8 haplotypes, and three haplotypes frequency distribution in the case group and control group were significantly different. Conclusion:The genetic polymorphism in promoter-1055C/T locus of IL-13 was associated with the susceptibility to COPD in Xinjiang Uyger population. The genetic polymorphism in Exon +2044G/A locus of IL-13 was not associated with the susceptibility to COPD in Xinjiang Uyger population. The genetic polymorphism in Intron+1923C/T locus of IL-13 was not associated with the susceptibility to COPD in Xinjiang Uyger population. There were no linkage disequilibrium in three SNPs. Three haplotypes may be associated with COPD in Xinjiang Uygur population.
引文
[1]Halbert RJ, Natoli JL, Gano A, et al. Global burden of COPD: systematic review and meta-analysis [J]. Eur Respir J,2006,28(3):523～532.
[2]Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the Diagnesis, management, and prevention of chronic obstructive pulmonary disease:GOLD executive summary [J]. Am J Respir Crit Care Med,2007,176:532～555.
[3]加孜那·托哈依,闫芳,何元兵,等.慢性阻塞性肺疾病患者骨密度改变的分析[J].国际呼吸杂志,2008,28(13)：787～790.
[4]Hu J, Meek P. Health-related quality of life in individuals with chronic obstructive pulmonary disease [J]. Heart Lung,2005,34(6):415-422.
[5]中华人民共和国卫生部.2006年中国卫生统计年鉴[M].北京：中国协和医科大学出版社,2006.260-299.
[6]严卫丽.复杂疾病遗传学研究方法[M].北京：科学出版社,2009.9-10.
[7]Dennis RJ, Maldonado D, Norman S, et al. Woodsmoke exposure and risk for obstruetive airways disease among women [J]. Chest,1996,109(1):115～119.
[8]Strachan DP, Seagroatt V, Cook DG. Chest illness in infancy and chronic respiratory disease in later life:an analysis by month of birth [J]. Int J Epidemiol,1994, 23(5):1060～1068.
[9]Silverman EK, Chapman HA, Drazen JM, et al. Genetic epidemiology of severe, early-onset chronic obstructive pulmonary disease:risk to relatives for airflow obstruction and chronic bronchitis [J]. Am J Respir Crit Care Med,1998, 157(6):1770～1778.
[10]Khoury MJ, Beaty TH, Newill CA, et al. Genetic-environmental interactions in Chronic airways obstruction [J]. Int J Epidemiol,1986,15(1):65～72.
[11]Joos L, Pare PD, Sandford AJ. Genetic risk factors for chronic obstructive pulmonary disease [J]. Swiss Med Wkly,2002,132:27-37.
[12]Shaw CJ, Lupski JR. Implications of human genome architecture for rearrangement-based disorders:the genomic basis of disease [J]. Hum Mol Genet, 2004,13(1):57～64.
[13]冯作化.医学分子生物学[M].北京：人民卫生出版社,2005.218-235.
[14]Alice MW, Robert AS. The genetics of chronic obstructive pulmonary disease [J]. Respiratory Research,2006,7(1):130～143.
[15]Schork NJ. Genetics of complex disease.Approches, problems, and solutions [J]. Am J Respir Crit Care Med,1997,156:s103～s109.
[16]Van Der Pouw Kraan TC, Kueukaycan M, Bakker AM, et al. Chronic obstructive pulmonary disease is associated with the-1055 IL-13 promoter polymorphism [J]. Genes Immun,2002,3:436～439.
[17]Jiang L, He B, Zhao MW, et al. Associate of gene polymorphism of tumour necrosis factor-alpha and interleukin-13 with chronic obstructive pulmonary disease in Han nationality in Beijing [J]. ChinMed J(Engl),2005,118(7):541～547.
[18]胡瑞成,徐永健,张珍祥.慢性阻塞性肺疾病易感性与中国汉族人白介素-13基因多态性的关联性研究[J].中华流行病学杂志,2004,25(7)：607～611.
[19]凌敏,荣艳,胡翠芬,等.新疆阿克苏农村地区慢性阻塞性肺疾病现况调查[J].中华结核和呼吸杂志,2009,32(9)：712～713.
[20]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修订版)[J].中华内科杂志,2007,46(3)：254～261.
[21]Graves PE, Kabesch M, Halonen M, et al. A cluster of seven tightly linked polymorphisms in the IL-13 gene is associated with total serum IgE levels in three populations of white children [J]. J Allergy Clin Immunol,2000,105(3):506-513.
[22]施侣元.流行病学[M].第5版.北京：人民卫生出版社,2003.91.
[23]李文英.归类分析基因频率和基因型频率的计算[J].科学教育,2004,10(5)：40-41.
[24]Shi YY, He L. SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci [J]. Cell Res,2005,15(2):97～98.
[25]孔祥东,张思仲,杨宇霞,等.血管紧张素原基因单倍型与原发性高血压的关联研究[J].中华医学遗传学杂志,2002,19(6)：488～490.
[26]张丽萍.新疆哈萨克族和维吾尔族人群原发性高血压与aENaC和β2-AR基因多态性的关联研究[D]：[博士学位论文].乌鲁木齐：新疆医科大学,2007.50-51.
[27]Kasper DL, Braunwald E, Hauser S, et al. Harrison's Principles of Internal Medicine, 16th Edition [M]. New York:Mc Graw-Hill Medical publishing Division,2006:1547.
[28]程显声,李景周,张珍祥,等.慢性阻塞性肺疾病、肺心病人群防治的研究基线资料分析.中华结核和呼吸杂志,1998,21(12)：749～752.
[29]Zhong N, Wang C, Yao W, et al. Prevalence of chronic obstructive pulmonary disease in china:a large, population-based survey. Am J Respir Crit Care Med,2007, 176(8):753～760.
[30]努尔曼·马贤,伊卜拉辛·马效智.伊斯兰伦理学[M].北京：宗教文化出版社,2005.347～348.
[31]王雯.IL-4、β2-AR基因多态性及EPC、IgE与维吾尔族哮喘的关系[D]：[博士学位论文].乌鲁木齐：新疆医科大学,2003.25.
[32]Fu WP, Sun C, Dai LM, et al. Relationship between COPD and polymorphisms of HOX-1 and mEPH in a Chinese population [J]. Oncol Rep,2007,17(2):483～488.
[33]Fu WP, Zhao ZH, Fang LZ, et al. Heme oxygenase-1 polymorphism associated with severity of chronic obstructive pulmonary disease [J]. Chin Med J(Engl),2007, 120(1):12～16.
[34]Keicho N, Matsushita I. Progress in the genetics of chronic obstructive pulmonary disease [J]. Nippon Rinsho,2007,65(4):611～614.
[35]Homma S, Sakamoto T, Hegab AE, et al. Association of phosphodiesterase4D gene polymorphisms with chronic obstructive pulmonary disease:relationship to interleukin 13 gene polymorphism [J]. Int J Mol Med,2006,18(5):933～939.
[36]Hersh CP, DeMeo DL, Raby BA, et al. Genetic linkage and association analysis of COPD-related traits on chromosome 8p [J]. COPD,2006,3(4):189～194.
[37]Liebhart J, Polak M, Dobek R, et al. TGF-beta1 gene polymorphism in chronic obstructive pulmonary disease [J]. Pneumonol Alergol Pol,2005,73(3):216～220.
[38]Laurell CB, Eriksson S. The electrophoretic alpha-1-globulin pattern of serum in alpha-1-antitrypsin deficiency [J]. Scand J Clin Lab Invest,1963,15(1):132～140.
[39]Alvarez-Granda L, Cabero-Perez MJ, Bustamante-Ruiz A, et al. PI SZ phenotype in chronic obstructive pulmonary disease [J]. Thorax,1997,52(7):659～661.
[40]Piitulainen E, Sveger T. Effect of environmental and clinical factors on lung function and respiratory symptoms in adolescents with alpha-1-antitrypsin deficiency [J]. Acta Paediatr,1998,87(11):1120～1124.
[41]Koyama H, Geddes DM. Genes, oxidative stress, and the risk of chronic obstructive pulmonary disease [J]. Thorax,1998,53(2):S10-S14.
[42]Sandford AJ, Spinelli JJ, Weir TD, et al. Mutation in the 3'region of the alpha-1-antitrypsin gene and chronic obstructive pulmonary disease [J]. J Med Genet, 1997,34(10):874～875.
[43]Rutkowski R, Moniuszko T. Cytokines in allergic inflammatory process [J]. Postepy Hig Med Dosw,2001,55(4):587～603.
[44]Zheng T, Zhu Z, Wang Z, et al. Inducible targeting of IL-13 to the adult lung causes matrix metalloproteinase-and cathepsin-dependent emphysema [J]. J Clin Invest, 2000,106(9):1081-1093.
[45]张扬帆.慢性阻塞性肺疾病患者对氧磷酶和氧化应激与全身炎性反应的研究[J].中华老年医学杂志,2009,28(6)：449～452.
[46]Lee CG, Homer RJ, Zhu Z, et al. Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor-β1[J]. J Exp Med,2001, 194(6):809～821.
[47]Wen FQ, Liu XD, Terasaki Y et al. Interferon-gamma reduces interleukin-4-and interleukin-13-augmented transforming growth factor-β2 production in human bronchial epithelial cells by targeting Smads [J]. Chest,2003,123(3)Suppl:372S-3S.
[48]Kuperman DA, Huang X, Koth LL, et al. Direct effects of IL-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma [J]. Nat Med, 2002,8:885～889.
[49]Postma DS, Kerstjens HAM. Characteristics of airway hyperresponsiveness in asthma and chronic obstructive pulmonary disease [J]. Am J Respi Crit Care Med, 1998,158(5):S187～S192.
[50]Odbileg R, Lee SI, Ohashi K, et al. Cloning and sequence analysis of llama (lama glama) Th2 (IL-4, IL-10 and IL-13) cytokines [J]. Vet Immunol Immunopathol.2005, 104:145-153.
[51]陈吉庆,孙海平,郭锡熔,等.白细胞介素-13基因多态性对哮喘患儿血清白细胞介素-13及总免疫球蛋白 E 水平的影响[J].中国实用儿科杂志,2004,19(4)：209～211.
[52]Van Der Pouw Kraan TC, van Veen A, Boeije LC, et al. An IL-13 promoter polymorphism associated with increased risk of allergic asthma [J]. Genes Immun, 1999,1(1):61～65.
[53]Faghih Z, Erfani N, Razmkhah M, et al. Interleukinl3 haplotypes and susceptibility of Iranian women to breast cancer [J]. Mol Biol Rep,2009,36:1923～1928.
[54]Dmitrieva-Zdorova EV, Voronko OE, Aksenova MG, et al. Association of interleukin-13 gene polymorphisms with atopic bronchial asthma [J]. Russian Journal of Genetics,2010,46(1):99～104.
[55]Kim JJ, Min JY, Lee JH. Polymorphisms in the IL-13 and IL-4 receptor alpha genes and allergic rhinitis [J]. Eur Arch Otorhinolaryngol,2007,264:395～399.
[56]Sadeghnejad A, Karmaus W, Arshad SH, et al. IL13 gene polymorphisms modify the effect of exposure to tobacco smoke on persistent wheeze and asthma in childhood, a longitudinal study [J]. Respiratory Research,2008,9:2～11.
[57]Sameni S, Ghayumi MA, Mortazavi G, et al. Lack of association between interleukin-13 gene polymorphisms(-1055C/T and+2044G/A)in Iranian patients with lung cancer [J]. Mol Biol Rep,2009,36:1001～1005.
[58]王修海,赵炜,刘世国,等.白细胞介素4和13基因多态性对支气管哮喘患者易感性及血清总IgE水平的影响[J].中华结核和呼吸杂志,2009,32(3)：161～164.
[59]Pantelidis P, Jones MG, Welsh KI, et al. Identification of four novel interleukin-13 gene polymorphisms [J]. Cenes Immun,2000,1(5):341～345.
[60]Zhou G, Zhai Y, Dong X, et al. Haplotype structure and evidence for positiveselection at the human IL-13 locus [J]. Molecular Biology and Evolution,2004,21(1):29～35.
[611陈竺.医学遗传学[M].北京：人民卫生出版社,2005.271-274.
[62]1杜胜军,惠汝太.关联性研究中的单体型分析[J].中国分子心脏病学杂志,2006,6(4)：249～251.
[63]孙树汉.医学分子遗传学[M].北京：科学出版社,2009.230-231.
[64]江玉梅,杨桂玲.连锁不平衡的研究与应用[J].江西植保,2004,27(2)：61-63.
[65]Davidson S. Research suggests importance of haplotypes over SNPs [J]. Nat Biotechnol,2000,18(11):1134-1135.
[66]Sachidanandam R, Weissman D, Schmidt SC, et al. The International SNP Map Working Group. A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms [J]. Nature,2001,409(6822):928-933.
[67]Venter JC, Adams MD, Myers EW, et al. The sequence of the human genome[J]. Science,2001,291(5507):1304-1351.
[68]Kruglyak L, Nickerson DA. Variation is the spice of life[J]. Nat Genet,2001, 27(3):234～236.
[69]Halushka MK, Fan JB, Bentley K, et al. Patterns of single nucleotide polymorphisms in candidate genes for blood pressure homeostasis[J].Nature Genet,1999,22:239-247.
[70]Tishkoff SA, Pakstis AJ, Ruano G, et al. The accuracy of statistical methods for estismation of haplotype frequencies:an example from the CD4 locus[J]. Am J Hum Genet,2000,67(2):518～522.
[71]Hegab AE, Sakamoto T, Saitoh W, et al. Polymorphisms of IL4, IL13, and ADRB2 genes in COPD [J]. Chest,2004,126(6):1832～1839.
[72]Risch NJ. Searching for genetic determinants in the new millennium [J]. Nature, 2000,405(15):847～856.
[73]奚慧峰,代卡·兰江.太平洋隔离群体萨摩亚人的遗传结构分析[J].中国优生优育,2007,13(s)：79～82.
[74]郭奕斌,潘宏达,孟亚仙,等.突变特异性扩增系统和变性高效液相色谱分析法结合 DNA 测序法快速产前诊断黏多糖贮积症Ⅱ型高危胎儿[J/OL].中华临床医师杂志(电子版),2010,4(5)：552～557.
[1]Halbert RJ, Natoli JL, Gano A, et al. Global burden of COPD:systematic review and meta-analysis [J]. Eur Respir J,2006,28(3):523～532.
[2]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修订版)[J].中华结核和呼吸杂志,2007,30(1)：8～17.
[3]Zheng T, Zhu Z, Wang Z, et al. Inducible targeting of IL-13 to the adult lung causes matrix metalloproteinase-and cathepsin-dependent emphysema [J]. J Clin Invest, 2000,106(9):1081～1093.
[4]Graves PE, Kabesch M, Halonen M, et al. A cluster of seven tightly linked polymorphisms in the IL-13 gene is associated with total serum IgE levels in three populations of white children [J]. J Allergy Clin Immunol,2000,105(3):506-513.
[5]Odbileg R, Lee SI, Ohashi K, et al. Cloning and sequence analysis of llama(lama glama)Th2(IL-4, IL-10 and IL-13)cytokines [J]. Vet Immunol Immunopathol.2005, 104:145～153.
[6]Dubourdeau M, Chene G, Coste A, et al. Opposite roles of STAT and PPAR gamm in the induction of p21WAFl expression by IL-13 in human peripheral blood monocytes [J]. Eur Cytokine Netw,2008,19(4):156～165.
[7]Minty A, Asselin S, Bensussan A, et al. The related cytokines interleukin-13 and interleukin-4 are distinguished by differential production and differential effects on T lymphocytes [J]. Eur Cytokine,1997,8(2):203～13.
[8]Mosmann TR, Coffman RL. Thl and Th2 cells:different patterns of lymphokine ecretion lead to different functional properties [J]. Annu Rev Immunol,1989, 7:145～173.
[9]de Waal Malefyt R, Abrams JS, Zurawski SM, et al. Differential regulation of IL-13 and IL-4 production by human CD8+and CD4+ThO, Thl and Th2 T cell clones and EBV-transformed B cells [J]. Int Immunol,1995,7(9):1405～1416.
[10]Jung T, Wijdenes J, Neumann C, et al. Interleukin-13 is produced by activated human CD45RA+and CD45RO+T cells:modulation by interleukin-4 and interleukin-12 [J]. Eur J Immunol,1996,26(3):571～577.
[11]Schmid-Grendelmeier p, Altznauer F, Fischer B, et al. Eosinophils express functional IL-13 in eosinophilic inflammatory diseases [J]. J Immunol,2002,169(2):1021～1027.
[12][Fort MM, Cheung J, Yen D, et al. IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo [J]. Immunity,2001,15(6):985～995.
[13]Elliott KA, Osna NA, Scofield MA, et al. Regulation of IL-13 production by histamine in cloned murine T helper type 2 cells [J]. Int Immunopharmacol,2001, 1(11):1923～1937.
[14]Pope SM, Brandt EB, Mishra A, et al. IL-13 induces eosinophil recruitment into the lung by an IL-5-and eotaxin-dependent mechanism [J]. J Allergy Clin Immunol,2001, 108(4):594～601.
[15]向敏,徐永健,张珍祥,等.白细胞介素-13在慢性阻塞性肺疾病患者肺组织中的表达[J].中华内科杂志,2007,46(12)：1033～1034.
[16]Richter A, Puddicombe SM, Lordan JL, et al. The contribution of interleukin(IL)-4 and IL-13 to the epithelial-mesenchymal trophic unit in asthma [J]. Am J Respir Cell Mol Biol,2001,25(3):385～391.
[17]Liu X, Kohyama T, Wang H, et al. Th2 cytokine regulation of type I collagen gel contraction mediated by human lung mesenchymal cells [J]. Am J Physiol Lung Cell Mol Physiol,2002,282(5):L1049-1056.
[18]Temann UA, Geba GP, Rankin JA, et al. Expression of interleukin 9 in the lungs of transgenic mice causes airway inflammation, mast cell hyperplasia, and bronchial hyperresponsiveness [J]. J Exp Med,1998,188(7):1307～1320.
[19]Temann UA, Ray P, Flavell RA. Pulmonary overexpression of IL-9 induces Th2 cytokine expression, leading to immune pathology [J]. J Clin Invest,2002,109(1): 29～39.
[20]Soler N, Ewig S, Torres A, et al. Airway inflammation and bronchial microbial patterns in patients with stable chronic obstructive pulmonary disease [J]. Eur Respir J, 1999,14(5):1015～1022.
[21]牛颖梅,童朝晖,王辰,等.稳定期慢性阻塞性肺疾病气道炎症的研究[J].国际呼吸杂志,2009,29(3)：132～136.
[22]胡瑞成,徐永健,张珍祥.慢性阻塞性肺疾病易感性与中国汉族人白介素-13基因多态性的关联性研究[J].中华流行病学杂志,2004,25(7)：607～611.
[23]Teramoto S. COPD pathogenesis from the viewpoint of risk factors [J]. Intern Med, 2007,46(2):77～79.
[24]Shaw CJ, Lupski JR. Implications of human genome architecture for rearrangement-based disorders:the genomic basis of disease [J]. Hum Mol Genet,2004, 13(1):57～64.
[25]Alice MW, Robert AS. The genetics of chronic obstructive pulmonary disease [J].Respiratory Research,2006,7(1):130～143.
[26]陈吉庆,孙海平,郭锡熔,等.白细胞介素-13基因多态性对哮喘患儿血清白细胞介素-13及总免疫球蛋白 E 水平的影响[J].中国实用儿科杂志,2004,19(4)：209～211.
[27]Van Der Pouw Kraan TC, Kueukaycan M, Bakker AM, et al. Chronic obstructive pulmonary disease is associated with the～1055 IL-13 promoter polymorphism [J]. Genes Immun,2002,3:436～439.
[28]Van Der Pouw Kraan TC, van Veen A, Boeije LC, et al. An IL-13 promoter poly-merphism associated with increased risk of allergic asthma [J]. Genes Immun,1999, 1(1):61～65.
[29]Hegab AE, Sakamoto T, Saitoh W, et al. Polymorphisms of IL4, IL13, and ADRB2 genes in COPD [J]. Chest,2004,126(6):1832～1839.
[30]Jiang L, He B, Zhao MW, et al. Associate of gene polymorphism of tumour necrosis factor-alpha and interleukin-13 with chronic obstructive pulmonary disease in Han nationality in Beijing [J]. ChinMed J(Engl),2005,118(7):541～547.
[2]Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the Diagnesis, management, and prevention of chronic obstructive pulmonary disease:GOLD executive summary [J]. Am J Respir Crit Care Med,2007,176:532～555.
[3]加孜那·托哈依,闫芳,何元兵,等.慢性阻塞性肺疾病患者骨密度改变的分析[J].国际呼吸杂志,2008,28(13)：787～790.
[4]Hu J, Meek P. Health-related quality of life in individuals with chronic obstructive pulmonary disease [J]. Heart Lung,2005,34(6):415-422.
[5]中华人民共和国卫生部.2006年中国卫生统计年鉴[M].北京：中国协和医科大学出版社,2006.260-299.
[6]严卫丽.复杂疾病遗传学研究方法[M].北京：科学出版社,2009.9-10.
[7]Dennis RJ, Maldonado D, Norman S, et al. Woodsmoke exposure and risk for obstruetive airways disease among women [J]. Chest,1996,109(1):115～119.
[8]Strachan DP, Seagroatt V, Cook DG. Chest illness in infancy and chronic respiratory disease in later life:an analysis by month of birth [J]. Int J Epidemiol,1994, 23(5):1060～1068.
[9]Silverman EK, Chapman HA, Drazen JM, et al. Genetic epidemiology of severe, early-onset chronic obstructive pulmonary disease:risk to relatives for airflow obstruction and chronic bronchitis [J]. Am J Respir Crit Care Med,1998, 157(6):1770～1778.
[10]Khoury MJ, Beaty TH, Newill CA, et al. Genetic-environmental interactions in Chronic airways obstruction [J]. Int J Epidemiol,1986,15(1):65～72.
[11]Joos L, Pare PD, Sandford AJ. Genetic risk factors for chronic obstructive pulmonary disease [J]. Swiss Med Wkly,2002,132:27-37.
[12]Shaw CJ, Lupski JR. Implications of human genome architecture for rearrangement-based disorders:the genomic basis of disease [J]. Hum Mol Genet, 2004,13(1):57～64.
[13]冯作化.医学分子生物学[M].北京：人民卫生出版社,2005.218-235.
[14]Alice MW, Robert AS. The genetics of chronic obstructive pulmonary disease [J]. Respiratory Research,2006,7(1):130～143.
[15]Schork NJ. Genetics of complex disease.Approches, problems, and solutions [J]. Am J Respir Crit Care Med,1997,156:s103～s109.
[16]Van Der Pouw Kraan TC, Kueukaycan M, Bakker AM, et al. Chronic obstructive pulmonary disease is associated with the-1055 IL-13 promoter polymorphism [J]. Genes Immun,2002,3:436～439.
[17]Jiang L, He B, Zhao MW, et al. Associate of gene polymorphism of tumour necrosis factor-alpha and interleukin-13 with chronic obstructive pulmonary disease in Han nationality in Beijing [J]. ChinMed J(Engl),2005,118(7):541～547.
[18]胡瑞成,徐永健,张珍祥.慢性阻塞性肺疾病易感性与中国汉族人白介素-13基因多态性的关联性研究[J].中华流行病学杂志,2004,25(7)：607～611.
[19]凌敏,荣艳,胡翠芬,等.新疆阿克苏农村地区慢性阻塞性肺疾病现况调查[J].中华结核和呼吸杂志,2009,32(9)：712～713.
[20]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修订版)[J].中华内科杂志,2007,46(3)：254～261.
[21]Graves PE, Kabesch M, Halonen M, et al. A cluster of seven tightly linked polymorphisms in the IL-13 gene is associated with total serum IgE levels in three populations of white children [J]. J Allergy Clin Immunol,2000,105(3):506-513.
[22]施侣元.流行病学[M].第5版.北京：人民卫生出版社,2003.91.
[23]李文英.归类分析基因频率和基因型频率的计算[J].科学教育,2004,10(5)：40-41.
[24]Shi YY, He L. SHEsis, a powerful software platform for analyses of linkage disequilibrium, haplotype construction, and genetic association at polymorphism loci [J]. Cell Res,2005,15(2):97～98.
[25]孔祥东,张思仲,杨宇霞,等.血管紧张素原基因单倍型与原发性高血压的关联研究[J].中华医学遗传学杂志,2002,19(6)：488～490.
[26]张丽萍.新疆哈萨克族和维吾尔族人群原发性高血压与aENaC和β2-AR基因多态性的关联研究[D]：[博士学位论文].乌鲁木齐：新疆医科大学,2007.50-51.
[27]Kasper DL, Braunwald E, Hauser S, et al. Harrison's Principles of Internal Medicine, 16th Edition [M]. New York:Mc Graw-Hill Medical publishing Division,2006:1547.
[28]程显声,李景周,张珍祥,等.慢性阻塞性肺疾病、肺心病人群防治的研究基线资料分析.中华结核和呼吸杂志,1998,21(12)：749～752.
[29]Zhong N, Wang C, Yao W, et al. Prevalence of chronic obstructive pulmonary disease in china:a large, population-based survey. Am J Respir Crit Care Med,2007, 176(8):753～760.
[30]努尔曼·马贤,伊卜拉辛·马效智.伊斯兰伦理学[M].北京：宗教文化出版社,2005.347～348.
[31]王雯.IL-4、β2-AR基因多态性及EPC、IgE与维吾尔族哮喘的关系[D]：[博士学位论文].乌鲁木齐：新疆医科大学,2003.25.
[32]Fu WP, Sun C, Dai LM, et al. Relationship between COPD and polymorphisms of HOX-1 and mEPH in a Chinese population [J]. Oncol Rep,2007,17(2):483～488.
[33]Fu WP, Zhao ZH, Fang LZ, et al. Heme oxygenase-1 polymorphism associated with severity of chronic obstructive pulmonary disease [J]. Chin Med J(Engl),2007, 120(1):12～16.
[34]Keicho N, Matsushita I. Progress in the genetics of chronic obstructive pulmonary disease [J]. Nippon Rinsho,2007,65(4):611～614.
[35]Homma S, Sakamoto T, Hegab AE, et al. Association of phosphodiesterase4D gene polymorphisms with chronic obstructive pulmonary disease:relationship to interleukin 13 gene polymorphism [J]. Int J Mol Med,2006,18(5):933～939.
[36]Hersh CP, DeMeo DL, Raby BA, et al. Genetic linkage and association analysis of COPD-related traits on chromosome 8p [J]. COPD,2006,3(4):189～194.
[37]Liebhart J, Polak M, Dobek R, et al. TGF-beta1 gene polymorphism in chronic obstructive pulmonary disease [J]. Pneumonol Alergol Pol,2005,73(3):216～220.
[38]Laurell CB, Eriksson S. The electrophoretic alpha-1-globulin pattern of serum in alpha-1-antitrypsin deficiency [J]. Scand J Clin Lab Invest,1963,15(1):132～140.
[39]Alvarez-Granda L, Cabero-Perez MJ, Bustamante-Ruiz A, et al. PI SZ phenotype in chronic obstructive pulmonary disease [J]. Thorax,1997,52(7):659～661.
[40]Piitulainen E, Sveger T. Effect of environmental and clinical factors on lung function and respiratory symptoms in adolescents with alpha-1-antitrypsin deficiency [J]. Acta Paediatr,1998,87(11):1120～1124.
[41]Koyama H, Geddes DM. Genes, oxidative stress, and the risk of chronic obstructive pulmonary disease [J]. Thorax,1998,53(2):S10-S14.
[42]Sandford AJ, Spinelli JJ, Weir TD, et al. Mutation in the 3'region of the alpha-1-antitrypsin gene and chronic obstructive pulmonary disease [J]. J Med Genet, 1997,34(10):874～875.
[43]Rutkowski R, Moniuszko T. Cytokines in allergic inflammatory process [J]. Postepy Hig Med Dosw,2001,55(4):587～603.
[44]Zheng T, Zhu Z, Wang Z, et al. Inducible targeting of IL-13 to the adult lung causes matrix metalloproteinase-and cathepsin-dependent emphysema [J]. J Clin Invest, 2000,106(9):1081-1093.
[45]张扬帆.慢性阻塞性肺疾病患者对氧磷酶和氧化应激与全身炎性反应的研究[J].中华老年医学杂志,2009,28(6)：449～452.
[46]Lee CG, Homer RJ, Zhu Z, et al. Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor-β1[J]. J Exp Med,2001, 194(6):809～821.
[47]Wen FQ, Liu XD, Terasaki Y et al. Interferon-gamma reduces interleukin-4-and interleukin-13-augmented transforming growth factor-β2 production in human bronchial epithelial cells by targeting Smads [J]. Chest,2003,123(3)Suppl:372S-3S.
[48]Kuperman DA, Huang X, Koth LL, et al. Direct effects of IL-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma [J]. Nat Med, 2002,8:885～889.
[49]Postma DS, Kerstjens HAM. Characteristics of airway hyperresponsiveness in asthma and chronic obstructive pulmonary disease [J]. Am J Respi Crit Care Med, 1998,158(5):S187～S192.
[50]Odbileg R, Lee SI, Ohashi K, et al. Cloning and sequence analysis of llama (lama glama) Th2 (IL-4, IL-10 and IL-13) cytokines [J]. Vet Immunol Immunopathol.2005, 104:145-153.
[51]陈吉庆,孙海平,郭锡熔,等.白细胞介素-13基因多态性对哮喘患儿血清白细胞介素-13及总免疫球蛋白 E 水平的影响[J].中国实用儿科杂志,2004,19(4)：209～211.
[52]Van Der Pouw Kraan TC, van Veen A, Boeije LC, et al. An IL-13 promoter polymorphism associated with increased risk of allergic asthma [J]. Genes Immun, 1999,1(1):61～65.
[53]Faghih Z, Erfani N, Razmkhah M, et al. Interleukinl3 haplotypes and susceptibility of Iranian women to breast cancer [J]. Mol Biol Rep,2009,36:1923～1928.
[54]Dmitrieva-Zdorova EV, Voronko OE, Aksenova MG, et al. Association of interleukin-13 gene polymorphisms with atopic bronchial asthma [J]. Russian Journal of Genetics,2010,46(1):99～104.
[55]Kim JJ, Min JY, Lee JH. Polymorphisms in the IL-13 and IL-4 receptor alpha genes and allergic rhinitis [J]. Eur Arch Otorhinolaryngol,2007,264:395～399.
[56]Sadeghnejad A, Karmaus W, Arshad SH, et al. IL13 gene polymorphisms modify the effect of exposure to tobacco smoke on persistent wheeze and asthma in childhood, a longitudinal study [J]. Respiratory Research,2008,9:2～11.
[57]Sameni S, Ghayumi MA, Mortazavi G, et al. Lack of association between interleukin-13 gene polymorphisms(-1055C/T and+2044G/A)in Iranian patients with lung cancer [J]. Mol Biol Rep,2009,36:1001～1005.
[58]王修海,赵炜,刘世国,等.白细胞介素4和13基因多态性对支气管哮喘患者易感性及血清总IgE水平的影响[J].中华结核和呼吸杂志,2009,32(3)：161～164.
[59]Pantelidis P, Jones MG, Welsh KI, et al. Identification of four novel interleukin-13 gene polymorphisms [J]. Cenes Immun,2000,1(5):341～345.
[60]Zhou G, Zhai Y, Dong X, et al. Haplotype structure and evidence for positiveselection at the human IL-13 locus [J]. Molecular Biology and Evolution,2004,21(1):29～35.
[611陈竺.医学遗传学[M].北京：人民卫生出版社,2005.271-274.
[62]1杜胜军,惠汝太.关联性研究中的单体型分析[J].中国分子心脏病学杂志,2006,6(4)：249～251.
[63]孙树汉.医学分子遗传学[M].北京：科学出版社,2009.230-231.
[64]江玉梅,杨桂玲.连锁不平衡的研究与应用[J].江西植保,2004,27(2)：61-63.
[65]Davidson S. Research suggests importance of haplotypes over SNPs [J]. Nat Biotechnol,2000,18(11):1134-1135.
[66]Sachidanandam R, Weissman D, Schmidt SC, et al. The International SNP Map Working Group. A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms [J]. Nature,2001,409(6822):928-933.
[67]Venter JC, Adams MD, Myers EW, et al. The sequence of the human genome[J]. Science,2001,291(5507):1304-1351.
[68]Kruglyak L, Nickerson DA. Variation is the spice of life[J]. Nat Genet,2001, 27(3):234～236.
[69]Halushka MK, Fan JB, Bentley K, et al. Patterns of single nucleotide polymorphisms in candidate genes for blood pressure homeostasis[J].Nature Genet,1999,22:239-247.
[70]Tishkoff SA, Pakstis AJ, Ruano G, et al. The accuracy of statistical methods for estismation of haplotype frequencies:an example from the CD4 locus[J]. Am J Hum Genet,2000,67(2):518～522.
[71]Hegab AE, Sakamoto T, Saitoh W, et al. Polymorphisms of IL4, IL13, and ADRB2 genes in COPD [J]. Chest,2004,126(6):1832～1839.
[72]Risch NJ. Searching for genetic determinants in the new millennium [J]. Nature, 2000,405(15):847～856.
[73]奚慧峰,代卡·兰江.太平洋隔离群体萨摩亚人的遗传结构分析[J].中国优生优育,2007,13(s)：79～82.
[74]郭奕斌,潘宏达,孟亚仙,等.突变特异性扩增系统和变性高效液相色谱分析法结合 DNA 测序法快速产前诊断黏多糖贮积症Ⅱ型高危胎儿[J/OL].中华临床医师杂志(电子版),2010,4(5)：552～557.
[1]Halbert RJ, Natoli JL, Gano A, et al. Global burden of COPD:systematic review and meta-analysis [J]. Eur Respir J,2006,28(3):523～532.
[2]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修订版)[J].中华结核和呼吸杂志,2007,30(1)：8～17.
[3]Zheng T, Zhu Z, Wang Z, et al. Inducible targeting of IL-13 to the adult lung causes matrix metalloproteinase-and cathepsin-dependent emphysema [J]. J Clin Invest, 2000,106(9):1081～1093.
[4]Graves PE, Kabesch M, Halonen M, et al. A cluster of seven tightly linked polymorphisms in the IL-13 gene is associated with total serum IgE levels in three populations of white children [J]. J Allergy Clin Immunol,2000,105(3):506-513.
[5]Odbileg R, Lee SI, Ohashi K, et al. Cloning and sequence analysis of llama(lama glama)Th2(IL-4, IL-10 and IL-13)cytokines [J]. Vet Immunol Immunopathol.2005, 104:145～153.
[6]Dubourdeau M, Chene G, Coste A, et al. Opposite roles of STAT and PPAR gamm in the induction of p21WAFl expression by IL-13 in human peripheral blood monocytes [J]. Eur Cytokine Netw,2008,19(4):156～165.
[7]Minty A, Asselin S, Bensussan A, et al. The related cytokines interleukin-13 and interleukin-4 are distinguished by differential production and differential effects on T lymphocytes [J]. Eur Cytokine,1997,8(2):203～13.
[8]Mosmann TR, Coffman RL. Thl and Th2 cells:different patterns of lymphokine ecretion lead to different functional properties [J]. Annu Rev Immunol,1989, 7:145～173.
[9]de Waal Malefyt R, Abrams JS, Zurawski SM, et al. Differential regulation of IL-13 and IL-4 production by human CD8+and CD4+ThO, Thl and Th2 T cell clones and EBV-transformed B cells [J]. Int Immunol,1995,7(9):1405～1416.
[10]Jung T, Wijdenes J, Neumann C, et al. Interleukin-13 is produced by activated human CD45RA+and CD45RO+T cells:modulation by interleukin-4 and interleukin-12 [J]. Eur J Immunol,1996,26(3):571～577.
[11]Schmid-Grendelmeier p, Altznauer F, Fischer B, et al. Eosinophils express functional IL-13 in eosinophilic inflammatory diseases [J]. J Immunol,2002,169(2):1021～1027.
[12][Fort MM, Cheung J, Yen D, et al. IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo [J]. Immunity,2001,15(6):985～995.
[13]Elliott KA, Osna NA, Scofield MA, et al. Regulation of IL-13 production by histamine in cloned murine T helper type 2 cells [J]. Int Immunopharmacol,2001, 1(11):1923～1937.
[14]Pope SM, Brandt EB, Mishra A, et al. IL-13 induces eosinophil recruitment into the lung by an IL-5-and eotaxin-dependent mechanism [J]. J Allergy Clin Immunol,2001, 108(4):594～601.
[15]向敏,徐永健,张珍祥,等.白细胞介素-13在慢性阻塞性肺疾病患者肺组织中的表达[J].中华内科杂志,2007,46(12)：1033～1034.
[16]Richter A, Puddicombe SM, Lordan JL, et al. The contribution of interleukin(IL)-4 and IL-13 to the epithelial-mesenchymal trophic unit in asthma [J]. Am J Respir Cell Mol Biol,2001,25(3):385～391.
[17]Liu X, Kohyama T, Wang H, et al. Th2 cytokine regulation of type I collagen gel contraction mediated by human lung mesenchymal cells [J]. Am J Physiol Lung Cell Mol Physiol,2002,282(5):L1049-1056.
[18]Temann UA, Geba GP, Rankin JA, et al. Expression of interleukin 9 in the lungs of transgenic mice causes airway inflammation, mast cell hyperplasia, and bronchial hyperresponsiveness [J]. J Exp Med,1998,188(7):1307～1320.
[19]Temann UA, Ray P, Flavell RA. Pulmonary overexpression of IL-9 induces Th2 cytokine expression, leading to immune pathology [J]. J Clin Invest,2002,109(1): 29～39.
[20]Soler N, Ewig S, Torres A, et al. Airway inflammation and bronchial microbial patterns in patients with stable chronic obstructive pulmonary disease [J]. Eur Respir J, 1999,14(5):1015～1022.
[21]牛颖梅,童朝晖,王辰,等.稳定期慢性阻塞性肺疾病气道炎症的研究[J].国际呼吸杂志,2009,29(3)：132～136.
[22]胡瑞成,徐永健,张珍祥.慢性阻塞性肺疾病易感性与中国汉族人白介素-13基因多态性的关联性研究[J].中华流行病学杂志,2004,25(7)：607～611.
[23]Teramoto S. COPD pathogenesis from the viewpoint of risk factors [J]. Intern Med, 2007,46(2):77～79.
[24]Shaw CJ, Lupski JR. Implications of human genome architecture for rearrangement-based disorders:the genomic basis of disease [J]. Hum Mol Genet,2004, 13(1):57～64.
[25]Alice MW, Robert AS. The genetics of chronic obstructive pulmonary disease [J].Respiratory Research,2006,7(1):130～143.
[26]陈吉庆,孙海平,郭锡熔,等.白细胞介素-13基因多态性对哮喘患儿血清白细胞介素-13及总免疫球蛋白 E 水平的影响[J].中国实用儿科杂志,2004,19(4)：209～211.
[27]Van Der Pouw Kraan TC, Kueukaycan M, Bakker AM, et al. Chronic obstructive pulmonary disease is associated with the～1055 IL-13 promoter polymorphism [J]. Genes Immun,2002,3:436～439.
[28]Van Der Pouw Kraan TC, van Veen A, Boeije LC, et al. An IL-13 promoter poly-merphism associated with increased risk of allergic asthma [J]. Genes Immun,1999, 1(1):61～65.
[29]Hegab AE, Sakamoto T, Saitoh W, et al. Polymorphisms of IL4, IL13, and ADRB2 genes in COPD [J]. Chest,2004,126(6):1832～1839.
[30]Jiang L, He B, Zhao MW, et al. Associate of gene polymorphism of tumour necrosis factor-alpha and interleukin-13 with chronic obstructive pulmonary disease in Han nationality in Beijing [J]. ChinMed J(Engl),2005,118(7):541～547.