Zur Genetik der chronisch-obstruktiven Lungenerkrankung

Zusammenfassung

Die COPD ist eine multifaktorielle Erkrankung, bei der sowohl Umweltfaktoren als auch die genetische Prädisposition eine wichtige Rolle spielen. Dies sieht man am deutlichsten am Beispiel des Nikotinkonsums. Obwohl das inhalative Zigarettenrauchen den wichtigsten Risikofaktor für die Erkrankung darstellt, erkrankt nur maximal die Hälfte aller Raucher an einer COPD. Für die Pathogenese der COPD sind 3 Hauptursachen zu nennen: 1. Imbalance zwischen Proteasen und Antiproteasen, 2. Oxidativer Stress, 3. Entzündungsreaktionen. Oxidativer Stress resultiert aus einem Ungleichgewicht zwischen exogenen Oxidantien, wie z. B. Zigarettenrauchen, und endogenen Antioxidantien. Der oxidative Stress löst eine Entzündungsreaktion aus, an der viele Mediatoren beteiligt sind. Durch die Mediatoren werden weitere Entzündungszellen angelockt. Diese setzen wiederum Proteasen und Oxidantien frei, dies führt zur Chronifizierung des Entzündungsgeschehens mit irreversibler Schädigung des Bronchialepithels. Individuelle genetische Variationen beeinflussen auf mannigfaltige Weise diese Prozesse. Das Ziel dieses Artikels liegt darin, eine Übersicht über die bisher untersuchten Kandidatengene und deren Funktion zu geben.

Abstract

COPD is a heterogenous disease caused by the interaction of genetic susceptibility and environmental influences. The best example to support this is tobacco smoke. Although cigarette smoking is the most important aetiological factor, only up to half of chronic smokers develop significant COPD. There are three main themes within the pathogenesis of COPD: 1) imbalance between proteases and anti-proteases, 2) oxidative stress, 3) inflammation. Disparity between levels of exogeneous oxidants, e. g., tobacco smoke, and endogeneous antioxidants leads to oxidative stress which, in turn, causes an inflammatory response involving pro-inflammatory mediators. The activated inflammatory cells release further proteases and oxidants, leading to chronic inflammation and irreversible destruction of connective tissue in the lung. Individual genetic variations influence these processes in many ways. This article summarises the results of recent candidate gene studies for COPD.

Literatur

• 1 Weißbuch Lunge 2000 .Defizite, Zukunftsperspektive, Forschungsansätze; die Lunge und ihre Erkrankungen: zur Lage und Zukunft der Pneumologie in Deutschland. Stuttgart-New York: Thieme 2000
• 2 Rabe K F, Hurd S, Anzueto A. et al . Global Strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary.  Am J Respir Crit Care Med. 2007;  176 532-555
• 3 European Respiratory Society .European lung white book. Huddersfield, UK. European Respiratory Society Journals 2003: 9
• 4 Nowak D, Dietrich E S, Oberender P. et al . Krankheitskosten von COPD in Deutschland.  Pneumologie. 2004;  58 837-844
• 5 Stein C E, Kumaran K, Fall C H. et al . Relation of fetal growth to adult lung function in South India.  Thorax. 1997;  52 895-899
• 6 Morgan W J. Maternal smoking and infant lung function: further evidence for an in utero effect.  Am J Respir Crit Care Med. 1998;  158 689-690
• 7 U.S. Surgeon General .The health consequences of smoking: chronic obstructive pulmonary disease. Washington DC: U.S. Department of health and human services. 1984: Publication No. 84-50 205
• 8 Chen J C, Mannino M D. Worldwide epidemiology of chronic obstructive pulmonary disease.  Current Opin Pulmon Med. 1995;  5 93-99
• 9 Behera D, Jindal S K. Respiratory symptoms in Indian women using domestic cooking fuels.  Chest. 1991;  100 385-388
• 10 Lundbäck B, Lindberg A, Lindström M. et al . Not 15 but 50 % of smokers develop COPD? – Report from the Obstructive Lung Disease in Northern Sweden Studies.  Respir Med. 2003;  97 115-122
• 11 Sandford A J, Silverman E K. Chronic obstructive pulmonary disease. 1: Susceptibility factors for COPD the genotype-environment interaction.  Thorax. 2002;  57 736-741
• 12 Kueppers F, Miller R D, Gordon H. et al . Familial prevalence of chronic obstructive pulmonary disease in a matched pair study.  Am J Med. 1977;  63 (3) 336-342
• 13 Fletcher C, Peto R. The natural history of chronic airflow obstruction.  Br Med J. 1977;  I (6077) 1645-1648
• 14 Carlson C S, Eberle M A, Kruglyak L. et al . Mapping complex disease loci in whole-genome association studies.  Nature. 2004;  429 (6990) 446-452
• 15 Hersh C P, De Meo D L, Lange C. et al . Attempted replication of reported chronic obstructive pulmonary disease candidate gene associations.  Am J Respir Cell Mol Biol. 2005;  33 (1) 71-78
• 16 Morton N E. Sequential tests for the detection of linkage.  Am J Hum Genet. 1955;  7 277-318
• 17 Thompson E A. Linkage analysis. In: Balding DJ, Bishop M, Cannings C (Hrsg). Handbook of statistical Genetics. Wiley 2001
• 18 Silverman E K, Mosley J D, Palmer L J. et al . Genome-wide linkage analysis of severe, early-onset chronic obstructive pulmonary disease: airflow obstruction and chronic bronchitis phenotypes.  Hum Mol Genet. 2002;  11 623-632
• 19 Silverman E K, Palmer L J, Mosley J D. et al . Genomewide linkage analysis of quantitative spirometric phenotypes in severe early-onset chronic obstructive pulmonary disease.  Am J Hum Genet. 2002;  70 1229-1239
• 20 Stemmler S, Arinir U, Klein W. et al . Association of interleukin-8 receptor α polymorphisms with chronic obstructive pulmonary disease and asthma.  Genes Immun. 2005;  6 225-230
• 21 Zhu G, Warren L, Aponte J. et al . The SERPINE2 gene is associated with chronic obstructive pulmonary disease in two large populations.  Am J Respir Crit Care Med. 2007;  176 167-173
• 22 Stockley R A. Neutrophils and protease/antiprotease imbalance.  Am J Respir Crit Care Med. 1999;  160 (5 Pt 2) S49-52
• 23 MacNee W. Oxidants/antioxidants and COPD.  Chest. 2000;  117 (5 Suppl I) 303S-317S
• 24 Needham M, Stockley R A. Alpha I-antitrypsin deficiency 3: Clinical manifestations and natural history.  Thorax. 2004;  59 441-445
• 25 O'Brien M L, Buist N R, Murphey W H. Neonatal screening for α1-antitrypsin deficiency.  J Pediatr. 1978;  92 1006-1010
• 26 Hersh C P, Dahl M, Ly N P. et al . Chronic obstructive pulmonary disease in α1-antitrypsin PI MZ heterozygotes: a metaanalysis.  Thorax. 2004;  59 843-849
• 27 Finlay G A, Russel K J, McMahon K J. et al . Elevated levels of matrix metalloproteinases in bronchoalveolar lavage fluid of emphematous patients.  Thorax. 1997;  52 502-506
• 28 D'Armiento J, Dalal S S, Okada Y. et al . Collagenase expression in the lungs of transgenic mice causes pulmonary emphysema.  Cell. 1992;  71 955-961
• 29 Hautamaki R D, Kobayasi D K, Senior R M. et al . Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice.  Science. 1997;  277 2002-2004
• 30 Joos L, He J Q, Sheperdson M B. et al . The role of matrix metalloproteinase polymorphisms in the rate of decline in lung function.  Hum Mol Genet. 2002;  11 569-576
• 31 Zhou M, Huang S G, Wan H Y. et al . Genetic polymorphism in matrix metalloproteinase-9 and the susceptibility to chronic obstructive pulmonary disease in Han population of south China.  Chin Med J (Engl). 2004;  117 1481-1484
• 32 Minematsu N, Nakamura H, Tateno H. et al . Genetic polymorphism in matrix metalloproteinase-9 and pulmonary emphysema.  Biochem Biophys Res Commun. 2001;  289 116-119
• 33 Howard E W, Bullen E C, Banda M J. Preferential inhibition of 72- and 92 kDa gelatinases by tissue inhibitor of metalloproteinases2.  J Biol Chem. 1991;  266 13 070-13 075
• 34 Hirano K, Sakamoto T, Uchida Y. et al . Tissue inhibitor of metalloproteinases2 gene polymorphisms in chronic obstructive pulmonary disease.  Eur Respir J. 2001;  18 748-752
• 35 Poller W, Faber J P, Scholz S. et al . Missence mutation of alpha1-antichymotrypsin gene associated with chronic lung disease.  Lancet. 1992;  339 1538
• 36 Ishii T, Matsuse T, Teramoto S. et al . Association between alpha1-antichymotrypsin polymorphism and susceptibility to chronic obstructive pulmonary disease.  Eur J Clin Invest. 2000;  30 543-548
• 37 Benetazzo M G, Gile L S, Bombieri C. et al . Alpha1-antichymotrypsin TAQ 1 polymorphism and alpha1-antichymotrypsin mutations in patients with obstructive pulmonary disease.  Respir Med. 1999;  93 648-654
• 38 Hunninghake G W, Crystal R G. Cigarette smoking and lung destruction. Accumulation of neutrophils in the lungs of cigarette smokers.  Am Rev Respir Dis. 1983;  128 833-838
• 39 Ali-Osman F, Akande O, Antoun G. et al . Molecular cloning, characterisation, and expression in E. coli of full-length cDNA of three human glutathione S-transferase Pi gene variants. Evidence for differential catalytic activity of the encoded proteins.  J Biol Chem. 1997;  272 10 004-10 012
• 40 Sundberg K, Johansson A S, Stenberg G. et al . Differences in the catalytic efficiencies of allelic variants of glutathione transferase P1 towards carcinogenic diol epoxides of polycyclic aromatic hydrocarbons.  Carcinogenesis. 1998;  19 433-436
• 41 Ishii T, Matsuse T, Teramoto S. et al . Glutathione S-transferase P1 polymorphism in patients with chronic obstructive pulmonary disease.  Thorax. 1999;  54 693-696
• 42 He J Q, Ruan J, Connett J E. et al . Antioxidant gene polymorphisms and susceptibility to a rapid decline in lung function in smokers.  Am J Respir Crit Care Med. 2002;  166 323-328
• 43 Vibhuti A, Arif E, Deepak D. et al . Genetic polymorphism of GSTP1 and mEPHX correlate with oxidative stress markers and lung function in COPD.  Biochem Biophys Res Commun. 2007;  359 136-142
• 44 Yim J J, Yoo C G, Lee C T. et al . Lack of association between glutathione S-transferase P1 polymorphism and COPD in Koreans.  Lung. 2002;  180 119-125
• 45 Harrison D J, Cantlay A M, Rae F. et al . Frequency of glutathione S-transferase M1 deletion in smokers with emphysema and lung cancer.  Hum Exp Toxicol. 1997;  16 356-360
• 46 Baranova H, Perriot J, Albuisson E. et al . Peculiarities of the GSTM 1 0/0 genotype in French heavy smokers with various types of chronic bronchitis.  Hum Genet. 1997;  99 822-826
• 47 Chan-Yeung M, Ho S P, Cheung A H. et al . Polymorphisms and functional activity in smokers with or without COPD.  Int J Tuberc Lung Dis. 2007;  11 508-514
• 48 Oury T D, Chang L Y, Marklund S L. et al . Immunocytochemical localization of extracellular superoxide dismutase in human lung.  Lab Invest. 1994;  70 889-898
• 49 Juul K, Tybaerg-Hansen A, Marklund S. et al . Genetically increased antioxidative protection and decreased chronic obstructive pulmonary disease.  Am J Respir Crit Care Med. 2006;  173 858-864
• 50 Young R P, Hopkins R, Black P N. et al . Functional variants of antioxidant genes in smokers with COPD and those with normal lung function.  Thorax. 2006;  61 394-399
• 51 Bartsch H, Petruzelli S, De Flora S. et al . Carcinogen metabolism in human lung tissues and the effect of tobacco smoking: results from a case-control multicenter study on lung cancer patients.  Environ Health Perspect. 1992;  98 119-124
• 52 Hassett C, Aicher L, Sidhu J S. et al . Human microsomal epoxide hydrolase: genetic polymorphism and functional expression in vitro of amino acid variants.  Hum Mol Genet. 1994;  3 421-428
• 53 Hosagrahara V P, Rettie A E, Hassett C. et al . Functional analysis of human microsomal epoxide hydrolase genetic variants.  Chem Biol Interact. 2004;  150 149-159
• 54 Smith C A, Harrison D J. Association between polymorphism in gene for microsomal epoxide hydrolase genotypes and susceptibility to emphysema.  Lancet. 1997;  350 630-633
• 55 Sandford A J, Chagani T, Weir T D. et al . Susceptibility genes for rapid decline of lung function in the lung health study.  Am J Respir Crit Care Med. 2001;  163 469-473
• 56 DeMeo D L, Hersh C P, Hoffman E A. et al . Genetic determinants of emphysema distribution in the National Emphysema Treatment Trial.  Am J Respir Crit Care Med. 2007;  176 42-48
• 57 Takeyabu K, Yamagouchi E, Suzuki I. et al . Gene polymorphism for microsomal epoxide hydrolase and susceptibility to emphysema in a Japanese population.  Eur Respir J. 2000;  15 891-894
• 58 Yim J J, Park G Y, Lee C T. et al . Genetic susceptibility to chronic obstructive pulmonary disease in Koreans: combined analysis of polymorphic genotypes for microsomal epoxide hydrolase and glutathione S-transferase M1 and T1.  Thorax. 2000;  55 121-125
• 59 Matheson M C, Raven J, Walters E H. et al . Microsomal epoxide hydrolase is not associated with COPD in a community-based sample.  Hum Biol. 2006;  78 705-717
• 60 Tenhunen R, Marver H S, Schmid R. The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase.  Proc Natl Acad Sci USA. 1968;  61 748-755
• 61 Maestrelli P, El Messlemani A H, De Fina O. et al . Increased expression of heme oxygenase (HO)-1 in alveolar walls of smokers.  Am J Respir Crit Care Med. 2001;  164 1508-1513
• 62 Yamada N, Yamaya M, Okinaga S. et al . Microsatellite polymorphism in the heme oxygenase-1 gene promoter is associated with susceptibility to emphysema.  Am J Hum Genet. 2000;  66 187-195
• 63 Guenegou A, Leynaert B, Benessiano J. et al . Association of lung function decline with the heme oxygenase-1 gene promoter microsatellite polymorphism in a general population sample. Results from the European Community Respiratory Health Survey (ECRHS), France.  J Med Genet. 2006;  43 e43
• 64 Fu W-P, Zhao Z-H, Fang L-Z. et al . Heme oxygenase-1 polymorphism associated with severity of chronic obstructive pulmonary disease.  Chin Med J. 2007;  120 12-16
• 65 Sevenoaks M J, Stockley R A. Chronic obstructive pulmonary disease, inflammation and co-morbidity – a common inflammatory phenotype?.  Respir Res. 2006;  7 70
• 66 Churg A, Wang R D, Tai H. et al . Tumor necrosis factor-alpha drives 70 % of cigarette smoke induced emphysema in the mouse.  Am J Respir Crit Care Med. 2004;  170 492-498
• 67 Wilson A G, Symons J A, McDowell T L. et al . Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation.  Proc Natl Acad Sci USA. 1997;  94 3195-3199
• 68 Huang S L, Su C H, Chang S C. Tumor necrosis factor-alpha gene polymorphism in chronic bronchitis.  Am J Respir Crit Care Med. 1997;  156 1436-1439
• 69 Sakao S, Tatsumi 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;  163 420-422
• 70 Matheson M C, Ellis J A, Raven J. et al . Association of IL8, CXCR2 and TNF-alpha polymorphisms and airway disease.  J Hum Genet. 2006;  51 196-203
• 71 Brogger J, Steen V M, Eiken H G. et al . Genetic association between COPD and polymorphisms in TNF, ADRB2 and EPHX1.  Eur Respir J. 2006;  27 682-688
• 72 Ruse C E, Hill M C, Tobin M. et al . Tumor necrosis factor gene complex polymorphisms in chronic obstructive pulmonary disease.  Respir Med. 2007;  101 340-344
• 73 Gingo M R, Silveira L J, Miller Y E. et al . Tumor necrosis factor gene polymorphisms are associated with COPD.  Eur Respir J. 2008;  31 1005-1012
• 74 Morris D G, Huang X, Kaminski N. et al . Loss of integrin alpha(v)beta6-mediated TGF-beta activation causes MMP12-dependent emphysema.  Nature. 2003;  422 169-173
• 75 Grainger D J, Heathcote K, Chiano M. et al . Genetic control of the circulating concentration of transforming growth factor type beta1.  Hum Mol Genet. 1999;  8 93-97
• 76 Suthanthiran M, Li B, Song J O. et al . Transforming growth factor-beta 1 hyperexpression in African-American hypertensives: A novel mediator of hypertension and/or target organ damage.  Proc Natl Acad Sci USA. 2000;  97 3479-3484
• 77 Wu L, Chau J, Young R P. et al . Transforming growth factor-beta 1 genotype and susceptibility to chronic obstructive pulmonary disease.  Thorax. 2004;  59 126-129
• 78 Celedon J C, Lange C, Raby B A. et al . The transforming growth factor-β1 (TGFβ1) gene is associated with chronic obstructive pulmonary disease (COPD).  Hum Mol Genet. 2004;  13 1649-1656
• 79 Van Diemen C C, Postma D S, Vonk J M. et al . Decorin and TGF-β1 polymorphisms and development of COPD in a general population.  Respir Res. 2006;  7 89
• 80 Yoon H I, Silverman E L, Lee H W. et al . Lack of association between COPD and transforming growth factor-β1 polymorphisms in Koreans.  Int J Tuberc Lung Dis. 2006;  10 504-509
• 81 Ogawa E, Ruan J, Connett J E. et al . Transforming growth factor-β1 polymorphisms, airway responsiveness and lung function decline in smokers.  Respir Med. 2007;  101 938-943
• 82 Yamamoto N, Homma S. Vitamin D3 (groupspecific component) is a precursor for the macrophage-activating signal factor from lysophosphatidylcholine-treated lymphocytes.  Proc Natl Acad Sci USA. 1991;  88 8539-8543
• 83 Kew R R, Webster R O. Gc-globulin (vitamin D-binding protein) enhances the neutrophil chemotactic activity of C5a and C5a des Arg.  J Clin Invest. 1988;  82 364-369
• 84 DiMartino S J, Shah A B, Trujillo G. et al . Elastase controls the binding of the vitamin D-binding protein (Gc-globulin) to neutrophils: a potential role in the regulation of C5a co-chemotactic activity.  J Immunol. 2001;  166 2688-2694
• 85 Ohkura K, Nagasawa H, Uto Y. et al . The role of Gc protein oligosaccharide structure as a risk factor for COPD.  Anticancer Res. 2006;  26 4073-4078
• 86 Horne S L, Cockcroft D W, Dosman J A. Possible protective effect against chronic obstructive airways disease by the GC2 allele.  Hum Hered. 1990;  40 173-176
• 87 Schellenberg D, Pare P D, Weir T D. et al . Vitamin D binding protein variants and the risk of COPD.  Am J Respir Crit Care Med. 1998;  157 957-961
• 88 Ishii T, Keicho N, Teramoto S. et al . Association of Gc-globulin variation with susceptibility to COPD and diffuse panbronchiolitis.  Eur Respir J. 2001;  18 753-757
• 89 Ito I, Nagai S, Hoshino Y. et al . Risk and severity of COPD is associated with the group-specific component of serum globulin 1F allele.  Chest. 2004;  125 63-70
• 90 Korytina G F, Akhmadishina L Z, Ianbaeva D G. et al . [Genotypes of vitamin-D-binding protein (DBP) in patients with chronic obstructive pulmonary disease and healthy population of Republic Bashkortostan].  Mol Biol (Mosk). 2006;  40 231-238
• 91 Kasuga I, Pare P D, Ruan J. et al . Lack of association of group specific component haplotypes with the lung function in smokers.  Thorax. 2003;  58 790-793
• 92 Wilk J B, Walter R E, Laramie J M. et al . Framingham Heart Study genome-wide association: results for pulmonary function measures.  BMC Med Genet. 2007;  8 S8
• 93 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 Clin Invest. 2000;  106 1081-1093
• 94 Pouw Kraan T C van der, Kucukaycan M, Bakker A M. et al . Chronic obstructive pulmonary disease is associated with the -1055 IL-13 promoter polymorphism.  Genes Immun. 2002;  3 436-439
• 95 Jiang L, He B, Zhao M W. et al . Association of gene polymorphisms of tumour necrosis factor-α and interleukin-13 with chronic obstructive pulmonary disease in Han nationality in Beijing.  Chin Med J. 2005;  118 541-547
• 96 Hegab A E, Sakamoto T, Saitoh W. et al . Polymorphisms of IL4, IL13 and ADRB2 genes in COPD.  Chest. 2004;  126 1832-1839
• 97 Sadeghnejad A, Meyers D A, Bottai M. et al . IL13 promoter polymorphism -1112C/T modulates the adverse effect of tobacco smoking on lung function.  Am J Respir Crit Care Med. 2007;  176 748-752
• 98 Guo X, Lin H M, Lin Z. et al . Surfactant protein gene A, B and D marker alleles in chronic obstructive pulmonary disease of a Mexican population.  Eur Respir J. 2001;  18 482-490
• 99 Hersh C P, DeMeo D L, Lazarus R. et al . Genetic association analysis of functional impairment in chronic obstructive pulmonary disease.  Am J Respir Crit Care Med. 2006;  173 977-984
• 100 Baker J B, Low D A, Simmer R L. et al . Protease-nexin: a cellular component that links thrombin and plasminogen activator and mediates their binding to cells.  Cell. 1980;  21 37-45
• 101 DeMeo D L, Mariani T J, Lange C. et al . The SERPINE2 gene is associated with chronic obstructive pulmonary disease.  Am J Hum Genet. 2006;  78 253-264
• 102 Chappell S, Daly L, Morgan K. et al . The SERPINE2 gene and chronic obstructive pulmonary disease.  Am J Hum Genet. 2006;  79 184-186; author reply 186 – 187
• 103 Zhu G, Warren L, Aponte J. et al . The SERPINE2 gene is associated with chronic obstructive pulmonary disease in two large populations.  Am J Respir Crit Care Med. 2007;  176 167-173
• 104 Weiss R B, Baker T B, Cannon D S. et al . A candidate gene approach identifies the CHRNA5-A3-B4 region as a risk factor for age-dependent nicotine addiction.  PLoS Genet. 2008;  4 e1000125
• 105 Laucht M, Becker K, Frank J. et al . Genetic variation in dopamine pathways differentially associated with smoking progression in adolescence.  J Am Acad Child Adolesc Psychiatry. 2008;  47 673-681
• 106 Rogausch A, Kochen M M, Meineke C. et al . Association between the BclI glucocorticoid receptor polymorphism and smoking in a sample of patients with obstructive airway disease.  Addict Biol. 2007;  12 93-99
• 107 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
• 108 Ott J. Association of genetic loci: replication or not, that is the question.  Neurology. 2004;  63 955-958
• 109 Kim E Y, Battaile J T, Patel A C. et al . Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease.  Nat Med. 2008;  14 633-640
• 110 Hizawa N, Makita H, Nasuhara Y. et al . Beta2-adrenergic receptor genetic polymorphisms and short-term bronchodilator responses in patients with COPD.  Chest. 2007;  132 1485-1492