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Association of interleukin-8 receptor α polymorphisms with chronic obstructive pulmonary disease and asthma

Genes & Immunity volume 6, pages 225–230 (2005)Cite this article

Abstract

Chronic obstructive pulmonary disease (COPD) and asthma are common complex diseases characterized by airflow obstruction and inflammatory processes in the small airways. lnterleukin 8 (IL-8) is a potent proinflammatory cytokine which interacts with the IL-8 receptor α (IL8RA, CXCR1) and β (IL8RB, CXCR2), leading to activation and migration of leukocytes. In order to evaluate the role of the IL8RA gene in the pathogenesis of COPD and asthma, we screened the coding region of IL8RA for mutations by means of single-strand conformation polymorphism analysis in 50 COPD patients and identified three exchanges (M31R, S276T and R335C). These three polymorphisms were subsequently genotyped in 182 adult patients with COPD, 68 adult patients and 130 children with asthma as well as 454 healthy controls. The frequencies of the IL8RA 31R and 335C alleles were significantly increased in patients with COPD and in children with asthma compared to healthy controls (P=0.0073 and 0.023, respectively). Thus, these polymorphisms may play a role in the pathogenesis of COPD and asthma.

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References

  1. Anto JM, Vermeire P, Vestbo J, Sunyer J . Epidemiology of chronic obstructive pulmonary disease. Eur Respir J 2001; 17: 982–994.

    Article  CAS  Google Scholar 

  2. Masoli M, Fabian D, Holt S, Beasley R . The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy 2004; 59: 469–478.

    Article  Google Scholar 

  3. Pauwels RA, Buist AS, Ma P, Jenkins CR, Hurd SS . Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: National Heart, Lung, and Blood Institute and World Health Organization Global Initiative for Chronic Obstructive Lung Disease (GOLD): executive summary. Respir Care 2001; 46: 798–825.

    CAS  PubMed  Google Scholar 

  4. Skrepnek GH, Skrepnek SV . Epidemiology, clinical and economic burden, and natural history of chronic obstructive pulmonary disease and asthma. Am J Manage Care 2004; 10: S129–S138.

    Google Scholar 

  5. Hakonarson H, Halapi E . Genetic analyses in asthma: current concepts and future directions. Am J Pharmacogenom 2002; 2: 155–166.

    Article  CAS  Google Scholar 

  6. Molfino NA . Genetics of COPD. Chest 2004; 125: 1929–1940.

    Article  Google Scholar 

  7. Meyers DA, Larj MJ, Lange L . Genetics of asthma and COPD: similar results for different phenotypes. Chest 2004; 126: 105S–110S (discussion 159S–161S).

    Article  CAS  Google Scholar 

  8. Norzila MZ, Fakes K, Henry RL, Simpson J, Gibson PG . Interleukin-8 secretion and neutrophil recruitment accompanies induced sputum eosinophil activation in children with acute asthma. Am J Respir Crit Care Med 2000; 161: 769–774.

    Article  CAS  Google Scholar 

  9. Pesci A, Balbi B, Majori M et al. Inflammatory cells and mediators in bronchial lavage of patients with chronic obstructive pulmonary disease. Eur Respir J 1998; 12: 380–386.

    Article  CAS  Google Scholar 

  10. Rutgers SR, Timens W, Kaufmann HF, van der Mark TW, Koeter GH, Postma DS . Comparison of induced sputum with bronchial wash, bronchoalveolar lavage and bronchial biopsies in COPD. Eur Respir J 2000; 15: 109–115.

    Article  CAS  Google Scholar 

  11. Yamamoto C, Yoneda T, Yoshikawa M et al. Airway inflammation in COPD assessed by sputum levels of interleukin-8. Chest 1997; 112: 505–510.

    Article  CAS  Google Scholar 

  12. Hull J, Thomson A, Kwiatkowski D . Association of respiratory syncytial virus bronchiolitis with the interleukin 8 gene region in UK families. Thorax 2000; 55: 1023–1027.

    Article  CAS  Google Scholar 

  13. Srivastava M, Eidelman O, Zhang J et al. Digitoxin mimics gene therapy with CFTR and suppresses hypersecretion of IL-8 from cystic fibrosis lung epithelial cells. Proc Natl Acad Sci USA 2004; 101: 7693–7698.

    Article  CAS  Google Scholar 

  14. Holmes WE, Lee J, Kuang WJ, Rice GC, Wood WI . Structure and functional expression of a human interleukin-8 receptor. Science 1991; 253: 1278–1280.

    Article  CAS  Google Scholar 

  15. Palmer LJ, Celedon JC, Chapman HA, Speizer FE, Weiss ST, Silverman EK . Genome-wide linkage analysis of bronchodilator responsiveness and post-bronchodilator spirometric phenotypes in chronic obstructive pulmonary disease. Hum Mol Genet 2003; 12: 1199–1210.

    Article  CAS  Google Scholar 

  16. Xu J, Postma DS, Howard TD et al. Major genes regulating total serum immunoglobulin E levels in families with asthma. Am J Hum Genet 2000; 67: 1163–1173.

    Article  CAS  Google Scholar 

  17. Lusuardi M, Capelli A, Cerutti CG, Spada EL, Donner CF . Airways inflammation in subjects with chronic bronchitis who have never smoked. Thorax 1994; 49: 1211–1216.

    Article  CAS  Google Scholar 

  18. Mukaida N . Pathophysiological roles of interleukin-8/CXCL8 in pulmonary diseases. Am J Physiol Lung Cell Mol Physiol 2003; 284: L566–L577.

    Article  CAS  Google Scholar 

  19. Kato H, Tsuchiya N, Tokunaga K . Single nucleotide polymorphisms in the coding regions of human CXC-chemokine receptors CXCR1, CXCR2 and CXCR3. Genes Immun 2000; 1: 330–337.

    Article  CAS  Google Scholar 

  20. Rajagopalan L, Rajarathnam K . Ligand selectivity and affinity of chemokine receptor CXCR1. Role of N-terminal domain. J Biol Chem 2004; 279: 30000–30008.

    Article  CAS  Google Scholar 

  21. Catusse J, Liotard A, Loillier B, Pruneau D, Paquet JL . Characterization of the molecular interactions of interleukin-8 (CXCL8), growth related oncogene alpha (CXCL1) and a non-peptide antagonist (SB 225002) with the human CXCR2. Biochem Pharmacol 2003; 65: 813–821.

    Article  CAS  Google Scholar 

  22. Bockaert J, Pin JP . Molecular tinkering of G protein-coupled receptors: an evolutionary success. EMBO J 1999; 18: 1723–1729.

    Article  CAS  Google Scholar 

  23. Peebles Jr RS . Viral infections, atopy, and asthma: is there a causal relationship? J Allergy Clin Immunol 2004; 113: S15–S18.

    Article  Google Scholar 

  24. Sigurs N, Bjarnason R, Sigurbergsson F, Kjellman B . Respiratory syncytial virus bronchiolitis in infancy is an important risk factor for asthma and allergy at age 7. Am J Respir Crit Care Med 2000; 161: 1501–1507.

    Article  CAS  Google Scholar 

  25. Heinzmann A, Ahlert I, Kurz T, Berner R, Deichmann KA . Association study suggests opposite effects of polymorphisms within IL8 on bronchial asthma and respiratory syncytial virus bronchiolitis. J Allergy Clin Immunol 2004; 114: 671–676.

    Article  CAS  Google Scholar 

  26. Hull J, Ackerman H, Isles K et al. Unusual haplotypic structure of IL8, a susceptibility locus for a common respiratory virus. Am J Hum Genet 2001; 69: 413–419.

    Article  CAS  Google Scholar 

  27. Hull J, Rowlands K, Lockhart E et al. Haplotype mapping of the bronchiolitis susceptibility locus near IL8. Hum Genet 2004; 114: 272–279.

    Article  CAS  Google Scholar 

  28. Arinir U, Klein W, Rohde G, Stemmler S, Epplen JT, Schultze-Werninghaus G . Polymorphisms in the IL8 gene in COPD and asthma. Electrophoresis (in press).

  29. Howard TD, Koppelman GH, Xu J et al. Gene–gene interaction in asthma: IL4RA and IL13 in a Dutch population with asthma. Am J Hum Genet 2002; 70: 230–236.

    Article  CAS  Google Scholar 

  30. Chen W, Ericksen MB, Levin LS, Khurana Hershey GK . Functional effect of the R110Q IL13 genetic variant alone and in combination with IL4RA genetic variants. J Allergy Clin Immunol 2004; 114: 553–560.

    Article  CAS  Google Scholar 

  31. Bugawan TL, Mirel DB, Valdes AM, Panelo A, Pozzilli P, Erlich HA . Association and interaction of the IL4R, IL4, and IL13 loci with type 1 diabetes among Filipinos. Am J Hum Genet 2003; 72: 1505–1514.

    Article  CAS  Google Scholar 

  32. Silverman EK, Palmer LJ, Mosley JD 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.

    Article  CAS  Google Scholar 

  33. DeMeo DL, Celedon JC, Lange C et al. Genomewide linkage of forced mid-expiratory flow in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004; 170: 1294–1301.

    Article  Google Scholar 

  34. Sears MR, Burrows B, Flannery EM, Herbison GP, Hewitt CJ, Holdaway MD . Relation between airway responsiveness and serum IgE in children with asthma and in apparently normal children. N Engl J Med 1991; 325: 1067–1071.

    Article  CAS  Google Scholar 

  35. Sherrill DL, Lebowitz MD, Halonen M, Barbee RA, Burrows B . Longitudinal evaluation of the association between pulmonary function and total serum IgE. Am J Respir Crit Care Med 1995; 152: 98–102.

    Article  CAS  Google Scholar 

  36. Hall IP, Wheatley A, Christie G, McDougall C, Hubbard R, Helms PJ . Association of CCR5 delta32 with reduced risk of asthma. Lancet 1999; 354: 1264–1265.

    Article  CAS  Google Scholar 

  37. Srivastava P, Helms PJ, Stewart D, Main M, Russell G . Association of CCR5Delta32 with reduced risk of childhood but not adult asthma. Thorax 2003; 58: 222–226.

    Article  CAS  Google Scholar 

  38. McGinnis R, Child F, Clayton S et al. Further support for the association of CCR5 allelic variants with asthma susceptibility. Eur J Immunogenet 2002; 29: 525–528.

    Article  CAS  Google Scholar 

  39. Nagy A, Kozma GT, Bojszko A, Krikovszky D, Falus A, Szalai C . No association between asthma or allergy and the CCR5Delta 32 mutation. Arch Dis Child 2002; 86: 426.

    Article  CAS  Google Scholar 

  40. Mitchell TJ, Walley AJ, Pease JE et al. Delta 32 deletion of CCR5 gene and association with asthma or atopy. Lancet 2000; 356: 1491–1492.

    Article  CAS  Google Scholar 

  41. Fukunaga K, Asano K, Mao XQ et al. Genetic polymorphisms of CC chemokine receptor 3 in Japanese and British asthmatics. Eur Respir J 2001; 17: 59–63.

    Article  CAS  Google Scholar 

  42. Adcock IM, Caramori G . Chemokine receptor inhibitors as a novel option in treatment of asthma. Curr Drug Targets Inflamm Allergy 2004; 3: 257–261.

    Article  CAS  Google Scholar 

  43. de Boer WI . Potential new drugs for therapy of chronic obstructive pulmonary disease. Expert Opin Investig Drugs 2003; 12: 1067–1086.

    Article  CAS  Google Scholar 

  44. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, November 1986. Am Rev Respir Dis 1987; 136: 225–244.

  45. Rohde G, Wiethege A, Borg I et al. Respiratory viruses in exacerbations of chronic obstructive pulmonary disease requiring hospitalisation: a case–control study. Thorax 2003; 58: 37–42.

    Article  CAS  Google Scholar 

  46. Goedde R, Sawcer S, Boehringer S et al. A genome screen for linkage disequilibrium in HLA-DRB1*15-positive Germans with multiple sclerosis based on 4666 microsatellite markers. Hum Genet 2002; 111: 270–277.

    Article  CAS  Google Scholar 

  47. Miller SA, Dykes DD, Polesky HF . A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988; 16: 1215.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Bundesministerium für Bildung und Forschung (BMBF) grant # 01GC 0101/TP6 and Forschungsförderung Ruhr-Universität Bochum Medizinische Fakultät (FoRUM) grants #175-99 and #F377-2003.

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Authors and Affiliations

  1. Department of Human Genetics, Ruhr-University, Bochum, Germany

    S Stemmler, U Arinir, W Klein, S Hoffjan, N Wirkus & J T Epplen

  2. Department of Internal Medicine III, Pneumology, Allergology and Sleep Medicine, University Hospital Bergmannsheil, Bochum, Germany

    G Rohde & G Schultze-Werninghaus

  3. Department of Experimental Pneumology, University Hospital Bergmannsheil, Bochum, Germany

    K Reinitz-Rademacher & A Bufe

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  1. S Stemmler
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Correspondence to S Stemmler.

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Stemmler, S., Arinir, U., Klein, W. et al. Association of interleukin-8 receptor α polymorphisms with chronic obstructive pulmonary disease and asthma. Genes Immun 6, 225–230 (2005). https://doi.org/10.1038/sj.gene.6364181

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