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. 2001 Nov;56(11):863–866. doi: 10.1136/thorax.56.11.863

Association of IL-1β and IL-1 receptor antagonist haplotypes with rate of decline in lung function in smokers

L Joos 1, L McIntyre 1, J Ruan 1, J Connett 1, N Anthonisen 1, T Weir 1, P Pare 1, A Sandford 1
PMCID: PMC1745962  PMID: 11641511

Abstract

BACKGROUND—There is increasing evidence that the cytokine network is central to the immunopathology of inflammatory airway diseases. The interleukin 1 (IL-1) receptor antagonist (IL-1RN) is a naturally occurring anti-inflammatory agent that binds to the IL-1 receptor but does not possess agonist activity. Each of the genes of the IL-1 locus on chromosome 2q14 is polymorphic. The IL1RN gene contains an 86 bp tandem repeat and allele 2 of this polymorphism has been associated with various inflammatory diseases. The IL-1β (IL1B) gene contains a promoter polymorphism (C-511T) that has been associated with inflammatory diseases and is in linkage disequilibrium with the IL1RN polymorphism.
METHODS—We investigated whether polymorphisms in the IL1B and IL1RN genes were associated with rate of decline of lung function. Genotypes were determined in 284 smokers with a rapid decline in lung function and 306 smokers with no decline in lung function.
RESULTS—None of the genotypes was associated with the rate of decline of lung function. However, the distribution of IL1B/IL1RN haplotypes was different between smokers with a rapid decline in lung function and those with no decline in lung function (p=0.0005).
CONCLUSION—These results suggest that IL1B/IL1RN haplotypes play a role in the rate of decline in lung function in smokers.



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Selected References

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  1. Abdelaziz M. M., Devalia J. L., Khair O. A., Calderon M., Sapsford R. J., Davies R. J. The effect of conditioned medium from cultured human bronchial epithelial cells on eosinophil and neutrophil chemotaxis and adherence in vitro. Am J Respir Cell Mol Biol. 1995 Dec;13(6):728–737. doi: 10.1165/ajrcmb.13.6.7576711. [DOI] [PubMed] [Google Scholar]
  2. Arend W. P., Malyak M., Guthridge C. J., Gabay C. Interleukin-1 receptor antagonist: role in biology. Annu Rev Immunol. 1998;16:27–55. doi: 10.1146/annurev.immunol.16.1.27. [DOI] [PubMed] [Google Scholar]
  3. Blakemore A. I., Cox A., Gonzalez A. M., Maskil J. K., Hughes M. E., Wilson R. M., Ward J. D., Duff G. W. Interleukin-1 receptor antagonist allele (IL1RN*2) associated with nephropathy in diabetes mellitus. Hum Genet. 1996 Mar;97(3):369–374. doi: 10.1007/BF02185776. [DOI] [PubMed] [Google Scholar]
  4. Blakemore A. I., Tarlow J. K., Cork M. J., Gordon C., Emery P., Duff G. W. Interleukin-1 receptor antagonist gene polymorphism as a disease severity factor in systemic lupus erythematosus. Arthritis Rheum. 1994 Sep;37(9):1380–1385. doi: 10.1002/art.1780370917. [DOI] [PubMed] [Google Scholar]
  5. Blakemore A. I., Watson P. F., Weetman A. P., Duff G. W. Association of Graves' disease with an allele of the interleukin-1 receptor antagonist gene. J Clin Endocrinol Metab. 1995 Jan;80(1):111–115. doi: 10.1210/jcem.80.1.7530255. [DOI] [PubMed] [Google Scholar]
  6. Brandolini L., Sergi R., Caselli G., Boraschi D., Locati M., Sozzani S., Bertini R. Interleukin-1 beta primes interleukin-8-stimulated chemotaxis and elastase release in human neutrophils via its type I receptor. Eur Cytokine Netw. 1997 Jun;8(2):173–178. [PubMed] [Google Scholar]
  7. Connett J. E., Kusek J. W., Bailey W. C., O'Hara P., Wu M. Design of the Lung Health Study: a randomized clinical trial of early intervention for chronic obstructive pulmonary disease. Control Clin Trials. 1993 Apr;14(2 Suppl):3S–19S. doi: 10.1016/0197-2456(93)90021-5. [DOI] [PubMed] [Google Scholar]
  8. Danis V. A., Millington M., Hyland V. J., Grennan D. Cytokine production by normal human monocytes: inter-subject variation and relationship to an IL-1 receptor antagonist (IL-1Ra) gene polymorphism. Clin Exp Immunol. 1995 Feb;99(2):303–310. doi: 10.1111/j.1365-2249.1995.tb05549.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Devlin B., Risch N., Roeder K. Disequilibrium mapping: composite likelihood for pairwise disequilibrium. Genomics. 1996 Aug 15;36(1):1–16. doi: 10.1006/geno.1996.0419. [DOI] [PubMed] [Google Scholar]
  10. Dinarello C. A., Wolff S. M. The role of interleukin-1 in disease. N Engl J Med. 1993 Jan 14;328(2):106–113. doi: 10.1056/NEJM199301143280207. [DOI] [PubMed] [Google Scholar]
  11. Feakes R., Sawcer S., Broadley S., Coraddu F., Roxburgh R., Gray J., Clayton D., Compston A. Interleukin 1 receptor antagonist (IL-1ra) in multiple sclerosis. J Neuroimmunol. 2000 Jun 1;105(1):96–101. doi: 10.1016/s0165-5728(00)00203-4. [DOI] [PubMed] [Google Scholar]
  12. Hurme M., Santtila S. IL-1 receptor antagonist (IL-1Ra) plasma levels are co-ordinately regulated by both IL-1Ra and IL-1beta genes. Eur J Immunol. 1998 Aug;28(8):2598–2602. doi: 10.1002/(SICI)1521-4141(199808)28:08<2598::AID-IMMU2598>3.0.CO;2-K. [DOI] [PubMed] [Google Scholar]
  13. Ishii T., Matsuse T., Teramoto S., Matsui H., Miyao M., Hosoi T., Takahashi H., Fukuchi Y., Ouchi Y. Neither IL-1beta, IL-1 receptor antagonist, nor TNF-alpha polymorphisms are associated with susceptibility to COPD. Respir Med. 2000 Sep;94(9):847–851. doi: 10.1053/rmed.2000.0808. [DOI] [PubMed] [Google Scholar]
  14. Mansfield J. C., Holden H., Tarlow J. K., Di Giovine F. S., McDowell T. L., Wilson A. G., Holdsworth C. D., Duff G. W. Novel genetic association between ulcerative colitis and the anti-inflammatory cytokine interleukin-1 receptor antagonist. Gastroenterology. 1994 Mar;106(3):637–642. doi: 10.1016/0016-5085(94)90696-3. [DOI] [PubMed] [Google Scholar]
  15. Mao X. Q., Kawai M., Yamashita T., Enomoto T., Dake Y., Sasaki S., Kataoka Y., Fukuzumi T., Endo K., Sano H. Imbalance production between interleukin-1beta (IL-1beta) and IL-1 receptor antagonist (IL-1Ra) in bronchial asthma. Biochem Biophys Res Commun. 2000 Sep 24;276(2):607–612. doi: 10.1006/bbrc.2000.3516. [DOI] [PubMed] [Google Scholar]
  16. Nemetz A., Nosti-Escanilla M. P., Molnár T., Köpe A., Kovács A., Fehér J., Tulassay Z., Nagy F., García-González M. A., Peña A. S. IL1B gene polymorphisms influence the course and severity of inflammatory bowel disease. Immunogenetics. 1999 Jun;49(6):527–531. doi: 10.1007/s002510050530. [DOI] [PubMed] [Google Scholar]
  17. Nishimura M., Mizuta I., Mizuta E., Yamasaki S., Ohta M., Kuno S. Influence of interleukin-1beta gene polymorphisms on age-at-onset of sporadic Parkinson's disease. Neurosci Lett. 2000 Apr 21;284(1-2):73–76. doi: 10.1016/s0304-3940(00)00991-5. [DOI] [PubMed] [Google Scholar]
  18. O'Connor G., Sparrow D., Taylor D., Segal M., Weiss S. Analysis of dose-response curves to methacholine. An approach suitable for population studies. Am Rev Respir Dis. 1987 Dec;136(6):1412–1417. doi: 10.1164/ajrccm/136.6.1412. [DOI] [PubMed] [Google Scholar]
  19. Pillay V., Gaillard M. C., Halkas A., Song E., Dewar J. B. Differences in the genotypes and plasma concentrations of the INTERLEUKIN-1 receptor antagonist in black and white South African asthmatics and control subjects. Cytokine. 2000 Jun;12(6):819–821. doi: 10.1006/cyto.1999.0637. [DOI] [PubMed] [Google Scholar]
  20. Pujol J. L., Cosso B., Daurès J. P., Clot J., Michel F. B., Godard P. Interleukin-1 release by alveolar macrophages in asthmatic patients and healthy subjects. Int Arch Allergy Appl Immunol. 1990;91(2):207–210. doi: 10.1159/000235117. [DOI] [PubMed] [Google Scholar]
  21. Santtila S., Savinainen K., Hurme M. Presence of the IL-1RA allele 2 (IL1RN*2) is associated with enhanced IL-1beta production in vitro. Scand J Immunol. 1998 Mar;47(3):195–198. doi: 10.1046/j.1365-3083.1998.00300.x. [DOI] [PubMed] [Google Scholar]
  22. Sousa A. R., Lane S. J., Nakhosteen J. A., Lee T. H., Poston R. N. Expression of interleukin-1 beta (IL-1beta) and interleukin-1 receptor antagonist (IL-1ra) on asthmatic bronchial epithelium. Am J Respir Crit Care Med. 1996 Oct;154(4 Pt 1):1061–1066. doi: 10.1164/ajrccm.154.4.8887608. [DOI] [PubMed] [Google Scholar]
  23. Steinkasserer A., Spurr N. K., Cox S., Jeggo P., Sim R. B. The human IL-1 receptor antagonist gene (IL1RN) maps to chromosome 2q14-q21, in the region of the IL-1 alpha and IL-1 beta loci. Genomics. 1992 Jul;13(3):654–657. doi: 10.1016/0888-7543(92)90137-h. [DOI] [PubMed] [Google Scholar]
  24. Takamatsu M., Yamauchi M., Maezawa Y., Saito S., Maeyama S., Uchikoshi T. Genetic polymorphisms of interleukin-1beta in association with the development of alcoholic liver disease in Japanese patients. Am J Gastroenterol. 2000 May;95(5):1305–1311. doi: 10.1111/j.1572-0241.2000.02030.x. [DOI] [PubMed] [Google Scholar]
  25. Tarlow J. K., Blakemore A. I., Lennard A., Solari R., Hughes H. N., Steinkasserer A., Duff G. W. Polymorphism in human IL-1 receptor antagonist gene intron 2 is caused by variable numbers of an 86-bp tandem repeat. Hum Genet. 1993 May;91(4):403–404. doi: 10.1007/BF00217368. [DOI] [PubMed] [Google Scholar]
  26. Tarlow J. K., Clay F. E., Cork M. J., Blakemore A. I., McDonagh A. J., Messenger A. G., Duff G. W. Severity of alopecia areata is associated with a polymorphism in the interleukin-1 receptor antagonist gene. J Invest Dermatol. 1994 Sep;103(3):387–390. doi: 10.1111/1523-1747.ep12395398. [DOI] [PubMed] [Google Scholar]
  27. Tountas N. A., Casini-Raggi V., Yang H., Di Giovine F. S., Vecchi M., Kam L., Melani L., Pizarro T. T., Rotter J. I., Cominelli F. Functional and ethnic association of allele 2 of the interleukin-1 receptor antagonist gene in ulcerative colitis. Gastroenterology. 1999 Oct;117(4):806–813. doi: 10.1016/s0016-5085(99)70338-0. [DOI] [PubMed] [Google Scholar]
  28. Tsang Y. T., Neelamegham S., Hu Y., Berg E. L., Burns A. R., Smith C. W., Simon S. I. Synergy between L-selectin signaling and chemotactic activation during neutrophil adhesion and transmigration. J Immunol. 1997 Nov 1;159(9):4566–4577. [PubMed] [Google Scholar]
  29. Tsukagoshi H., Sakamoto T., Xu W., Barnes P. J., Chung K. F. Effect of interleukin-1 beta on airway hyperresponsiveness and inflammation in sensitized and nonsensitized Brown-Norway rats. J Allergy Clin Immunol. 1994 Feb;93(2):464–469. doi: 10.1016/0091-6749(94)90355-7. [DOI] [PubMed] [Google Scholar]
  30. Watson M. L., Smith D., Bourne A. D., Thompson R. C., Westwick J. Cytokines contribute to airway dysfunction in antigen-challenged guinea pigs: inhibition of airway hyperreactivity, pulmonary eosinophil accumulation, and tumor necrosis factor generation by pretreatment with an interleukin-1 receptor antagonist. Am J Respir Cell Mol Biol. 1993 Apr;8(4):365–369. doi: 10.1165/ajrcmb/8.4.365. [DOI] [PubMed] [Google Scholar]
  31. Whyte M., Hubbard R., Meliconi R., Whidborne M., Eaton V., Bingle C., Timms J., Duff G., Facchini A., Pacilli A. Increased risk of fibrosing alveolitis associated with interleukin-1 receptor antagonist and tumor necrosis factor-alpha gene polymorphisms. Am J Respir Crit Care Med. 2000 Aug;162(2 Pt 1):755–758. doi: 10.1164/ajrccm.162.2.9909053. [DOI] [PubMed] [Google Scholar]
  32. di Giovine F. S., Takhsh E., Blakemore A. I., Duff G. W. Single base polymorphism at -511 in the human interleukin-1 beta gene (IL1 beta). Hum Mol Genet. 1992 Sep;1(6):450–450. doi: 10.1093/hmg/1.6.450. [DOI] [PubMed] [Google Scholar]

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