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. 2005 Aug;60(8):623–628. doi: 10.1136/thx.2004.026930

A novel tissue inhibitor of metalloproteinase-1 (TIMP-1) polymorphism associated with asthma in Australian women

F Lose 1, P Thompson 1, D Duffy 1, G Stewart 1, M Kedda 1
PMCID: PMC1747496  PMID: 16061701

Abstract

Background: Airway remodelling is a characteristic feature of chronic asthma and there is evidence that an airway imbalance between levels of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinases-1 (TIMP-1) is associated with airway remodelling. On this basis, we hypothesised that polymorphisms in the MMP-9 and TIMP-1 genes were associated with the disease process.

Methods: A number of MMP-9 and TIMP-1 gene polymorphisms were examined in an adult white Australian population of mild (n = 259), moderate (n = 213) and severe (n = 71) asthmatics and non-asthmatic controls (n = 406) using PCR-RFLP and PCR-SSCP analyses.

Results: MMP-9 –1562C>T and 836G>A (Arg279Gln) were not associated with asthma (p⩾0.15) or asthma severity (p⩾0.13), and TIMP-1 434T>C (Phe124Phe) was not associated with asthma in women (p = 0.094) or men (p = 0.207). In this population, MMP-9 –861C>T and TIMP-1 323C>T (Pro87Pro) were not informative (with minor allele frequencies of <1%), and MMP-9 –1702T>A and TIMP-1 595C>T (Ser178Phe) were not detectable. However, a novel polymorphism was detected in the TIMP-1 gene 536C>T (Ile158Ile) which was significantly associated with asthma in women (p = 0.011; OR = 5.54, 95% CI 1.66 to 34.4) but not in men (p = 1.0). 536C>T was found to be in linkage disequilibrium with 434T>C, and haplotype analysis supported an association with asthma (p = 0.014).

Conclusions: This is the first reported association between a polymorphism in the TIMP-1 gene and asthma, and supports the hypothesis that the protease/antiprotease balance has an important role in this common disease.

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Selected References

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  1. Belleguic C., Corbel M., Germain N., Léna H., Boichot E., Delaval P. H., Lagente V. Increased release of matrix metalloproteinase-9 in the plasma of acute severe asthmatic patients. Clin Exp Allergy. 2002 Feb;32(2):217–223. doi: 10.1046/j.1365-2222.2002.01219.x. [DOI] [PubMed] [Google Scholar]
  2. Blencowe B. J. Exonic splicing enhancers: mechanism of action, diversity and role in human genetic diseases. Trends Biochem Sci. 2000 Mar;25(3):106–110. doi: 10.1016/s0968-0004(00)01549-8. [DOI] [PubMed] [Google Scholar]
  3. Cartegni Luca, Chew Shern L., Krainer Adrian R. Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat Rev Genet. 2002 Apr;3(4):285–298. doi: 10.1038/nrg775. [DOI] [PubMed] [Google Scholar]
  4. Cartegni Luca, Wang Jinhua, Zhu Zhengwei, Zhang Michael Q., Krainer Adrian R. ESEfinder: A web resource to identify exonic splicing enhancers. Nucleic Acids Res. 2003 Jul 1;31(13):3568–3571. doi: 10.1093/nar/gkg616. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cataldo Didier D., Bettiol Jane, Noël Agnes, Bartsch Pierre, Foidart Jean-Michel, Louis Renaud. Matrix metalloproteinase-9, but not tissue inhibitor of matrix metalloproteinase-1, increases in the sputum from allergic asthmatic patients after allergen challenge. Chest. 2002 Nov;122(5):1553–1559. doi: 10.1378/chest.122.5.1553. [DOI] [PubMed] [Google Scholar]
  6. Cataldo Didier D., Tournoy Kurt G., Vermaelen Karim, Munaut Carine, Foidart Jean-Michel, Louis Renaud, Noël Agnès, Pauwels Romain A. Matrix metalloproteinase-9 deficiency impairs cellular infiltration and bronchial hyperresponsiveness during allergen-induced airway inflammation. Am J Pathol. 2002 Aug;161(2):491–498. doi: 10.1016/S0002-9440(10)64205-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Colapietro Patrizia, Gervasini Cristina, Natacci Federica, Rossi Livia, Riva Paola, Larizza Lidia. NF1 exon 7 skipping and sequence alterations in exonic splice enhancers (ESEs) in a neurofibromatosis 1 patient. Hum Genet. 2003 Sep 6;113(6):551–554. doi: 10.1007/s00439-003-1009-2. [DOI] [PubMed] [Google Scholar]
  8. Dudbridge Frank. Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol. 2003 Sep;25(2):115–121. doi: 10.1002/gepi.10252. [DOI] [PubMed] [Google Scholar]
  9. Hollá L. I., Vasků A., Stejskalová A., Znojil V. Functional polymorphism in the gelatinase B gene and asthma. Allergy. 2000 Sep;55(9):900–901. doi: 10.1034/j.1398-9995.2000.00736.x. [DOI] [PubMed] [Google Scholar]
  10. Hoshino M., Nakamura Y., Sim J., Shimojo J., Isogai S. Bronchial subepithelial fibrosis and expression of matrix metalloproteinase-9 in asthmatic airway inflammation. J Allergy Clin Immunol. 1998 Nov;102(5):783–788. doi: 10.1016/s0091-6749(98)70018-1. [DOI] [PubMed] [Google Scholar]
  11. Kedda Mary-Anne, Shi Jing, Duffy David, Phelps Stephanie, Yang Ian, O'Hara Kirrily, Fong Kwun, Thompson Philip J. Characterization of two polymorphisms in the leukotriene C4 synthase gene in an Australian population of subjects with mild, moderate, and severe asthma. J Allergy Clin Immunol. 2004 May;113(5):889–895. doi: 10.1016/j.jaci.2004.02.008. [DOI] [PubMed] [Google Scholar]
  12. Kelly E. A., Busse W. W., Jarjour N. N. Increased matrix metalloproteinase-9 in the airway after allergen challenge. Am J Respir Crit Care Med. 2000 Sep;162(3 Pt 1):1157–1161. doi: 10.1164/ajrccm.162.3.9908016. [DOI] [PubMed] [Google Scholar]
  13. Krawczak M., Reiss J., Cooper D. N. The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences. Hum Genet. 1992 Sep-Oct;90(1-2):41–54. doi: 10.1007/BF00210743. [DOI] [PubMed] [Google Scholar]
  14. Krämer Franziska, Mohr Nicole, Kellner Ulrich, Rudolph Günther, Weber Bernhard H. F. Ten novel mutations in VMD2 associated with Best macular dystrophy (BMD). Hum Mutat. 2003 Nov;22(5):418–418. doi: 10.1002/humu.9189. [DOI] [PubMed] [Google Scholar]
  15. Mattos Waldo, Lim Sam, Russell Richard, Jatakanon Anon, Chung K. Fan, Barnes Peter J. Matrix metalloproteinase-9 expression in asthma: effect of asthma severity, allergen challenge, and inhaled corticosteroids. Chest. 2002 Nov;122(5):1543–1552. doi: 10.1378/chest.122.5.1543. [DOI] [PubMed] [Google Scholar]
  16. Mautino G., Capony F., Bousquet J., Vignola A. M. Balance in asthma between matrix metalloproteinases and their inhibitors. J Allergy Clin Immunol. 1999 Sep;104(3 Pt 1):530–533. doi: 10.1016/s0091-6749(99)70319-2. [DOI] [PubMed] [Google Scholar]
  17. Minematsu N., Nakamura H., Tateno H., Nakajima T., Yamaguchi K. Genetic polymorphism in matrix metalloproteinase-9 and pulmonary emphysema. Biochem Biophys Res Commun. 2001 Nov 23;289(1):116–119. doi: 10.1006/bbrc.2001.5936. [DOI] [PubMed] [Google Scholar]
  18. Murphy G., Willenbrock F. Tissue inhibitors of matrix metalloendopeptidases. Methods Enzymol. 1995;248:496–510. doi: 10.1016/0076-6879(95)48032-3. [DOI] [PubMed] [Google Scholar]
  19. Oshita Y., Koga T., Kamimura T., Matsuo K., Rikimaru T., Aizawa H. Increased circulating 92 kDa matrix metalloproteinase (MMP-9) activity in exacerbations of asthma. Thorax. 2003 Sep;58(9):757–760. doi: 10.1136/thorax.58.9.757. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Pöllänen P. J., Karhunen P. J., Mikkelsson J., Laippala P., Perola M., Penttilä A., Mattila K. M., Koivula T., Lehtimäki T. Coronary artery complicated lesion area is related to functional polymorphism of matrix metalloproteinase 9 gene: an autopsy study. Arterioscler Thromb Vasc Biol. 2001 Sep;21(9):1446–1450. doi: 10.1161/hq0901.095545. [DOI] [PubMed] [Google Scholar]
  21. Stetler-Stevenson W. G., Krutzsch H. C., Wacher M. P., Margulies I. M., Liotta L. A. The activation of human type IV collagenase proenzyme. Sequence identification of the major conversion product following organomercurial activation. J Biol Chem. 1989 Jan 25;264(3):1353–1356. [PubMed] [Google Scholar]
  22. Vignola A. M., Riccobono L., Mirabella A., Profita M., Chanez P., Bellia V., Mautino G., D'accardi P., Bousquet J., Bonsignore G. Sputum metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio correlates with airflow obstruction in asthma and chronic bronchitis. Am J Respir Crit Care Med. 1998 Dec;158(6):1945–1950. doi: 10.1164/ajrccm.158.6.9803014. [DOI] [PubMed] [Google Scholar]
  23. Wang X., Tromp G., Cole C. W., Verloes A., Sakalihasan N., Yoon S., Kuivaniemi H. Analysis of coding sequences for tissue inhibitor of metalloproteinases 1 (TIMP1) and 2 (TIMP2) in patients with aneurysms. Matrix Biol. 1999 Apr;18(2):121–124. doi: 10.1016/s0945-053x(99)00008-6. [DOI] [PubMed] [Google Scholar]
  24. Wenzel Sally E., Balzar Silvana, Cundall Meghan, Chu Hong Wei. Subepithelial basement membrane immunoreactivity for matrix metalloproteinase 9: association with asthma severity, neutrophilic inflammation, and wound repair. J Allergy Clin Immunol. 2003 Jun;111(6):1345–1352. doi: 10.1067/mai.2003.1464. [DOI] [PubMed] [Google Scholar]
  25. Zhang B., Henney A., Eriksson P., Hamsten A., Watkins H., Ye S. Genetic variation at the matrix metalloproteinase-9 locus on chromosome 20q12.2-13.1. Hum Genet. 1999 Nov;105(5):418–423. doi: 10.1007/s004390051124. [DOI] [PubMed] [Google Scholar]
  26. Zhang B., Ye S., Herrmann S. M., Eriksson P., de Maat M., Evans A., Arveiler D., Luc G., Cambien F., Hamsten A. Functional polymorphism in the regulatory region of gelatinase B gene in relation to severity of coronary atherosclerosis. Circulation. 1999 Apr 13;99(14):1788–1794. doi: 10.1161/01.cir.99.14.1788. [DOI] [PubMed] [Google Scholar]

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