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A novel tissue inhibitor of metalloproteinase-1 (TIMP-1) polymorphism associated with asthma in Australian women
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  1. F Lose1,2,
  2. P J Thompson1,3,
  3. D Duffy5,
  4. G A Stewart4,
  5. M-A Kedda1,2,3
  1. 1Asthma and Allergy Research Institute and Centre for Asthma, Allergy and Respiratory Research, University of Western Australia, Perth, WA 6009, Australia
  2. 2Western Australian Institute for Medical Research and the Centre for Medical Research, University of Western Australia, Perth, WA 6009, Australia
  3. 3The CRC for Asthma, Australia
  4. 4Microbiology, School of Biomedical and Chemical Sciences, University of Western Australia, Perth, WA 6009, Australia
  5. 5Genetic Epidemiology Laboratory, Queensland Institute of Medical Research, Brisbane, QLD 4006, Australia
  1. Correspondence to:
    A/Prof P J Thompson
    Asthma and Allergy Research Institute, QEII Medical Centre, Nedlands, WA 6009, Australia; aariaari.uwa.edu.au

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.

  • ECM, extracellular matrix
  • EPA, erythroid potentiating activity
  • ESE, exonic splice enhancer
  • HCI, human collagenase inhibitor
  • FEV1, forced expiratory volume in 1 second
  • MMP-9, matrix metalloproteinase-9
  • OR, odds ratio
  • PCR-RFLP, polymerase chain reaction-restriction fragment length polymorphism
  • PCR-SSCP, polymerase chain reaction-single strand conformation polymorphism
  • SFRS2, splicing factor, arginine/serine-rich 2
  • SFRS6, splicing factor, arginine/serine-rich 6
  • SNP, single nucleotide polymorphism
  • TIMP-1, tissue inhibitor of metalloproteinases-1
  • matrix metalloproteinase-9 (MMP-9)
  • tissue inhibitor of metalloproteinases-1 (TIMP-1)
  • asthma
  • polymorphism
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    • [view PDF] - Supplemental figure: Sequence analysis of the novel 536C>T polymorphism.
      i) CC homozygote
      ii) CT heterozygote
      iii) TT homozygote

Footnotes

  • This project was funded by the Asthma and Allergy Research Institute and the National Health and Medical Research Council of Australia

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