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Airway MMP-12 and DNA methylation in COPD : an integrative approach

Eriksson Ström, Jonas ; Kebede Merid, Simon ; Linder, Robert LU orcid ; Pourazar, Jamshid ; Lindberg, Anne ; Melén, Erik and Behndig, Annelie F. (2025) In Respiratory Research 26. p.1-12
Abstract

Background: In COPD, the balance between matrix metalloproteinases (MMPs) and their natural inhibitors [tissue inhibitors of metalloproteinases (TIMPs)] is shifted towards excessive degradation, reflected in bronchoalveolar lavage (BAL) as increased MMP concentrations. Because of their critical role in lung homeostasis, MMP activity is tightly regulated, but to what extent this regulation occurs through epigenetic mechanisms remains unknown. Methods: To explore the interplay between MMPs, TIMPs, and DNA methylation (DNAm) we (1) analysed MMP-9, -12, and TIMP-1 concentrations in BAL fluid, and profiled DNAm in BAL cells from 18 COPD and 30 control subjects, (2) estimated protein–COPD relationships using multivariable regression, (3)... (More)

Background: In COPD, the balance between matrix metalloproteinases (MMPs) and their natural inhibitors [tissue inhibitors of metalloproteinases (TIMPs)] is shifted towards excessive degradation, reflected in bronchoalveolar lavage (BAL) as increased MMP concentrations. Because of their critical role in lung homeostasis, MMP activity is tightly regulated, but to what extent this regulation occurs through epigenetic mechanisms remains unknown. Methods: To explore the interplay between MMPs, TIMPs, and DNA methylation (DNAm) we (1) analysed MMP-9, -12, and TIMP-1 concentrations in BAL fluid, and profiled DNAm in BAL cells from 18 COPD and 30 control subjects, (2) estimated protein–COPD relationships using multivariable regression, (3) identified protein quantitative trait methylation loci (pQTMs) with COPD as a potential modifier in a separate interaction model, and (4) integrated significant interactions with a previous COPD GWAS meta-analysis. Results: COPD was associated with higher levels of BAL MMP-12 (p = 0.016) but not with MMP-9 or TIMP-1. Further examination of MMP-12 identified association with DNAm at 34 loci (pQTMs), with TGFBR2 (p = 2.25 × 10–10) and THBS4 (p = 1.11 × 10–9) among the top ten pQTM genes. The interaction model identified 66 sites where the DNAm–MMP-12 association was significantly different in COPD compared to controls. Of these, one was colocalized with SNPs previously associated with COPD. Conclusions: Our findings indicate that airway MMP-12 may partially be regulated by epigenetic mechanisms and that this regulation is disrupted in COPD. Furthermore, integration with COPD GWAS data suggests that this dysregulation is influenced by a combination of environmental factors, disease processes, and genetics, with the latter potentially playing a lesser role.

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publishing date
type
Contribution to journal
publication status
published
subject
keywords
Bronchoscopy, Chronic obstructive pulmonary disease (COPD), DNA methylation, Extracellular matrix remodelling, Matrix metalloproteinases (MMPs), Multiomics, Chronic obstructive pulmonary disease (COPD), KOL, DNA Methylation, DNA metylering, Matrix metalloproteases, metalloproteinaser, Extracellular matrix remodelling, remodellering av extracellulärmatrix, Multiomics, multiomik, Bronchoscopy, bronkoskopi
in
Respiratory Research
volume
26
article number
10
pages
1 - 12
publisher
BioMed Central (BMC)
external identifiers
  • scopus:85215351109
  • pmid:39794761
ISSN
1465-9921
DOI
10.1186/s12931-024-03088-3
language
English
LU publication?
no
additional info
Publisher Copyright: © The Author(s) 2025.
id
ecb8973e-850d-429f-8c96-49d41b544bbd
date added to LUP
2025-05-16 10:27:24
date last changed
2025-07-11 14:45:28
@article{ecb8973e-850d-429f-8c96-49d41b544bbd,
  abstract     = {{<p>Background: In COPD, the balance between matrix metalloproteinases (MMPs) and their natural inhibitors [tissue inhibitors of metalloproteinases (TIMPs)] is shifted towards excessive degradation, reflected in bronchoalveolar lavage (BAL) as increased MMP concentrations. Because of their critical role in lung homeostasis, MMP activity is tightly regulated, but to what extent this regulation occurs through epigenetic mechanisms remains unknown. Methods: To explore the interplay between MMPs, TIMPs, and DNA methylation (DNAm) we (1) analysed MMP-9, -12, and TIMP-1 concentrations in BAL fluid, and profiled DNAm in BAL cells from 18 COPD and 30 control subjects, (2) estimated protein–COPD relationships using multivariable regression, (3) identified protein quantitative trait methylation loci (pQTMs) with COPD as a potential modifier in a separate interaction model, and (4) integrated significant interactions with a previous COPD GWAS meta-analysis. Results: COPD was associated with higher levels of BAL MMP-12 (p = 0.016) but not with MMP-9 or TIMP-1. Further examination of MMP-12 identified association with DNAm at 34 loci (pQTMs), with TGFBR2 (p = 2.25 × 10<sup>–10</sup>) and THBS4 (p = 1.11 × 10<sup>–9</sup>) among the top ten pQTM genes. The interaction model identified 66 sites where the DNAm–MMP-12 association was significantly different in COPD compared to controls. Of these, one was colocalized with SNPs previously associated with COPD. Conclusions: Our findings indicate that airway MMP-12 may partially be regulated by epigenetic mechanisms and that this regulation is disrupted in COPD. Furthermore, integration with COPD GWAS data suggests that this dysregulation is influenced by a combination of environmental factors, disease processes, and genetics, with the latter potentially playing a lesser role.</p>}},
  author       = {{Eriksson Ström, Jonas and Kebede Merid, Simon and Linder, Robert and Pourazar, Jamshid and Lindberg, Anne and Melén, Erik and Behndig, Annelie F.}},
  issn         = {{1465-9921}},
  keywords     = {{Bronchoscopy; Chronic obstructive pulmonary disease (COPD); DNA methylation; Extracellular matrix remodelling; Matrix metalloproteinases (MMPs); Multiomics; Chronic obstructive pulmonary disease (COPD); KOL; DNA Methylation; DNA metylering; Matrix metalloproteases; metalloproteinaser; Extracellular matrix remodelling; remodellering av extracellulärmatrix; Multiomics; multiomik; Bronchoscopy; bronkoskopi}},
  language     = {{eng}},
  pages        = {{1--12}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Respiratory Research}},
  title        = {{Airway MMP-12 and DNA methylation in COPD : an integrative approach}},
  url          = {{http://dx.doi.org/10.1186/s12931-024-03088-3}},
  doi          = {{10.1186/s12931-024-03088-3}},
  volume       = {{26}},
  year         = {{2025}},
}