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

Publisher: BioMed Central Ltd Country of Publication: England NLM ID: 101090633 Publication Model: Electronic Cited Medium: Internet ISSN: 1465-993X (Electronic) Linking ISSN: 14659921 NLM ISO Abbreviation: Respir Res Subsets: MEDLINE

Publication: 2001- : London : BioMed Central Ltd.
Original Publication: London : Current Science Ltd., c2000-

Pulmonary Disease, Chronic Obstructive*/genetics ; Pulmonary Disease, Chronic Obstructive*/metabolism ; Pulmonary Disease, Chronic Obstructive*/enzymology ; Matrix Metalloproteinase 12*/genetics ; Matrix Metalloproteinase 12*/metabolism ; Matrix Metalloproteinase 12*/biosynthesis ; DNA Methylation*; Humans ; Male ; Female ; Middle Aged ; Aged ; Bronchoalveolar Lavage Fluid/chemistry ; Tissue Inhibitor of Metalloproteinase-1/genetics ; Tissue Inhibitor of Metalloproteinase-1/metabolism ; Epigenesis, Genetic ; Genome-Wide Association Study/methods

Competing Interests: Declarations. Ethics approval and consent to participate: Informed consent was obtained from all volunteers after verbal and written information. The Ethics Committee at Umeå University, Sweden, granted approval for the study; registration number 2011-147-31M (original study) and 2017-91-32M (additional approval for DNA methylation measurement). The study was performed in accordance with the Declaration of Helsinki. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.
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.
(© 2025. The Author(s).)

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Keywords: Bronchoscopy; Chronic obstructive pulmonary disease (COPD); DNA methylation; Extracellular matrix remodelling; Matrix metalloproteinases (MMPs); Multiomics

EC 3.4.24.65 (Matrix Metalloproteinase 12)
EC 3.4.24.65 (MMP12 protein, human)
0 (Tissue Inhibitor of Metalloproteinase-1)
0 (TIMP1 protein, human)

Date Created: 20250110 Date Completed: 20250110 Latest Revision: 20250113

20250113

PMC11724436

10.1186/s12931-024-03088-3

39794761