Abstract

Background: Matrix metalloproteinase-12 (MMP-12) is increased in bronchoalveolar lavage (BAL) from COPD subjects. Inflammation, oxidative stress, and genetic variation have been suggested to affect MMP-12 expression, but the role of DNA methylation (DNAm) has not been investigated.

Objectives: Our hypothesis was that BAL cell DNAm would be associated with MMP-12 concentrations and that this relationship would be altered in COPD.

Methods: Bronchoscopy with BAL was performed in 18 COPD and 30 control subjects, all recruited from the population-based OLIN COPD study. BAL MMP-12 levels were assayed using enzyme-linked immunosorbent assay kits. DNAm in BAL cells was measured using Illumina?s MethylationEPIC 850k array. The relationship between COPD and MMP-12 wasevaluated using multivariable regression. A protein-epigenome-wide association study was performed to identify CpG-protein associations (protein quantitative trait methylation loci [pQTMs]). COPD was tested as a potential modifier of the DNAm?MMP-12-relationship in an interaction model.

Results: COPD was associated with higher levels of BAL MMP-12 (? = 0.445, p = 0.016). Analysis of CpG-protein associations identified 34 Bonferroni-significant pQTMs. Among the top ten pQTMs, four were annotated genes: LZTS1-AS1, ERO1A, TRMT13, and THBS4. The interaction model found 45 Bonferroni-significant pQTMs.

Discussion: In addition to replicating the finding of increased MMP-12 in COPD airways, our resultsindicate that secretion of MMP-12 might be regulated byepigenetic mechanisms and that this regulation is disrupted in COPD.The genes annotated to the top pQTMs have all previously been implicated in either remodeling of the extracellular matrixor lung disease.