Eriksson Ström Jonas, Kebede Merid Simon, Linder Robert, Pourazar Jamshid, Lindberg Anne, Melén Erik, Behndig Annelie F
Department of Public Health and Clinical Medicine, Section of Medicine, Umeå University, 901 87, Umeå, Sweden.
Department of Clinical Sciences and Education, Karolinska Institutet, Stockholm, Sweden.
Respir Res. 2025 Jan 10;26(1):10. doi: 10.1186/s12931-024-03088-3.
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.
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.
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) and THBS4 (p = 1.11 × 10) 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.
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.
在慢性阻塞性肺疾病（COPD）中，基质金属蛋白酶（MMPs）与其天然抑制剂[金属蛋白酶组织抑制剂（TIMPs）]之间的平衡向过度降解方向转变，这在支气管肺泡灌洗（BAL）中表现为MMP浓度升高。由于MMP活性在肺内稳态中起关键作用，其受到严格调控，但这种调控在多大程度上通过表观遗传机制发生仍不清楚。
为了探究MMPs、TIMPs和DNA甲基化（DNAm）之间的相互作用，我们（1）分析了18例COPD患者和30例对照受试者BAL液中MMP - 9、- 12和TIMP - 1的浓度，并对BAL细胞中的DNAm进行了分析，（2）使用多变量回归估计蛋白质与COPD的关系，（3）在一个单独的相互作用模型中确定以COPD作为潜在修饰因子的蛋白质定量性状甲基化位点（pQTMs），（4）将显著的相互作用与先前的COPD全基因组关联研究（GWAS）荟萃分析进行整合。
COPD与BAL中较高水平的MMP - 12相关（p = 0.016），但与MMP - 9或TIMP - 1无关。对MMP - 12的进一步研究发现其与34个位点的DNAm相关（pQTMs），在前十位pQTM基因中有转化生长因子β受体2（TGFBR2，p = 2.25×10）和血小板反应蛋白4（THBS4，p = 1.11×10）。相互作用模型确定了66个位点，在这些位点上，与对照组相比，COPD中DNAm - MMP - 12的关联存在显著差异。其中一个位点与先前与COPD相关的单核苷酸多态性（SNPs）共定位。
我们的研究结果表明，气道MMP - 12可能部分受表观遗传机制调控，且这种调控在COPD中被破坏。此外，与COPD GWAS数据的整合表明，这种失调受环境因素、疾病过程和遗传学的综合影响，其中遗传学可能起较小作用。
