Chronic Obstructive Pulmonary Disease Is Associated with Epigenome-Wide Differential Methylation in BAL Lung Cells.
Chronic Obstructive Pulmonary Disease Is Associated with Epigenome-Wide Differential Methylation in BAL Lung Cells.
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慢性阻塞性肺疾病与BAL肺细胞表观基因组差异甲基化有关。
DOI：
10.1165/rcmb.2021-0403oc
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发表时间：
2022-06
影响因子：
6.4
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中科院分区：
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慢性肺阻塞性疾病 (COPD) 中的 DNA 甲基化模式可能为疾病发病机制提供新的见解。为了评估 COPD 主要靶器官的甲基化谱，我们对 BAL 细胞进行了表观基因组范围的关联研究。对 18 名 COPD 受试者和 15 名对照受试者（前吸烟者和当前吸烟者）进行了支气管镜检查。使用 Illumina MmethylationEPIC BeadChip 试剂盒测量 DNA 甲基化，覆盖超过 850,000 个 CpG。检查差异甲基化位置 (DMP) 的 1) 途径和功能基因关系的富集，使用《京都基因和基因组百科全书》和基因本体论，2) 使用 Horvath 的表观遗传时钟加速衰老，3) 与基因表达的相关性，以及 4) 与遗传变异的共定位。我们发现 1,155 个 Bonferroni 显着性 (P < 6.74 × 10−8) DMP 与 COPD 相关，其中许多具有较大的效应量。功能分析确定了生物学上合理的途径和基因关系，包括转录因子活性的富集。 DNA 甲基化与实际年龄之间存在很强的相关性，但 COPD 与加速衰老之间没有相关性。对于 79 种独特的 DMP，DNA 甲基化与 BAL 细胞中的基因表达显着相关。 39% 的 DMP 与 COPD 相关的 SNP 共定位。据我们所知，这是第一个针对 BAL 细胞的 COPD 全表观基因组关联研究，我们的分析揭示了许多差异甲基化位点。与 mRNA 数据的整合显示了相关基因的强大功能读数，识别出 DNA 甲基化可能直接影响表达的位点。几乎一半的 DMP 与之前 COPD 全基因组关联研究中发现的 SNP 位于同一位置，这表明与疾病相关的联合遗传和表观遗传途径。
DNA methylation patterns in chronic pulmonary obstructive disease (COPD) might offer new insights into disease pathogenesis. To assess methylation profiles in the main COPD target organ, we performed an epigenome-wide association study on BAL cells. Bronchoscopies were performed in 18 subjects with COPD and 15 control subjects (ex- and current smokers). DNA methylation was measured using the Illumina MethylationEPIC BeadChip Kit, covering more than 850,000 CpGs. Differentially methylated positions (DMPs) were examined for 1) enrichment in pathways and functional gene relationships using the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology, 2) accelerated aging using Horvath’s epigenetic clock, 3) correlation with gene expression, and 4) colocalization with genetic variation. We found 1,155 Bonferroni-significant (P < 6.74 × 10−8) DMPs associated with COPD, many with large effect sizes. Functional analysis identified biologically plausible pathways and gene relationships, including enrichment for transcription factor activity. Strong correlation was found between DNA methylation and chronological age but not between COPD and accelerated aging. For 79 unique DMPs, DNA methylation correlated significantly with gene expression in BAL cells. Thirty-nine percent of DMPs were colocalized with COPD-associated SNPs. To the best of our knowledge, this is the first epigenome-wide association study of COPD on BAL cells, and our analyses revealed many differential methylation sites. Integration with mRNA data showed a strong functional readout for relevant genes, identifying sites where DNA methylation might directly affect expression. Almost half of DMPs were colocated with SNPs identified in previous genome-wide association studies of COPD, suggesting joint genetic and epigenetic pathways related to disease.