Integrative Epidemiology Group, Department of Chronic Diseases Epidemiology, National Center for Epidemiology, Carlos III Health Institute, 28029, Madrid, Spain.
Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, USA.
Clin Epigenetics. 2022 Jun 9;14(1):75. doi: 10.1186/s13148-022-01294-8.
Epigenetic modifications, including DNA methylation (DNAm), are often related to environmental exposures, and are increasingly recognized as key processes in the pathogenesis of chronic lung disease. American Indian communities have a high burden of lung disease compared to the national average. The objective of this study was to investigate the association of DNAm and lung function in the Strong Heart Study (SHS). We conducted a cross-sectional study of American Indian adults, 45-74 years of age who participated in the SHS. DNAm was measured using the Illumina Infinium Human MethylationEPIC platform at baseline (1989-1991). Lung function was measured via spirometry, including forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC), at visit 2 (1993-1995). Airflow limitation was defined as FEV1 < 70% predicted and FEV1/FVC < 0.7, restriction was defined as FEV1/FVC > 0.7 and FVC < 80% predicted, and normal spirometry was defined as FEV1/FVC > 0.7, FEV1 > 70% predicted, FVC > 80% predicted. We used elastic-net models to select relevant CpGs for lung function and spirometry-defined lung disease. We also conducted bioinformatic analyses to evaluate the biological plausibility of the findings.
Among 1677 participants, 21.2% had spirometry-defined airflow limitation and 13.6% had spirometry-defined restrictive pattern lung function. Elastic-net models selected 1118 Differentially Methylated Positions (DMPs) as predictors of airflow limitation and 1385 for restrictive pattern lung function. A total of 12 DMPs overlapped between airflow limitation and restrictive pattern. EGFR, MAPK1 and PRPF8 genes were the most connected nodes in the protein-protein interaction network. Many of the DMPs targeted genes with biological roles related to lung function such as protein kinases.
We found multiple differentially methylated CpG sites associated with chronic lung disease. These signals could contribute to better understand molecular mechanisms involved in lung disease, as assessed systemically, as well as to identify patterns that could be useful for diagnostic purposes. Further experimental and longitudinal studies are needed to assess whether DNA methylation has a causal role in lung disease.
表观遗传修饰，包括 DNA 甲基化（DNAm），通常与环境暴露有关，并且越来越被认为是慢性肺部疾病发病机制中的关键过程。与全国平均水平相比，美洲印第安人社区的肺部疾病负担较高。本研究的目的是调查 Strong Heart 研究（SHS）中 DNAm 与肺功能的关系。我们对参加 SHS 的 45-74 岁的美洲印第安成年人进行了横断面研究。在基线（1989-1991 年）使用 Illumina Infinium Human MethylationEPIC 平台测量 DNAm。在第二次就诊（1993-1995 年）时通过肺活量测定法测量肺功能，包括 1 秒用力呼气量（FEV1）和用力肺活量（FVC）。气流受限定义为 FEV1<70%预计值和 FEV1/FVC<0.7，限制定义为 FEV1/FVC>0.7 和 FVC<80%预计值，正常肺活量测定法定义为 FEV1/FVC>0.7，FEV1>70%预计值，FVC>80%预计值。我们使用弹性网络模型选择与肺功能和肺活量测定法定义的肺部疾病相关的相关 CpG。我们还进行了生物信息学分析，以评估研究结果的生物学合理性。
在 1677 名参与者中，21.2%的人有肺活量测定法定义的气流受限，13.6%的人有肺活量测定法定义的限制性肺功能模式。弹性网络模型选择了 1118 个差异甲基化位置（DMP）作为气流受限的预测因子，选择了 1385 个作为限制性肺功能模式的预测因子。气流受限和限制性模式之间共有 12 个 DMP 重叠。EGFR、MAPK1 和 PRPF8 基因是蛋白质-蛋白质相互作用网络中最相关的节点。许多 DMP 靶向与肺功能相关的生物作用的基因，例如蛋白激酶。
我们发现了多个与慢性肺部疾病相关的差异甲基化 CpG 位点。这些信号可能有助于更好地了解系统性评估中肺部疾病涉及的分子机制，以及识别可能对诊断有用的模式。需要进一步的实验和纵向研究来评估 DNA 甲基化是否在肺部疾病中具有因果关系。
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