Epidemiology Branch.
Department of Ophthalmology, University of Massachusetts Medical School, Worcester, Massachusetts.
Am J Respir Crit Care Med. 2022 Aug 1;206(3):321-336. doi: 10.1164/rccm.202108-1907OC.
Methylation integrates factors present at birth and modifiable across the lifespan that can influence pulmonary function. Studies are limited in scope and replication. To conduct large-scale epigenome-wide meta-analyses of blood DNA methylation and pulmonary function. Twelve cohorts analyzed associations of methylation at cytosine-phosphate-guanine probes (CpGs), using Illumina 450K or EPIC/850K arrays, with FEV, FVC, and FEV/FVC. We performed multiancestry epigenome-wide meta-analyses (total of 17,503 individuals; 14,761 European, 2,549 African, and 193 Hispanic/Latino ancestries) and interpreted results using integrative epigenomics. We identified 1,267 CpGs (1,042 genes) differentially methylated (false discovery rate, <0.025) in relation to FEV, FVC, or FEV/FVC, including 1,240 novel and 73 also related to chronic obstructive pulmonary disease (1,787 cases). We found 294 CpGs unique to European or African ancestry and 395 CpGs unique to never or ever smokers. The majority of significant CpGs correlated with nearby gene expression in blood. Findings were enriched in key regulatory elements for gene function, including accessible chromatin elements, in both blood and lung. Sixty-nine implicated genes are targets of investigational or approved drugs. One example novel gene highlighted by integrative epigenomic and druggable target analysis is Mendelian randomization and colocalization analyses suggest that epigenome-wide association study signals capture causal regulatory genomic loci. We identified numerous novel loci differentially methylated in relation to pulmonary function; few were detected in large genome-wide association studies. Integrative analyses highlight functional relevance and potential therapeutic targets. This comprehensive discovery of potentially modifiable, novel lung function loci expands knowledge gained from genetic studies, providing insights into lung pathogenesis.
甲基化整合了出生时存在且可在整个生命周期中改变的因素，这些因素可能会影响肺功能。研究的范围和复制性有限。进行大规模的全基因组血液 DNA 甲基化与肺功能的元分析。分析了 12 个队列中胞嘧啶-磷酸-鸟嘌呤探针（CpG）的甲基化与 FEV、FVC 和 FEV/FVC 的相关性，使用了 Illumina 450K 或 EPIC/850K 芯片。我们进行了多祖先全基因组元分析（总共 17503 人；14761 名欧洲人、2549 名非洲人、193 名西班牙裔/拉丁裔），并使用综合表观基因组学来解释结果。我们确定了 1267 个 CpG（1042 个基因）在与 FEV、FVC 或 FEV/FVC 相关的情况下发生了差异甲基化（错误发现率<0.025），其中包括 1240 个新的和 73 个与慢性阻塞性肺疾病（1787 例）也相关的 CpG。我们发现了 294 个仅存在于欧洲或非洲血统中的 CpG 和 395 个仅存在于从不或曾经吸烟者中的 CpG。大多数显著的 CpG 与血液中附近基因的表达相关。在血液和肺部中，关键的基因功能调节元件（包括可及染色质元件）中富集了发现的 CpG。有 69 个受牵连的基因是研究性或批准药物的靶点。一个通过综合表观基因组学和可用药靶点分析突出的新基因是 Mendelian randomization 和 colocalization 分析表明，全基因组关联研究信号捕获了因果调节基因组位点。我们确定了许多与肺功能相关的新型差异甲基化的新基因座；在大型全基因组关联研究中很少检测到这些基因座。综合分析突出了功能相关性和潜在的治疗靶点。这一全面发现潜在的可修饰的、新的肺功能基因座，扩展了从遗传研究中获得的知识，为肺发病机制提供了新的见解。
