Pulmonary Function and Blood DNA Methylation: A Multiancestry Epigenome-Wide Association Meta-analysis.
Pulmonary Function and Blood DNA Methylation: A Multiancestry Epigenome-Wide Association Meta-analysis.
复制标题
DOI：
10.1164/rccm.202108-1907oc
复制
发表时间：
2022-08-01
影响因子：
24.7
通讯作者：
中科院分区：
文献类型：
--
作者：
甲基化整合了出生时存在且在整个生命周期中可改变的、能够影响肺功能的因素。研究在范围和重复性方面存在局限。
对血液DNA甲基化和肺功能进行大规模全表观基因组的荟萃分析。
12个队列使用Illumina 450K或EPIC/850K芯片分析了胞嘧啶 - 磷酸 - 鸟嘌呤探针（CpGs）的甲基化与第一秒用力呼气容积（FEV1）、用力肺活量（FVC）以及FEV1/FVC的关联。我们进行了多血统全表观基因组的荟萃分析（共17503人；14761名欧洲人、2549名非洲人以及193名西班牙裔/拉丁裔血统），并使用整合表观基因组学来解释结果。
我们确定了1267个CpGs（1042个基因）在与FEV1、FVC或FEV1/FVC相关方面存在差异甲基化（错误发现率<0.025），包括1240个新的以及73个也与慢性阻塞性肺疾病相关的（1787例）。我们发现294个CpGs为欧洲或非洲血统所特有，395个CpGs为从不吸烟者或曾经吸烟者所特有。大多数显著的CpGs与血液中附近基因的表达相关。研究结果在血液和肺中都富集于基因功能的关键调控元件，包括可接近的染色质元件。69个相关基因是研究性或已批准药物的靶点。通过整合表观基因组学和可成药靶点分析突出的一个新基因示例是TNFRSF4。孟德尔随机化和共定位分析表明，全表观基因组关联研究信号捕捉到了因果调控的基因组位点。
我们确定了许多与肺功能相关的差异甲基化的新位点；在大型全基因组关联研究中很少能检测到这些位点。整合分析突出了功能相关性和潜在的治疗靶点。对潜在可改变的新型肺功能位点的这一全面发现扩展了从遗传学研究中获得的知识，为肺部发病机制提供了见解。
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 FEV1, FVC, and FEV1/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 FEV1, FVC, or FEV1/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 TNFRSF4. 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.