DNA methylation profiling in human lung tissue identifies genes associated with COPD

Chronic obstructive pulmonary disease (COPD) is a smoking-related disease characterized by genetic and phenotypic heterogeneity. Although association studies have identified multiple genomic regions with replicated associations to COPD, genetic variation only partially explains the susceptibility to lung disease, and suggests the relevance of epigenetic investigations. We performed genome-wide DNA methylation profiling in homogenized lung tissue samples from 46 control subjects with normal lung function and 114 subjects with COPD, all former smokers. The differentially methylated loci were integrated with previous genome-wide association study results. The top 535 differentially methylated sites, filtered for a minimum mean methylation difference of 5% between cases and controls, were enriched for CpG shelves and shores. Pathway analysis revealed enrichment for transcription factors. The top differentially methylated sites from the intersection with previous GWAS were in <i>CHRM1, GLT1D1</i>, and <i>C10orf11</i>; sorted by GWAS <i>P</i>-value, the top sites included <i>FRMD4A, THSD4</i>, and <i>C10orf11</i>. Epigenetic association studies complement genetic association studies to identify genes potentially involved in COPD pathogenesis. Enrichment for genes implicated in asthma and lung function and for transcription factors suggests the potential pathogenic relevance of genes identified through differential methylation and the intersection with a broader range of GWAS associations.

慢性阻塞性肺疾病（Chronic obstructive pulmonary disease, COPD）是一种与吸烟相关的疾病，其特征为遗传与表型异质性。尽管关联研究已鉴定出多个与慢阻肺存在重复验证关联的基因组区域，但遗传变异仅能部分解释该肺部疾病的易感性，这提示表观遗传学研究的必要性。本研究对46名肺功能正常的既往吸烟者对照受试者，以及114名慢阻肺患者的匀化肺组织样本开展了全基因组DNA甲基化谱分析。将差异甲基化位点与既往全基因组关联研究（genome-wide association study, GWAS）结果进行整合：以病例与对照间平均甲基化差异至少5%为筛选标准，最终得到的前535个差异甲基化位点显著富集于CpG岛架（CpG shelves）与CpG岛岸（CpG shores）。通路分析显示其显著富集于转录因子相关通路。与既往GWAS结果取交集得到的Top差异甲基化位点位于CHRM1、GLT1D1及C10orf11基因区域；按GWAS P值排序的Top位点则包括FRMD4A、THSD4及C10orf11。表观遗传学关联研究可作为遗传关联研究的补充，用于鉴定潜在参与慢阻肺发病机制的基因。本研究鉴定的差异甲基化基因及与更多GWAS关联结果取交集得到的基因，显著富集于哮喘、肺功能相关基因及转录因子编码基因，提示这些基因具有潜在的致病相关性。