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

Abstract

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 CHRM1, GLT1D1, and C10orf11; sorted by GWAS Pvalue, the top sites included FRMD4A, THSD4, and C10orf11. 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.

Regulation of MUC5B Expression in Idiopathic Pulmonary Fibrosis

“…Epigenetic alterations are associated with a wide variety of diseases including cancers (reviewed in [224]), imprinting disorders [225], and more recently lung diseases [226,227]. IPF is associated with genome-wide changes in chromatin structure [228][229][230] and DNA methylation [231][232][233][234][235].…”

Genetic polymorphism and chronic obstructive pulmonary disease

“…In skeletal muscle, it mainly reduces muscle tissue by inhibiting the differentiation of muscle satellite cells and thus increases the incidence of COPD. The study of Morrow et al on DNA methylation in COPD patients showed that the loci of differential methylation were located in CHRM1, GLT1D1 and C10 or f11, and if they were ranked by GWAS P -value, the top loci included FRMD4A, THSD4 and C10 or f11 57. In the process of muscle development, microRNAs (miRNAs) play an important role, and many miRNAs are tissue-specific, and miR-1, miR-133 and miR-206 are abundant in skeletal muscle.…”

Identification of novel differentially methylated sites with potential as clinical predictors of impaired respiratory function and COPD

“…The results of previous epigenome-wide association studies (EWASs) of spirometric measures of respiratory function and respiratory disease have produced inconsistent results, with some identifying significant associations, [3][4][5][6] and others not. [7][8][9] Moreover, there has been little consistency between the positive findings reported.…”

“…[7][8][9] Moreover, there has been little consistency between the positive findings reported. 9,10 Studies of lung tissue 5,8 have been constrained by sample availability, with the largest study to date comprising 160 subjects. 5 Inconsistency amongst the results of the peripheral bloodbased studies 3,6,7,9,11 is likely to be due to a number of factors, including small sample size (e.g., two studies had less than 200 samples) 6,11 and/or investigation of a relatively small number (~27,000) of CpG loci.…”

“…9,10 Studies of lung tissue 5,8 have been constrained by sample availability, with the largest study to date comprising 160 subjects. 5 Inconsistency amongst the results of the peripheral bloodbased studies 3,6,7,9,11 is likely to be due to a number of factors, including small sample size (e.g., two studies had less than 200 samples) 6,11 and/or investigation of a relatively small number (~27,000) of CpG loci. 3,11 The study with the largest number of samples (n=1,085) analysed only 27,000 CpG loci, while the largest study using the 450K array (the predecessor to the array used here) analysed 920 samples.…”