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Research Paper

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

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Pages 730-739 | Received 06 Jul 2016, Accepted 10 Aug 2016, Published online: 01 Nov 2016
 

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 P-value, 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.

Disclosure of potential conflicts of interest

Drs. Morrow, DeMeo, Cho, Pinto-Plata, Celli, Marchetti, Criner, Bueno, Glass, Quackenbush, and Choi report no competing interests related to this manuscript. Dr. Washko has been a consultant for GSK, Genentech, Emmes, PulmonX. Dr. Hersh has been a consultant for CSL Behring and Mylan. Dr. Silverman has received honoraria and consulting fees from Merck, grant support and consulting fees from GlaxoSmithKline, and honoraria from Novartis.

Acknowledgments

We thank Drs. Amund Gulsvik, Per Bakke, Augusto Litonjua, Pantel Vokonas, Ruth Tal-Singer, and the GenKOLS, NETT/NAS, ECLIPSE, and COPDGene studies for use of their GWAS meta-analysis data.

Funding

NIH grants P01 HL105339, R01 HL111759, P01 HL114501. The COPDGene study (R01 HL089856 and R01 HL089897). (NCT00608764) was funded by the National Institutes of Health is also sup- 460 ported by the COPD Foundation through contributions made to an Industry Advisory Board comprised of AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer, Siemens, GSK and Sunovion. The National Emphysema Treatment Trial was supported by the NHLBI N01HR76101, N01HR76102, N01HR76103, N01HR76104, N01HR76105, N01HR76106, N01HR76107, N01HR76108, 465 N01HR76109, N01HR76110, N01HR76111, N01HR76112, N01HR76113, N01HR76114, N01HR76115, N01HR76116, N01HR76118 and N01HR76119, the Centers for Medicare and Medicaid Services and the Agency for Healthcare Research and Quality. The Normative Aging Study is supported by the Cooperative Studies Program/ERIC of the US 470 Department of Veterans Affairs and is a component of the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC). The Norway GenKOLS study (Genetics of Chronic Obstructive Lung Disease, GSK code RES11080), the ECLIPSE study (NCT00292552; GSK code SCO104960), and the ICGN study were funded by GlaxoSmithKline.

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