Variable DNA Methylation Is Associated with Chronic Obstructive Pulmonary Disease and Lung Function

Abstract

Rationale: Chronic obstructive pulmonary disease (COPD) is associated with local (lung) and systemic (blood) inflammation and manifestations. DNA methylation is an important regulator of gene transcription, and global and specific gene methylation marks may vary with cigarette smoke exposure. Objectives: To perform a comprehensive assessment of methylation marks in DNA from subjects well phenotyped for nonneoplastic lung disease. Methods: We conducted array-based methylation screens, using a test-replication approach, in two family-based cohorts (n ¼ 1,085 and 369 subjects). Measurements and Main Results: We observed 349 CpG sites significantly associated with the presence and severity of COPD in both cohorts. Seventy percent of the associated CpG sites were outside of CpG islands, with the majority of CpG sites relatively hypomethylated. Gene ontology analysis based on these 349 CpGs (330 genes) suggested the involvement of a number of genes responsible for immune and inflammatory system pathways, responses to stress and external stimuli, as well as wound healing and coagulation cascades. Interestingly, our observations include significant, replicable associations between SERPINA1 hypomethylation and COPD and lower average lung function phenotypes (combined P values: COPD, 1.5 3 10 223; FEV 1 /FVC, 1.5 3 10 235; FEV 1 , 2.2 3 10 240 ). Conclusions: Genetic and epigenetic pathways may both contribute to COPD. Many of the top associations between COPD and DNA methylation occur in biologically plausible pathways. This largescale analysis suggests that DNA methylation may be a biomarker of COPD and may highlight new pathways of COPD pathogenesis.Keywords: chronic obstructive pulmonary disease; epigenetics; DNA methylation; smoking Chronic obstructive pulmonary disease (COPD) is a multifactorial complex human disease of the lungs with world-wide impact (1). Genome-wide genetic association studies have identified variants associated with COPD (2, 3) and lung function (4-6), yet each identified locus explains only a small amount of the risk for COPD. Variation in the a 1 -antitrypsin (AAT) gene (SER-PINA1) is a monogenic cause of COPD, but even in the presence of AAT deficiency the development of COPD is unpredictable. COPD fits well in the common disease genetic and epigenetic hypothesis, which promulgates that epigenetic variation may be an important mediator between genetic variation and environmental exposures (7). Specifically, DNA methylation may provide further explanation for features of COPD that are not explained fully by DNA sequence variation, such as the variable susceptibility to develop lung disease in smokers, as well as the continued elevated risk for lung function decline years after smoking cessation (8). Epigenetic studies might shed new insights into the pathogenesis of COPD susceptibility and severity.Cigarette smoking is the major environmental risk factor for lung function decline and COPD. Cigarette smoking has been demonstrated to impact global hypomethylation of repetitive genomic elements (...

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