Variable DNA Methylation Patterns May Identify Smokers Susceptible To Develop COPD.

Dl, DeMeo; Boutaoui, Nadia; Klanderman, Barbara J.; Baccarelli, A.; Silverman, EK

doi:10.1164/ajrccm-conference.2009.179.1_meetingabstracts.a3981

C19. Beyond the Code: Epigenetics in Differentiation and Disease 2009

DOI: 10.1164/ajrccm-conference.2009.179.1_meetingabstracts.a3981

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Variable DNA Methylation Patterns May Identify Smokers Susceptible To Develop COPD.

DeMeo Dl¹,

Nadia Boutaoui²,

Barbara J. Klanderman³

et al.

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2012

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“…To pursue this hypothesis we conducted methylation screens, using the HumanMethylation27 array (Illumina, San Diego, CA) for the assay of 27,578 CpG sites in DNA from 1,454 subjects with and without a history of COPD from two distinct family-based cohorts (n ¼ 1,085 and 369), to identify CpG sites associated with the presence and severity of COPD. Some of the results have been reported in the form of an abstract (20).…”

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confidence: 99%

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

Qiu

Baccarelli

Carey

et al. 2012

Am J Respir Crit Care Med

204

196

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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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mentioning

confidence: 99%

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

Qiu

Baccarelli

Carey

et al. 2012

Am J Respir Crit Care Med

204

196

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Variable DNA Methylation Patterns May Identify Smokers Susceptible To Develop COPD.

Cited by 1 publication

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

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

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