A total of 7 differentially methylated CpG sites associated with mortality in people with ≥10 pack-years smoking history were identified in a genome-wide analysis. Findings from this study were published in the American Journal of Respiratory and Critical Care Medicine.

The longitudinal COPDGene study consists of 10,000 non-Hispanic white and black patients enrolled at 21 different centers across the United States. For the current analysis, investigators identified current and former smokers with and without airflow obstruction and a ≥10 pack-years smoking history from the COPDGene study (n=667). The DNA methylation analysis was performed using peripheral blood samples from patients. The investigators also performed replication in 231 patients from the ECLIPSE study.

There were 7 CpG sites associated with mortality at a false discovery rate threshold of <20%, which was replicated in the ECLIPSE study (P <.05). These CpG sites included cg08007647, cg19828537, cg02618319, cg04226365, cg24542441, cg03971555, and cg12033075.

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The 2 PIK3CD sites, cg03971555 and cg12033075, demonstrated large effect sizes (absolute adjusted mean difference in DNA methylation between the deceased and survived, 5% and 4.7%, respectively), with higher DNA methylation showing a correlation with mortality. None of the DNA methylation marks were associated with long-term decline in lung function in survivors, nor was there an association with smoking history or current smoking status. The investigators did observe significant associations for the 2 PIK3CD sites for lung function and emphysema phenotypes (P <.05).

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A study limitation was the lack of patients with <10 pack-year smoking history, which may reduce generalizability of the findings across the broader population.

According to the researchers, these findings provide greater insight into the predictive relevance of DNA “…methylation marks for the identified sites in a population of smokers, irrespective of lung disease presentation, helping to inform the selection of smokers at greater risk of death, while highlighting targets for functional validation and therapeutic intervention.”


Morrow JD, Make B, Regan E, et al. DNA methylation is predictive of mortality in current and former smokers [published online January 29, 2020]. Am J Respir Crit Care Med. doi:10.1164/rccm.201902-0439OC