Smoking results in at least a decade lower life expectancy. Mortality among current smokers is two to three times as high as never smokers. DNA methylation is an epigenetic modification of the human genome that has been associated with both cigarette smoking and mortality.
We sought to identify DNA methylation marks in blood predictive of mortality in a subset of the COPDGene study, representing 101 deaths among 667 current and former smokers.
We assayed genome-wide DNA methylation in non-Hispanic white smokers with and without COPD using blood samples from the COPDGene enrollment visit. We tested whether DNA methylation was associated with mortality in models adjusted for COPD status, age, sex, current-smoking status, and pack-years of cigarette smoking. Replication was performed in a subset of 231 individuals from the ECLIPSE study.
We identified seven CpG sites associated with mortality (FDR < 20%) that replicated in the ECLIPSE cohort (p < 0.05). None of these marks were associated with longitudinal lung function decline in survivors, smoking history or current smoking status. However, differential methylation of two replicated PIK3CD sites were associated with lung function at enrollment (p < 0.05). We also observed associations between DNA methylation and gene expression for the PIK3CD sites.
This study is the first to identify variable DNA methylation associated with all-cause mortality in smokers with and without COPD. Evaluating predictive epigenomic marks of smokers in peripheral blood may allow for targeted risk stratification and aid in delivery of future tailored therapeutic interventions.

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