Based on DNA methylation at 121 CpG sites, the Epigenetic Smoking Status Estimator (EpiSmokEr) predicts smoking characteristics. In a population of older persons, researchers sought to compare the relationships of EpiSmokEr-predicted vs. self-reported smoking phenotypes with pulmonary function and all-cause death.

From 1999 to 2012, the prospective Normative Aging Study gathered DNA methylation measures, with a follow-up until 2016. Based on DNA methylation levels measured by the Illumina HumanMethylation450 Beadchip, the R package EpiSmokEr predicted smoking characteristics. Every 3-5 years, spirometry was taken. Airflow restriction was described as a forced expiratory volume in 1s divided by forced vital capacity <0.7. Periodic mailings were used to keep track of vital condition.

The EpiSmokEr-predicted smoking phenotypes matched the self-reported phenotypes for 228 (97%) never smokers and 22 (71%) current smokers among 784 subjects with 5414 person-years of follow-up. EpiSmokEr, on the other hand, classed 407 (79%) self-reported former smokers as never smokers. Nonetheless, when compared to the self-reported former smoking phenotype (airflow limitation: HR = 2.21, 95% CI=1.13-4.33; mortality: HR=1.08, 95% CI=0.86-1.36), the EpiSmokEr-predicted former smoking phenotype was more strongly associated with incident airflow limitation (HR=3.15, 95% CI=1.50-6.59) and mortality (HR=2.11, 95% CI=1.56-2.85). The risk of airflow restriction and mortality was not different between self-reported never smokers and former smokers categorized as never smokers. Compared to self-reported phenotypes, the discriminative accuracy of EpiSmokEr-predicted phenotypes for incident airflow restriction and mortality was enhanced.

The EpiSmokEr classifier, based on DNA methylation, may be a viable proxy for smoking-induced lung damage and identify former smokers who are most at risk of unfavorable smoking-related health outcomes.