The findings extend reports linking hypomethylated CYSLTR1/ADORA2B/CCDC88C and hypermethylated TIGIT with more severe fixed airflow limitation in COPD patients, identifying hypomethylated IFRD1/hypermethylated ZNF323 as biomarkers of frequent exacerbation, and providing direct evidence that perturbation of MPV17L signaling through epigenetic programming may play a role in the mediation of both inflammatory and allergic responses in ACO. This evidence concerns the gene IFRD1 and chronic obstructive pulmonary disease.