The putative causal relationships identified between EPAS1 and trans genes associated with methylation changes in the EPAS1 promoter region, the association of EPAS1 with COPD severity measures, and its differences between the CTRL and COPD groups indicate that EPAS1 is a putative key causal regulator of multiple COPD severity phenotypes in human and emphysema severity associated genes in mouse. This evidence concerns the gene EPAS1 and chronic obstructive pulmonary disease.