We report three lead CpGs differentially methylated in PAH, the most significant of which locates in close proximity to the gene encoding Cathepsin Z, CTSZ, and two more closest to COG6 and ZNF678. We further demonstrated that the predicted loss of CTSZ expression, associated with hypermethylation, alters the function of hPAEC, driving enhanced apoptosis in response to inflammatory stimuli, a characteristic feature of early PAH. The gene discussed is ZNF678; the disease is pulmonary arterial hypertension.