Journal Article

Blood DNA methylation profiling identifies cathepsin Z dysregulation in pulmonary arterial hypertension

Draisma, Harmen, Wu, Yukyee, Morrell, Nicholas W., Wharton, John, Rhodes, Christopher J., Toshner, Mark, Ulrich, Anna, Church, Colin, Howard, Luke S., Condliffe, Robin, Balkhiyarova, Zhanna, Prokopenko, Inga, Gräf, Stefan, Pepke-Zaba, Joanna, Swietlik, Emilia M., Auvinen, Juha, Wilkins, Martin R., Vasilaki, Eleni, Jarvelin, Marjo-Riitta, Coghlan, J. Gerry, Herzig, Karl-Heinz, Lawrie, Allan, Kiely, David G., Cebola, Inês, Wort, Stephen J., Lordan, James

2024

Overview

Pulmonary arterial hypertension (PAH) is characterised by pulmonary vascular remodelling causing premature death from right heart failure. Established DNA variants influence PAH risk, but susceptibility from epigenetic changes is unknown. We addressed this through epigenome-wide association study (EWAS), testing 865,848 CpG sites for association with PAH in 429 individuals with PAH and 1226 controls. Three loci, at Cathepsin Z ( CTSZ , cg04917472 ) , Conserved oligomeric Golgi complex 6 ( COG6 , cg27396197 ) , and Zinc Finger Protein 678 ( ZNF678 , cg03144189 ) , reached epigenome-wide significance ( p  < 10 −7 ) and are hypermethylated in PAH, including in individuals with PAH at 1-year follow-up. Of 16 established PAH genes, only cg10976975 in BMP10 shows hypermethylation in PAH. Hypermethylation at CTSZ is associated with decreased blood cathepsin Z mRNA levels. Knockdown of CTSZ expression in human pulmonary artery endothelial cells increases caspase-3/7 activity ( p  < 10 −4 ). DNA methylation profiles are altered in PAH, exemplified by the pulmonary endothelial function modifier CTSZ , encoding protease cathepsin Z. Pulmonary arterial hypertension is a complex disease characterised by high morbidity and mortality. Here, the authors report methylation profiling of patients, finding disease associations in genes CTSZ , COG6 and ZNF678 .

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38/22 / 38/61 / 45 / 49 / 49/105 / 631/208/176/1988 / 692/308/2056 / 692/4019/592/2727 / Blood / Bone Morphogenetic Proteins / Caspase-3 / Cathepsin Z / Congestive heart failure / CpG islands / Deoxyribonucleic acid / DNA / DNA fingerprinting / DNA methylation / DNA Methylation - genetics / Endothelial Cells / Epigenetics / Familial Primary Pulmonary Hypertension / Gene expression / Genes / Golgi apparatus / Humanities and Social Sciences / Humans / Hypertension / Morbidity / mRNA / multidisciplinary / Pulmonary Arterial Hypertension / Pulmonary arteries / Pulmonary artery / Pulmonary hypertension / Science / Science (multidisciplinary) / Zinc finger proteins