Anna Ulrich, Yukyee Wu, Harmen Draisma, John Wharton, Emilia M. Swietlik, Inês Cebola, Eleni Vasilaki, Zhanna Balkhiyarova, Marjo-Riitta Jarvelin, Juha Auvinen, Karl-Heinz Herzig, J. Gerry Coghlan, James Lordan, Colin Church, Luke S. Howard, Joanna Pepke-Zaba, Mark Toshner, Stephen J. Wort, David G. Kiely, Robin Condliffe, Allan Lawrie, Stefan Gräf, Nicholas W. Morrell, Martin R. Wilkins, Inga Prokopenko, Christopher J. Rhodes
University of Surrey. Imperial College London. University of Cambridge. University of Oulu. Brunel University London. Poznan University of Medical Sciences. University College London. University of Newcastle. Golden Jubilee National Hospital and University of Glasgow. Royal Papworth Hospital. Royal Brompton Hospital. University of Sheffield. Royal Hallamshire Hospital. Cambridge Biomedical Campus.
United Kingdom, Finland and Poland
Nature Communications
Nat Commun 2024; 15:
DOI: 10.1038/s41467-023-44683-0
Abstract
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.
Category
Genetic Factors Associated with Pulmonary Vascular Disease
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes