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Lookup NU author(s): Dr James Lordan
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2024, The Author(s).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.
Author(s): Ulrich A, Wu Y, Draisma H, Wharton J, Swietlik EM, Cebola I, Vasilaki E, Balkhiyarova Z, Jarvelin M-R, Auvinen J, Herzig K-H, Coghlan JG, Lordan J, Church C, Howard LS, Pepke-Zaba J, Toshner M, Wort SJ, Kiely DG, Condliffe R, Lawrie A, Graf S, Morrell NW, Wilkins MR, Prokopenko I, Rhodes CJ
Publication type: Article
Publication status: Published
Journal: Nature Communications
Year: 2024
Volume: 15
Issue: 1
Online publication date: 06/01/2024
Acceptance date: 28/12/2023
Date deposited: 20/02/2024
ISSN (electronic): 2041-1723
Publisher: Nature Research
URL: https://doi.org/10.1038/s41467-023-44683-0
DOI: 10.1038/s41467-023-44683-0
Data Access Statement: Data from the UK PAH Cohort study are available upon reasonable request to the access committee cohortcoordination@medschl.cam.ac.uk. The remainder of the data and code access statements are available in the published article.
PubMed id: 38184627
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