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

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

doi:10.1038/s41467-023-44683-0

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

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

Anna Ulrich, Yukyee Wu, Harmen Draisma, John Wharton, Emilia M Swietlik, Ines Cebola, Eleni Vasilaki, Zhanna Balkhiiarova, Marjo-Riitta Jarvelin, Juha Auvinen, …

Nature communications, Vol.15(1), 330

06/01/2024

DOI: https://doi.org/10.1038/s41467-023-44683-0

PMID: 38184627

Abstract

Bone Morphogenetic Proteins

Cathepsin Z

DNA Methylation - genetics

Endothelial Cells

Familial Primary Pulmonary Hypertension

Humans

Pulmonary Arterial Hypertension

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 ) 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 ). DNA methylation profiles are altered in PAH, exemplified by the pulmonary endothelial function modifier CTSZ, encoding protease cathepsin Z.

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Title: Blood DNA methylation profiling identifies cathepsin Z dysregulation in pulmonary arterial hypertension
Creators: Anna Ulrich (Author) - University of Surrey, School of Biosciences
Yukyee Wu (Author) - Imperial College London
Harmen Draisma (Author) - Imperial College London
John Wharton (Author) - Imperial College London
Emilia M Swietlik (Author) - University of Cambridge
Ines Cebola (Author) - Imperial College London
Eleni Vasilaki (Author) - Imperial College London
Zhanna Balkhiiarova (Author) - University of Surrey, School of Biosciences
Marjo-Riitta Jarvelin (Author) - Brunel University London
Juha Auvinen (Author) - University of Oulu
Karl-Heinz Herzig (Author) - Poznan University of Medical Sciences
J. G. Coghlan (Author) - University College London
James Lordan (Author) - Newcastle University
Colin Church (Author) - Golden Jubilee National Hospital
Luke S Howard (Author) - Imperial College London
Joanna Pepke-Zaba (Author) - Papworth Hospital
Mark Toshner (Author) - University of Cambridge
Robin Condliffe (Author) - University of Sheffield
Stephen J Wort (Author) - Imperial College London
Allan Lawrie (Author) - University of Sheffield
David G Kiely (Author) - University of Sheffield
Stefan Gräf (Author) - University of Cambridge
Nicholas W. Morrell (Author) - University of Cambridge
Martin R Wilkins (Author) - Imperial College London
Inga Prokopenko (Author) - University of Surrey, School of Biosciences
Christopher J Rhodes (Corresponding Author) - Imperial College London
Publication Details: Nature communications, Vol.15(1), 330
Date published: 06/01/2024
Date accepted: 28/12/2023
Grants: 20/0006307, Diabetes UK (United Kingdom, London)
Longitools, H2020-SCI-2019-874739, Horizon 2020
Identifiers: 99911166502346
Academic Unit: School of Biosciences
Language: English
Resource Type: Journal article
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 use of the Materials or Data must be for research projects and work that falls under the remit of the National Cohort Study of Idiopathic and Heritable PAH or are collaborative projects with one or more of the Partners – see https://www.ipahcohort.com/ for details. The EWAS summary statistics will be deposited at ewascatalog.org accessible at https://doi.org/10.5281/zenodo.10276821. Data used in the preparation of this article were obtained from the Parkinson’s Progression Markers Initiative (PPMI) database (www.ppmi-info.org/access-dataspecimens/download-data). For up-to-date information on the study, visit ppmi-info.org. Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). The Northern Finland Birth Cohort data used in this study are available upon collaboration and formal data request only, please see http://www.oulu.fi/nfbc. The GTEx data used for the analyses described in this manuscript were obtained from the GTEx Portal on 05/11/2021. Source data are provided with this paper.

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

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