Germline and somatic variants in DNMT3A and other clonal haematopoiesis of indeterminate potential genes contribute to pulmonary arterial hypertension.
Article in European heart journal, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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1 · What the graph read from it
What it found
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2 · The registry
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Isaac M EmonDepartment of Medicine, Queen's University, Biosciences Complex Room 1520, 116 Barrie Street, Kingston, Ontario, Canada K7L 3N6.ORCID 0009-0002-6375-1074
François PotusPulmonary Hypertension Research Group, Instituted Universitaire de Cardiologie et de Pneumology de Québec Research Center, Laval University, Quebec City, Canada G1V 4G5.ORCID 0000-0003-1745-6445
Ashley Y MartinDepartment of Medicine, Queen's University, Biosciences Complex Room 1520, 116 Barrie Street, Kingston, Ontario, Canada K7L 3N6.ORCID 0009-0005-8170-1638
Patricia D A LimaDepartment of Medicine, Queen's University, Biosciences Complex Room 1520, 116 Barrie Street, Kingston, Ontario, Canada K7L 3N6.ORCID 0000-0002-6456-2470
Benjamin P OttTranslational Institute of Medicine (TIME) and Queen's Cardiopulmonary Unit (QCPU), Queen's University, Kingston, Ontario, Canada K7L 3N6.ORCID 0009-0008-8894-3500
Curtis NoordhofTranslational Institute of Medicine (TIME) and Queen's Cardiopulmonary Unit (QCPU), Queen's University, Kingston, Ontario, Canada K7L 3N6.ORCID 0009-0006-5072-0585
Marco M ButtigiegDepartment of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada K7L 2V7.ORCID 0000-0002-9584-9861
Amy J M McNaughtonDepartment of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada K7L 2V7.ORCID 0000-0002-9447-9010
Charles C T HindmarchDepartment of Medicine, Queen's University, Biosciences Complex Room 1520, 116 Barrie Street, Kingston, Ontario, Canada K7L 3N6.ORCID 0000-0002-6036-1292
Alexander G BickDepartment of Medicine, Vanderbilt University Medical Center, Nashville, TN 37235, USA.ORCID 0000-0001-5824-9595
William C NicholsDivision of Human Genetics, Cincinnati Children's Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.ORCID 0000-0003-1242-9237
Wendy K ChungDepartment of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.ORCID 0000-0003-3438-5685
Paul M HassounDepartment of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21218, USA.ORCID 0000-0003-0601-4975
Rachel L DamicoDepartment of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21218, USA.ORCID 0000-0002-2584-1557
Na ZhuDepartment of Systems Biology, Columbia University Medical Center, New York, NY 10027, USA.ORCID 0000-0001-6460-3087
Yufeng ShenDepartment of Systems Biology, Columbia University Medical Center, New York, NY 10027, USA.ORCID 0000-0002-1299-5979
Michael J RauhDepartment of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada K7L 2V7.ORCID 0000-0002-8346-5537
Stephen L ArcherDepartment of Medicine, Queen's University, Biosciences Complex Room 1520, 116 Barrie Street, Kingston, Ontario, Canada K7L 3N6.ORCID 0000-0003-1106-3202
Funding
National Biological Sample and Data Repository for PAHR24HL105333 · NHLBI · CINCINNATI CHILDRENS HOSP MED CTR · PI NICHOLS, WILLIAM C · 2012 to 2016
$10.1M
Risk stratification in pulmonary arterial hypertension: Intersection of OMICs and longitudinal phenotypes through the PAH BiobankR01HL160941 · NHLBI · CINCINNATI CHILDRENS HOSP MED CTR · PI DESAI, ANKIT A, NICHOLS, WILLIAM C · 2022 to 2025
$3.2M
O2 sensing in the human and rabbit ductus arteriosus.R01HL071115 · NHLBI · UNIVERSITY OF CHICAGO · PI ARCHER, STEPHEN L · 2004 to 2015
$3.1M
The Role of DRP-1 and Mitochondrial Fission in Pulmonary Arterial HypertensionR01HL113003 · NHLBI · QUEEN'S UNIVERSITY AT KINGSTON · PI ARCHER, STEPHEN L · 2013 to 2016
$1.1M
Canada Foundation for Innovation 229252Canada Foundation for Innovation 33012Canadian Vascular Network Scholar AwardCancer Pathology Translational Research GrantCIHR 451147CIHR Canada Graduate ScholarshipFDN 143261JPB FoundationNHLBI NIH HHS 1R01HL113003-01A1NHLBI NIH HHS 2R01HL071115-06A1NHLBI NIH HHS R01 HL071115NHLBI NIH HHS R01 HL113003NHLBI NIH HHS R01 HL160941NHLBI NIH HHS R01HL160941NHLBI NIH HHS R24 HL105333NHLBI NIH HHS R24HL105333NIH HHS 1R01HL113003-01A1NIH HHS 2R01HL071115-06A1NIH HHS R01HL160941NIH HHS R24HL105333Ontario Institute for Cancer ResearchOntario Molecular Pathology Research NetworkTier 1 Canada Research Chair in Mitochondrial Dynamics and Translational Medicine 950-229252US National Institutes of HealthWilliam J. Henderson Foundation
6 · The paper itself
Abstract
BACKGROUND AND
aimsMultiple germline gene variants promote familial and idiopathic pulmonary arterial hypertension (PAH); however, none are consistently identified in associated PAH with connective tissue disease (APAH-CTD). Moreover, the role of somatic variants in genes mediating clonal haematopoiesis of indeterminate potential (CHIP) in PAH is unknown. Here, somatic and germline DNMT3A variants and CHIP gene variants in PAH were evaluated.
methodsExome sequencing (ES) was compared between PAH Biobank participants (n = 1832 European ancestry/2572 total), vs. gnomAD controls (7509 European ancestry/141 456 total). Subsequently, targeted panel sequencing (TPS) of 22 CHIP genes, including DNMT3A, was performed in PAH (n = 1659) vs. controls (n = 3644). Somatic CHIP variants in the UK Biobank using ES (controls = 448 239; PAH = 2559) were also assessed. DNMT3A mRNA expression was measured in peripheral blood mononuclear cells (PBMCs) of patients with scleroderma APAH-CTD (n = 50), idiopathic PAH (n = 30), scleroderma without PAH (n = 19), and healthy controls (n = 41). Hemodynamic were evaluated in haematopoietic Dnmt3a-knockout mice.
resultsPredicted deleterious germline DNMT3A variants were increased in subjects of European ancestry (6/1832) vs. controls (6/7509) (relative risk [RR] = 4.1, P = .018). In the entire PAH Biobank cohort (n = 2572), DNMT3A germline and somatic variants were further enriched (PAH: 1.28% vs. controls: .43%, P = 1.65 × 10-10). Eight DNMT3A mutations (.39%) were likely germline (female/male: 7/1) and 25 (.82%) likely somatic (female/male: 21/4), including 13/33 APAH-CTD participants. TPS identified CHIP in 242 PAH subjects (48% DNMT3A). DNMT3A- and all-CHIP variants were associated with PAH after correcting for age, sex, and age-CHIP interactions (odds ratio [OR]: 25.44, P = 4.50 × 10-5; OR: 23.35, P = 2.87 × 10-8, respectively). In the UK Biobank, CHIP mutations were increased in PAH (PAH = 5.35% vs. Control = 3.45%, P ≤ .0001). DNMT3A was reduced in PAH-PBMCs (area under curve [AUC] = .82) (P < .0001). Haematopoietic Dnmt3a-knockout in mice caused inflammatory PAH, which was attenuated by IL-1β antibody therapy.
conclusionsGermline DNMT3A variants and somatic variants of DNMT3A and CHIP genes increase the risk of PAH, including APAH-CTD, promote inflammation, and constitute potential biomarkers and therapeutic targets.
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.
Germline and somatic variants in DNMT3A and other clonal haematopoiesis of indeterminate potential genes contribute to pulmonary arterial hypertension. · full record | OpenQuestion