Novel Mutations and Decreased Expression of the Epigenetic Regulator TET2 in Pulmonary Arterial Hypertension

Author:

Potus François1,Pauciulo Michael W.2,Cook Elina K.3,Zhu Na4,Hsieh Alexander4,Welch Carrie L.5,Shen Yufeng4,Tian Lian1,Lima Patricia6,Mewburn Jeffrey1,D’Arsigny Christine L.17,Lutz Katie A.2,Coleman Anna W.2,Damico Rachel8,Snetsinger Brooke1,Martin Ashley Y.1,Hassoun Paul M.8,Nichols William C.2,Chung Wendy K.59,Rauh Michael J.3,Archer Stephen L.1ORCID

Affiliation:

1. Department of Medicine (F.P., L.T., J.M., C.L.D., B.S., A.Y.M., S.L.A.), Queen’s University, Kingston, Ontario, Canada.

2. Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Ohio (M.W.P., K.A.L., A.W.C., W.C.N.).

3. Department of Pathology and Molecular Medicine (E.K.C., M.J.R.), Queen’s University, Kingston, Ontario, Canada.

4. Department of Systems Biology (N.Z., A.H., Y.S.), Columbia University Medical Center, New York.

5. Department of Pediatrics (C.L.W., W.K.C.), Columbia University Medical Center, New York.

6. Queen’s Cardiopulmonary Unit, Translational Institute of Medicine, Department of Medicine (P.L.), Queen’s University, Kingston, Ontario, Canada.

7. Department of Critical Care (C.L.D.), Queen’s University, Kingston, Ontario, Canada.

8. Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (R.D., P.M.H.).

9. Department of Medicine (W.K.C.), Columbia University Medical Center, New York.

Abstract

Background: Pulmonary arterial hypertension (PAH) is a lethal vasculopathy. Hereditary cases are associated with germline mutations in BMPR2 and 16 other genes; however, these mutations occur in <25% of patients with idiopathic PAH and are rare in PAH associated with connective tissue diseases. Preclinical studies suggest epigenetic dysregulation, including altered DNA methylation, promotes PAH. Somatic mutations of Tet-methylcytosine-dioxygenase-2 ( TET2 ), a key enzyme in DNA demethylation, occur in cardiovascular disease and are associated with clonal hematopoiesis, inflammation, and adverse vascular remodeling. The role of TET2 in PAH is unknown. Methods: To test for a role of TET2 , we used a cohort of 2572 cases from the PAH Biobank. Within this cohort, gene-specific rare variant association tests were performed using 1832 unrelated European patients with PAH and 7509 non-Finnish European subjects from the Genome Aggregation Database (gnomAD) as control subjects. In an independent cohort of 140 patients, we quantified TET2 expression in peripheral blood mononuclear cells. To assess causality, we investigated hemodynamic and histological evidence of PAH in hematopoietic Tet2 -knockout mice. Results: We observed an increased burden of rare, predicted deleterious germline variants in TET2 in PAH patients of European ancestry (9/1832) compared with control subjects (6/7509; relative risk=6; P =0.00067). Assessing the whole cohort, 0.39% of patients (10/2572) had 12 TET2 mutations (75% predicted germline and 25% somatic). These patients had no mutations in other PAH-related genes. Patients with TET2 mutations were older (71±7 years versus 48±19 years; P <0.0001), were more unresponsive to vasodilator challenge (0/7 versus 140/1055 [13.2%]), had lower pulmonary vascular resistance (5.2±3.1 versus 10.5±7.0 Wood units; P =0.02), and had increased inflammation (including elevation of interleukin-1β). Circulating TET2 expression did not correlate with age and was decreased in >86% of PAH patients. Tet2 -knockout mice spontaneously developed PAH, adverse pulmonary vascular remodeling, and inflammation, with elevated levels of cytokines, including interleukin-1β. Long-term therapy with an antibody targeting interleukin-1β blockade resulted in regression of PAH. Conclusions: PAH is the first human disease related to potential TET2 germline mutations. Inherited and acquired abnormalities of TET2 occur in 0.39% of PAH cases. Decreased TET2 expression is ubiquitous and has potential as a PAH biomarker.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

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