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

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 under 25% of idiopathic PAH patients (IPAH) and are rare in PAH associated with connective tissue diseases (APAH). 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 utilized a cohort of 2572 cases from the PAH Biobank. Within this cohort, gene-specific rare variant association tests were performed using 1832 unrelated European PAH patients and 7509 non-Finnish European gnomAD subjects as controls. In an independent cohort of 140 patients, we quantified TET2 expression in peripheral blood mononuclear cells. To assess causality, we investigated hemodynamic and histologic 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 to controls (6/7509; relative risk=6, p=0.00067). Assessing the whole cohort, 0.39% (10/2572) of patients 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) unresponsive to vasodilator challenge (0/7 vs 140/1055 (13.2%)), had lower PVR (5.2±3.1 versus 10.5±7.0 Woods units, p=0.02) and had increased inflammation (including elevation of IL-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 IL-1β. Chronic therapy with an antibody targeting IL-1β blockade regressed 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.

The role of clonal haematopoiesis in cardiovascular diseases: epidemiology and experimental studies

“…In agreement with these experimental findings, it has been reported that individuals that harbour TET2mediated clonal haematopoiesis exhibit significantly higher serum levels of IL-1b and IL-6 in the TOPMed cohort [30]. Finally, a recent study reported that rare germline variants in TET2 may contribute to pulmonary arterial hypertension via an IL-1b-dependent mechanism [31].…”

Inhibition of Glucose-6-Phosphate Dehydrogenase Activity Attenuates Right Ventricle Pressure and Hypertrophy Elicited by VEGFR Inhibitor + Hypoxia

“…We and others have recently proposed that DNA methylation and other epigenetic modifications potentially promote maladaptive gene expression, a determinant of inflammatory and hyperproliferative cell phenotype, in remodeled PA (Hu et al, 2019;Joshi et al, 2020;Potus et al, 2020). Furthermore, we recently showed that expression of Tet2, a DNA demethylase considered as a master regulator of differentiated fate of SMC This article has not been copyedited and formatted.…”

DNA methyltransferase 3B deficiency unveils a new pathological mechanism of pulmonary hypertension

“…Recently, one study showed diminished TET2 in peripheral blood cells of PAH patients, which engenders the epigenetic link of DNA demethylation to PAH progression ( 16 ). However, DNA methylation regulated by DNMTs and TETs is strain, species, organ, and stimuli dependent.…”