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

Article

关键词: CLONAL HEMATOPOIESIS;    GENETIC-VARIATION;    CANCER RISK;    DNMT3A;    INFLAMMATION;    MECHANISMS;    RECEPTOR;    ROLES;   

DOI  :  10.1161/CIRCULATIONAHA.119.044320

来源: SCIE

【 摘 要 】

Background: Pulmonary arterial hypertension (PAH) is a lethal vasculopathy. Hereditary cases are associated with germline mutations inBMPR2and 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 ofTET2in PAH is unknown. Methods: To test for a role ofTET2, 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 quantifiedTET2expression in peripheral blood mononuclear cells. To assess causality, we investigated hemodynamic and histological evidence of PAH in hematopoieticTet2-knockout mice. Results: We observed an increased burden of rare, predicted deleterious germline variants inTET2in 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 12TET2mutations (75% predicted germline and 25% somatic). These patients had no mutations in other PAH-related genes. Patients withTET2mutations 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-1 beta). CirculatingTET2expression 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-1 beta. Long-term therapy with an antibody targeting interleukin-1 beta blockade resulted in regression of PAH. Conclusions: PAH is the first human disease related to potentialTET2germline mutations. Inherited and acquired abnormalities ofTET2occur in 0.39% of PAH cases. DecreasedTET2expression is ubiquitous and has potential as a PAH biomarker.

【 授权许可】

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