{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T19:34:24Z","timestamp":1790883264763,"version":"4.1.0"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"24","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2020,6,16]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>\n              Pulmonary arterial hypertension (PAH) is a lethal vasculopathy. Hereditary cases are associated with germline mutations in\n              <jats:italic>BMPR2<\/jats:italic>\n              and 16 other genes; however, these mutations occur in &lt;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 (\n              <jats:italic>TET2<\/jats:italic>\n              ), a key enzyme in DNA demethylation, occur in cardiovascular disease and are associated with clonal hematopoiesis, inflammation, and adverse vascular remodeling. The role of\n              <jats:italic>TET2<\/jats:italic>\n              in PAH is unknown.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              To test for a role of\n              <jats:italic>TET2<\/jats:italic>\n              , 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\n              <jats:italic>TET2<\/jats:italic>\n              expression in peripheral blood mononuclear cells. To assess causality, we investigated hemodynamic and histological evidence of PAH in hematopoietic\n              <jats:italic>Tet2<\/jats:italic>\n              -knockout mice.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              We observed an increased burden of rare, predicted deleterious germline variants in\n              <jats:italic>TET2<\/jats:italic>\n              in PAH patients of European ancestry (9\/1832) compared with control subjects (6\/7509; relative risk=6;\n              <jats:italic>P<\/jats:italic>\n              =0.00067). Assessing the whole cohort, 0.39% of patients (10\/2572) had 12\n              <jats:italic>TET2<\/jats:italic>\n              mutations (75% predicted germline and 25% somatic). These patients had no mutations in other PAH-related genes. Patients with\n              <jats:italic>TET2<\/jats:italic>\n              mutations were older (71\u00b17 years versus 48\u00b119 years;\n              <jats:italic>P<\/jats:italic>\n              &lt;0.0001), were more unresponsive to vasodilator challenge (0\/7 versus 140\/1055 [13.2%]), had lower pulmonary vascular resistance (5.2\u00b13.1 versus 10.5\u00b17.0 Wood units;\n              <jats:italic>P<\/jats:italic>\n              =0.02), and had increased inflammation (including elevation of interleukin-1\u03b2). Circulating\n              <jats:italic>TET2<\/jats:italic>\n              expression did not correlate with age and was decreased in &gt;86% of PAH patients.\n              <jats:italic>Tet2<\/jats:italic>\n              -knockout mice spontaneously developed PAH, adverse pulmonary vascular remodeling, and inflammation, with elevated levels of cytokines, including interleukin-1\u03b2. Long-term therapy with an antibody targeting interleukin-1\u03b2 blockade resulted in regression of PAH.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              PAH is the first human disease related to potential\n              <jats:italic>TET2<\/jats:italic>\n              germline mutations. Inherited and acquired abnormalities of\n              <jats:italic>TET2<\/jats:italic>\n              occur in 0.39% of PAH cases. Decreased\n              <jats:italic>TET2<\/jats:italic>\n              expression is ubiquitous and has potential as a PAH biomarker.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.119.044320","type":"journal-article","created":{"date-parts":[[2020,3,20]],"date-time":"2020-03-20T09:00:35Z","timestamp":1584694835000},"page":"1986-2000","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":124,"title":["Novel Mutations and Decreased Expression of the Epigenetic Regulator\n            <i>TET2<\/i>\n            in Pulmonary Arterial Hypertension"],"prefix":"10.1161","volume":"141","author":[{"given":"Fran\u00e7ois","family":"Potus","sequence":"first","affiliation":[{"name":"Department of Medicine (F.P., L.T., J.M., C.L.D., B.S., A.Y.M., S.L.A.), Queen\u2019s University, Kingston, Ontario, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael W.","family":"Pauciulo","sequence":"additional","affiliation":[{"name":"Division of Human Genetics, Cincinnati Children\u2019s 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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elina K.","family":"Cook","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Medicine (E.K.C., M.J.R.), Queen\u2019s University, Kingston, Ontario, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Systems Biology (N.Z., A.H., Y.S.), Columbia University Medical Center, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Department of Systems Biology (N.Z., A.H., Y.S.), Columbia University Medical Center, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carrie L.","family":"Welch","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (C.L.W., W.K.C.), Columbia University Medical Center, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufeng","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Systems Biology (N.Z., A.H., Y.S.), Columbia University Medical Center, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lian","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Medicine (F.P., L.T., J.M., C.L.D., B.S., A.Y.M., S.L.A.), Queen\u2019s University, Kingston, Ontario, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Lima","sequence":"additional","affiliation":[{"name":"Queen\u2019s Cardiopulmonary Unit, Translational Institute of Medicine, Department of Medicine (P.L.), Queen\u2019s University, Kingston, Ontario, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Mewburn","sequence":"additional","affiliation":[{"name":"Department of Medicine (F.P., L.T., J.M., C.L.D., B.S., A.Y.M., S.L.A.), Queen\u2019s University, Kingston, Ontario, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine L.","family":"D\u2019Arsigny","sequence":"additional","affiliation":[{"name":"Department of Medicine (F.P., L.T., J.M., C.L.D., B.S., A.Y.M., S.L.A.), Queen\u2019s University, Kingston, Ontario, Canada."},{"name":"Department of Critical Care (C.L.D.), Queen\u2019s University, Kingston, Ontario, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie A.","family":"Lutz","sequence":"additional","affiliation":[{"name":"Division of Human Genetics, Cincinnati Children\u2019s 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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna W.","family":"Coleman","sequence":"additional","affiliation":[{"name":"Division of Human Genetics, Cincinnati Children\u2019s 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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Damico","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (R.D., P.M.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brooke","family":"Snetsinger","sequence":"additional","affiliation":[{"name":"Department of Medicine (F.P., L.T., J.M., C.L.D., B.S., A.Y.M., S.L.A.), Queen\u2019s University, Kingston, Ontario, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley Y.","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Medicine (F.P., L.T., J.M., C.L.D., B.S., A.Y.M., S.L.A.), Queen\u2019s University, Kingston, Ontario, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul M.","family":"Hassoun","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (R.D., P.M.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William C.","family":"Nichols","sequence":"additional","affiliation":[{"name":"Division of Human Genetics, Cincinnati Children\u2019s 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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy K.","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (C.L.W., W.K.C.), Columbia 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