Pulmonary vascular disease & thromboembolismMechanistic study
Novel Mutations and Decreased Expression of the Epigenetic Regulator TET2 in Pulmonary Arterial Hypertension
- Genetic association and mechanistic study
- rare variant association tests
- independent expression cohort
- hematopoietic Tet2-knockout mice
Authors' conclusion
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.
Study context
- Population
- Patients with pulmonary arterial hypertension (PAH) from the PAH Biobank2,572 PAH Biobank cases
- Participants
- 1,832 vs 7,509
- Comparison
- PAH patients vs Genome Aggregation Database (gnomAD) control subjects
- PAHn = 1,832
- gnomAD controlsn = 7,509reference
Main finding
As reported in the abstract
Rare, predicted deleterious germline TET2 variants
Relative risk
6
P = 0.00067
Events by group
PAH
9
events
gnomAD controls
6
events
- Patients with TET2 mutations in whole cohort
- 0.39% (10/2572)
Further findings
Clinical features, TET2 mutation vs no mutation
- Age, years
- 71±7 versus 48±19; P<0.0001
- Vasodilator responders
- 0/7 versus 140/1055 [13.2%]
- Pulmonary vascular resistance, Wood units
- 5.2±3.1 versus 10.5±7.0; P=0.02
Circulating TET2 expression (independent cohort, n = 140)
- Decreased in PAH patients
- >86%
Hematopoietic Tet2-knockout mice
- Spontaneous PAH, adverse pulmonary vascular remodeling and inflammation; anti-interleukin-1β therapy led to regression of PAH
Original publication
Novel Mutations and Decreased Expression of the Epigenetic Regulator TET2 in Pulmonary Arterial Hypertension. Circulation. Published 20 March 2020. doi:10.1161/circulationaha.119.044320
Summarised from the published abstract; every number is checked against it