Pulmonary vascular disease & thromboembolismResearch article
Germline and somatic variants in DNMT3A and other clonal haematopoiesis of indeterminate potential genes contribute to pulmonary arterial hypertension
- Genetic association study
- exome sequencing
- targeted panel sequencing
- UK Biobank replication
- mouse model
Authors' conclusion
Germline DNMT3A variants and somatic variants of DNMT3A and CHIP genes increase the risk of PAH, including APAH-CTD, promote inflammation, and constitute potential biomarkers and therapeutic targets.
Study context
- Population
- Patients with pulmonary arterial hypertension (PAH), including associated PAH with connective tissue disease (APAH-CTD) (PAH Biobank)1,832 European ancestry
- Participants
- 2,572 patients
- Comparison
- PAH vs controls
- Outcome
- Predicted deleterious germline DNMT3A variants
Main finding
As reported in the abstract
Deleterious germline DNMT3A variants, European ancestry
Relative risk
4.1
P = 0.018
Events by group
PAH
6/1832
6 events
Controls
6/7509
6 events
Further findings
CHIP mutations, UK Biobank
P ≤ 0.0001
| Outcome | PAH | Controls | OR | P value |
|---|---|---|---|---|
| DNMT3A germline and somatic variants, entire PAH Biobank cohort | 1.28% | .43% | P = 1.65 × 10-10 | |
| CHIP on TPS (PAH n = 1659 vs controls n = 3644) | 25.44 | P = 4.50 × 10-5 | ||
| CHIP on TPS (PAH n = 1659 vs controls n = 3644) | 23.35 | P = 2.87 × 10-8 |
- DNMT3A germline and somatic variants, entire PAH Biobank cohort — Likely germline DNMT3A mutations (female/male 7/1)
- 8 (.39%)
- DNMT3A germline and somatic variants, entire PAH Biobank cohort — Likely somatic DNMT3A mutations (female/male 21/4), incl. 13/33 APAH-CTD
- 25 (.82%)
- Clonal haematopoiesis of indeterminate potential (CHIP) on targeted panel sequencing (TPS) (PAH n = 1659 vs controls n = 3644) — PAH subjects with CHIP (48% DNMT3A)
- 242
- CHIP on TPS (PAH n = 1659 vs controls n = 3644): DNMT3A variants; adjusted for age, sex, age-CHIP interactions
- CHIP on TPS (PAH n = 1659 vs controls n = 3644): all-CHIP variants; adjusted for age, sex, age-CHIP interactions
DNMT3A mRNA in peripheral blood mononuclear cells (PBMCs)
- DNMT3A reduced in PAH-PBMCs, AUC
- .82
- P
- P < 0.0001
Haematopoietic Dnmt3a-knockout mice
- Caused inflammatory PAH, attenuated by IL-1β antibody therapy
Original publication
Germline and somatic variants in DNMT3A and other clonal haematopoiesis of indeterminate potential genes contribute to pulmonary arterial hypertension. Eur Heart J. Published 29 August 2025. doi:10.1093/eurheartj/ehaf611
Summarised from the published abstract; every number is checked against it