Iron status mediates the causal effects of high-altitude adaptation signals in the HIF–PHD axis on pulmonary vascular and right-heart outcomes

Background: The high-altitude adaptation genes EPAS1 (HIF-2α) and EGLN1 (PHD2) in the HIF–PHD oxygen-sensing pathway regulate erythropoiesis and iron homeostasis and are implicated in hypoxia-related pulmonary vascular disease, yet causal roles are unclear. Methods: This study applied a drug-target Mendelian randomization (DTMR) framework. Cis-eQTLs were used to instrument EPAS1/EGLN1 expression; gene-restricted erythroid instruments were built from genome-wide significant variants within ± 100 kb for hemoglobin (HGB), hematocrit (HCT), and red blood cell count (RBC). Primary analyses used inverse-variance weighted (IVW) and summary-data-based Mendelian randomization (SMR) with eight sensitivity approaches. Outcomes included pulmonary embolism (PE), pulmonary arterial hypertension (PAH), pulmonary-artery structural indices, and right-heart MRI traits. Two-step mediation MR evaluated iron-status traits. Results: In SMR-DTMR, higher EPAS1 expression associated with lower PE risk (OR = 0.861; 95% CI, 0.758–0.979). In IVW-DTMR, EGLN1-mediated increases in HGB/HCT/RBC raised PE risk (HGB: OR 2.55; HCT: OR 2.45; RBC: OR 1.91) and were associated with lower systolic pulmonary artery–to–aorta ratio (PA/Ao) (HGB β−0.322; HCT β−0.282; RBC β−0.425). EPAS1-mediated HGB/HCT/RBC were associated with reduced right ventricular peak filling rate (RVP-FR; β−33.8 to −28.1). Mediation indicated serum iron partially mediated the EGLN1→(HGB/HCT)→PE pathway (3.6–3.8%), with a potential effect for RBC; ferritin potentially mediated the EPAS1→RBC→PA/Ao pathway. Multiple sensitivity analyses supported robustness. Conclusions: EGLN1-driven erythropoietic upregulation increases PE risk and adversely affects pulmonary artery structure, whereas higher EPAS1 expression reduces PE risk. These genetic findings support targeted modulation of HIF-2α and iron metabolism.