Objective: To investigate the role of Id genes in the development of pulmonary hypertension (PH) in heart failure (HF) and evaluate genetic variants of the ID genes associated with HF-PH.
Design: Experimental study using an AKR/J mouse model of HF-PH and a genetic association study using the UK Biobank cohort.
Setting: Laboratory animal study and population-based cohort study.
Participants: AKR/J mice with HF-PH and participants with HF from the UK Biobank cohort.
Interventions: Administration of tacrolimus (Id signaling inducer) in the mouse model.
Main outcome measures: Tissue-specific gene expression of Id1, Id2, and Id3 in HF-PH mice; severity of HF-PH after tacrolimus treatment; associations of single nucleotide polymorphisms of ID1, ID2, and ID3 with PH development and mortality in participants with HF.
Results: Id1 was upregulated in the left ventricle (Fold Change (FC) = 1.65; P = 3.0 × 10-4) of HF-PH mice. In adipose tissue, Id1 and Id3 were downregulated (FC = 0.33; P = 5.2 × 10-3 and FC = 0.50; P = 0.01, respectively), while Id2 was upregulated (FC = 1.78; P = 7 × 10-4). Tacrolimus worsened PH and diastolic dysfunction, upregulating only Id2 in adipose tissue. In the clinical cohort, rs7425561 and rs10174593 (expression quantitative loci for ID2) trended toward reduced risk of PH in HF and all-cause mortality in participants with HF-PH.
Conclusion: The results suggest ID1, ID2, and ID3 are involved in HF-PH pathogenesis, but more research is needed to characterize their exact role.
Keywords: Gene expression; Heart failure; Inhibitors of DNA-binding; Pulmonary hypertension; Single nucleotide polymorphisms; Tacrolimus; UK Biobank.
© 2026 The Authors.