Role of Forkhead box F1 in the Pathobiology of Pulmonary Arterial Hypertension.

Rationale: Approximately 80% of patients with non-familial pulmonary arterial hypertension (PAH) lack identifiable pathogenic genetic variants. While most genetic studies of PAH have focused on predicted loss-of-function variants, recent approaches have identified ultra-rare missense variants associated with the disease. encodes a highly conserved transcription factor, essential for angiogenesis and vasculogenesis in human and mouse lungs.

Objectives: We identified a rare missense coding variant in two unrelated probands with PAH. is an evolutionarily conserved transcription factor required for lung vascular development and vascular integrity. Our aims were to determine the frequency of variants in larger PAH cohorts compared to the general population, study expression in explanted lung tissue from PAH patients versus control (failed-donor) lungs, and define potential downstream targets linked to PAH development.

Methods: Three independent, international, multicenter cohorts were analyzed to evaluate the frequency of rare variants. Various composite prediction models assessed the deleteriousness of individual variants. Bulk RNA sequencing datasets from human explanted lung tissues were compared to failed-donor controls to determine expression. Bioinformatic tools identified putative binding targets, which were orthogonally validated using mouse ChIP-seq datasets.

Measurements And Main Results: Seven novel or ultra-rare missense coding variants were identified across three patient cohorts in different regions of the gene, including the DNA binding domain. expression was dysregulated in PAH lungs, correlating with disease severity. Histological analysis showed heterogeneous expression, with the lowest levels in phenotypically abnormal endothelial cells within complex vascular lesions in PAH samples. A hybrid bioinformatic approach identified FOXF1 downstream targets potentially involved in PAH pathogenesis, including .

Conclusions: Large genomic and transcriptomic datasets suggest that decreased expression or predicted dysfunction is associated with PAH.