Proteogenomic Profiling of Idiopathic Pulmonary Arterial Hypertension Identifies Sex‐Differential Proteins and Candidate Therapeutic Targets

BACKGROUND: Current biomarkers for idiopathic pulmonary arterial hypertension (IPAH) lack disease specificity and provide limited biological insight. We hypothesized that integrating population-based proteomics with genetic evidence would identify robust IPAH-associated proteins relevant to risk stratification, early detection, prognosis, sex differences, and candidate drug-repurposing opportunities. METHODS: We analyzed 2,918 plasma proteins in 44,137 predominantly European-ancestry UK Biobank participants aged 40-69 years, including 252 incident and 141 prevalent IPAH cases. Proteins associated with IPAH were identified using Cox and logistic regression analyses, prioritized by cis-Mendelian randomization, and assessed through cross-ancestry effect-direction concordance and sensitivity analyses. Unsupervised clustering, nested cross-validated prediction models, and target-drug annotation were used for downstream evaluation. RESULTS: Eighteen proteins showed convergent epidemiological and genetic evidence, and 12 remained supported in cross-ancestry and sensitivity analyses. These proteins defined a high-mortality endotype characterized by vascular and ventricular remodeling. Combined clinical and proteomic models achieved AUCs of 0.779 for incident IPAH and 0.768 for mortality. Proteomic contributions differed by sex, and target-drug annotation identified six drug-linked proteins, highlighting ANXA2-linked Artenimol as a repurposing candidate. CONCLUSIONS: Twelve biologically plausible IPAH-associated proteins inform risk stratification, prediction, sex-related characterization, and therapeutic prioritization. Independent multi-ancestry validation and mechanistic studies are warranted.