Browsing by Author "Gomez Aleman, Adrian"

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    Transcriptomic Analysis of Survival of Pulmonary Arterial Hypertension Patients
    (2025-05) Gomez Aleman, Adrian; Liu, Yunlong; Schwantes-An , Tae-Hwi Linus; Fadel, William; Reiter, Jill
    Pulmonary arterial hypertension (PAH) is a rare and often fatal condition characterized by obliterative PA remodeling, inflammation, and metabolic reprogramming leading to increased pulmonary vascular resistance (PVR) and right heart failure. To elucidate the genetic causes for disease risk, progression, and outcomes in PAH, many genetic studies, including genome-wide association studies (GWAS), have been conducted. These efforts culminated in identifying both rare and common genetic variants that alter the risk for developing PAH. However, the genetic underpinning of outcomes in PAH remains largely unidentified. To address this crucial gap in developing treatments for PAH, we sought to leverage available data to identify transcriptomic signatures that stratify the hazard for death among patients with PAH, affecting all-cause mortality using the PAH Biobank, which included over 1,000 patients with PAH from diverse genetic ancestry groups. Using available whole-blood RNA-Seq data, we conducted a survival analysis for all-cause mortality or transplant stratified by genetic ancestry groups using the Cox proportional hazards model. RNA-Seq data were quantified using SALMON and normalized using the DESeq2 package in R. Both normalized and tertile gene expression levels were tested for association with survival while adjusting for age at diagnosis, sex, type of PAH, PVR, neutrophils, and the 5 principal components in the survival analysis. A two-stage analysis with EUR as the discovery cohort and AFR and AMR as two independent replication cohorts was performed. A Bonferroni correction was applied to adjust for the number of discovery tests conducted. In total, there were 848 EUR (European genetic ancestry), 81 AFR (African genetic ancestry), and 103 AMR (Admixed American genetic ancestry) participants for analyses. In the discovery cohort, 45,915 genes were tested, and 8 genes were statistically significantly associated with the hazard. Three gene associations (REXO2, FHL2, and CABP4) were replicated (p-value < 0.05 with an exact direction of effect on hazard) in both replication cohorts (AFR, AMR). Using one of the largest cohorts of patients with PAH, we identified three genes that are significantly associated with all-cause mortality across populations. These genes represent potential targets for therapeutic developments as well as for understanding the biological underpinning of progression in PAH.