A107-05 Pseudogene Transcripts Associated With Pulmonary Hypertension Identified in the RNA Sequencing Study From the PVDOMICS Cohort

Abstract Rationale Pulmonary hypertension (PH) is a heterogeneous condition classified into 5 WSPH groups but lacking detailed molecular distinction. The PVDOMICS cohort includes all PH groups alongside healthy and disease comparators, is deeply clinically phenotyped and has RNA sequencing data. Pseudogenes are conserved genome elements that due to sequence-defects cannot be translated into functional proteins. Some pseudogenes never-the-less produce RNA-transcripts which can regulate the expression of other, protein coding genes. Therefore, our study was focused on identifying differentially expressed pseudogene-transcripts within the dataset from the PVDOMICS study and gaining insights into their potential function. Methods Peripheral venous whole blood was collected from PVDOMICS participants n = 525 PH patients; n = 312 controls without PH who were comparators (n = 256) or healthy (n = 56). RNA was isolated, RNA sequencing was performed. After quality control, differential transcript expression between PH and control groups was analyzed using the limma-voom pipeline, rSEA with adjustment for age, sex, race, smoking, WSPH group, latent factors and false discovery rate. We focused on a) transcripts expressed at increased levels (n = 218): the first 200 DEG (differentially-expressed-genes)-transcripts based on log2 difference plus increased DEG within the first 200 most significant p-values; and b) transcripts expressed at decreased levels (n = 292): last 200 DEG based on log2 difference plus decreased DEG within the first 200 most significant p-values. Results Six pseudogene transcripts were among the increased and 35 pseudogene transcripts were among the decreased DEG in the PH group compared to controls. Some of the differentially expressed pseudogenes (DEP) belonged to gene families, like the ribosomal protein family (7 DEP), mitochondria expressed transcripts (3 DEP), zinc finger proteins (2 DEP). Associations of pseudogenes with biological function or disease were extracted via GeneCards(R) and information from GWAS analysis. The DUSP8P5 pseudogene was among the DEP and is known for its association with left heart disease and hypertension; 2 additional DEP have known association with hypertension. Further known associations were with inhibitory or inflammatory immune processes (8 DEP), bone density (6 DEP), metabolism and diabetes (6 DEP), respiratory function or disease (4 DEP), erythrocyte biology (3 DEP), cancer (5 DEP), kidney disease (1 DEP), and demographic parameters like eye or hair color (2 DEP). Ten DEP had no known association with function or disease. Conclusions We identified pseudogene RNA-transcripts associated with PH across WSPH groups. The local vs. systemic effects of these pseudogene transcripts on PH remain to be determined and regulators of pseudogene-transcript expression (e.g. environmental exposures) identified. This abstract is funded by: 1 X01 HL148611 (TopMed), PVDOMICS NHLBI, PVDOMICS Pulmonary Hypertension Association, HT9425-25-1-0533 (GG), 1R21OH012955-01 (GG)