Abstract 13301: Rasa3 is a Novel Candidate Gene in Sickle Cell Disease-Associated Pulmonary Hypertension and Pulmonary Arterial Hypertension

Abstract

Introduction: Pulmonary hypertension (PH) is associated with significant morbidity and mortality. RASA3, a GTPase-activating protein, is integral to processes highly relevant to PH. We explore the association of RASA3 genetic variation with PH risk in patients with sickle cell disease (SCD)-associated PH and pulmonary arterial hypertension (PAH). Methods: Using peripheral blood mononuclear cells (PBMC) from 3 cohorts of subjects with SCD, cis-expression quantitative trait loci (eQTL) were queried for RASA3 . Genome-wide single nucleotide polymorphisms (SNP) near or in the RASA3 gene that associate with lung RASA3 expression were identified using Genotype Tissue Expression project data, reduced to 9 tagging SNPs for RASA3 and associated with PH markers. Associations between the top RASA3 SNP and PAH severity were tested using whole genome genotype data from PAH Biobank subjects. Using RNAseq samples aligned with SNP arrays from lung tissue from the Pulmonary Hypertension Breakthrough Initiative (PHBI), we evaluated the frequency of the risk allele at our SNP of interest. Results: PBMC RASA3 expression was significantly lower in patients with SCD-associated PH using elevated TRV≥2.5m/s and RHC data and associated with significantly higher mortality. One eQTL for RASA3 was identified, rs9525228, with the risk allele correlating with PH risk and severity in patients with SCD-associated PH. Analyzing this SNP in PAH patients based on either European or African ancestry (EA, AA), we found that rs9525228 associated with markers of PH in EA but not AA individuals (Table 1). There was a trend towards decreased survival in EA individuals carrying rs9525228 (p=0.08) that was not seen among AA individuals. Using PHBI samples, individuals homozygous for the risk allele had lower RASA3 expression (p=0.05). Conclusions: RASA3 is a novel candidate gene in SCD-associated PH and PAH and appears to be protective. Further studies are ongoing to delineate the role of RASA3 in PH.