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RASA3 is a GTPase activating\u00a0protein integral to angiogenesis and endothelial barrier function. In this study, we explore the association of RASA3 genetic variation with PH risk in patients with sickle cell disease (SCD)\u2010associated\u00a0PH and pulmonary arterial hypertension (PAH).\u00a0<jats:italic>Cis<\/jats:italic>\u2010expression quantitative trait loci (eQTL)\u00a0were queried for <jats:italic>RASA3<\/jats:italic> using whole genome genotype arrays and gene expression profiles derived from peripheral blood mononuclear cells (PBMC)\u00a0of three SCD cohorts. Genome\u2010wide single nucleotide polymorphisms (SNPs)\u00a0near or in the <jats:italic>RASA3<\/jats:italic> gene that may associate with lung RASA3 expression were identified, reduced to 9 tagging SNPs for RASA3 and associated with markers of PH. Associations between the top RASA3 SNP and PAH severity were corroborated using data from the PAH Biobank and analyzed based on European or African ancestry (EA,\u00a0AA).\u00a0We found that PBMC RASA3 expression was lower in patients with SCD\u2010associated PH as defined by echocardiography and right heart catheterization and was associated with higher mortality. One eQTL for RASA3 (rs9525228) was identified, with the risk allele correlating with PH risk, higher tricuspid regurgitant jet velocity and higher pulmonary vascular resistance in patients with SCD\u2010associated PH. rs9525228 associated with markers of precapillary PH and decreased survival in individuals of EA but not AA. In conclusion, <jats:italic>RASA3<\/jats:italic> is a novel candidate gene in SCD\u2010associated PH and PAH, with RASA3 expression appearing to be protective. Further studies are ongoing to delineate the role of RASA3 in PH.<\/jats:p>","DOI":"10.1002\/pul2.12227","type":"journal-article","created":{"date-parts":[[2023,4,13]],"date-time":"2023-04-13T11:51:53Z","timestamp":1681386713000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["<i>RASA3<\/i> is a candidate gene in sickle cell disease\u2010associated pulmonary hypertension and pulmonary arterial hypertension"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9097-5762","authenticated-orcid":false,"given":"Clare C.","family":"Prohaska","sequence":"first","affiliation":[{"name":"Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine Indiana University Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, 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