RASA3 is a candidate gene in sickle cell disease‐associated pulmonary hypertension and pulmonary arterial hypertension

Abstract

Pulmonary hypertension (PH) is associated with significant morbidity and mortality. RASA3 is a GTPase activating protein 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)‐associated PH and pulmonary arterial hypertension (PAH). Cis ‐expression quantitative trait loci (eQTL) were queried for RASA3 using whole genome genotype arrays and gene expression profiles derived from peripheral blood mononuclear cells (PBMC) of three SCD cohorts. Genome‐wide single nucleotide polymorphisms (SNPs) near or in the RASA3 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, AA). We found that PBMC RASA3 expression was lower in patients with SCD‐associated 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‐associated PH. rs9525228 associated with markers of precapillary PH and decreased survival in individuals of EA but not AA. In conclusion, RASA3 is a novel candidate gene in SCD‐associated PH and PAH, with RASA3 expression appearing to be protective. Further studies are ongoing to delineate the role of RASA3 in PH.

Pulmonary Hypertension in Sickle Cell Disease: Novel Findings of Gene Polymorphisms Related to Pathophysiology

“…The SNP rs9525228 correlated with PH risk, higher TRV values and higher pulmonary vascular resistance. Moreover, it was associated with precapillary PH values and decreased survival in a subgroup of the patients [64]. The above results are summarized in Table 1.…”

“…Another reasonable approach for future studies is to examine SCD patients for polymorphisms identified in patients with idiopathic pulmonary arterial hypertension, unrelated to SCD.For example, Tang et al, (2022), suggested several genes as possible markers for PH pathogenesis and potential targets for the prevention of pulmonary vascular restructure including SLC4A1, AHSP, ALAS2, CA1, HBD, SNCA, HBM, SELENBP1, SERPINE1, ITGA2B, TEAD4, TGIF2LY, GATA5, GATA1, GATA2, and FOS [67].It would be interesting to investigate whether these data can be confirmed in SCD, with special attention to the ancestral composition of the patient population. The recent identification of the RASA3 gene as a candidate gene involved in the pathogenesis and prognosis of PH in SCD as well as pulmonary arterial hypertension in non-SCD patients is also an important finding [64]. Validation of each study in larger groups as well as wider ancestral groups is necessary to confirm causative associations.…”

Pulmonary Hypertension in Sickle Cell Disease: Novel Findings of Gene Polymorphisms Related to Pathophysiology

“…The SNP rs9525228 correlated with PH risk, higher TRV values, and higher pulmonary vascular resistance. Moreover, it was associated with precapillary PH values and decreased survival in a subgroup of patients [75]. The above results are summarized in Table 2.…”

“…It would be interesting to investigate whether these data can be confirmed in SCD, with special attention on the ancestral composition of the patient population. The recent identification of the RASA3 gene as a candidate gene involved in the pathogenesis and prognosis of PH in SCD, as well as pulmonary arterial hypertension in non-SCD patients, is also an important finding [75]. Validation of each study with larger groups as well as broader ancestral groups is necessary to confirm causative associations.…”

Insights into Sickle-cell Disease Cardiomyopathy: Early 3-D Echocardiographic Indicators and Pathophysiological Understanding

“…Similarly, the microvascular factors, the common background of SCD, di cultly can be evaluated quantitatively. In every way, the primary role played by PAH in promoting RV damage and a consequent chain of adverse cardiac events is evident, so much to hypothesize the interfering action of other genes, still unknown [4].…”