Association of Rare Variants in Pulmonary Arterial Hypertension-Related Genes With a Distinct Vasculopathy Phenotype and Worse Outcomes in Patients With Systemic Lupus Erythematosus-Associated Pulmonary Arterial Hypertension.

Abstract

Systemic lupus erythematosus (SLE)-associated pulmonary arterial hypertension (PAH) exhibits marked clinical heterogeneity. Although pathogenic variants in the BMPR2 gene and other PAH-related genes drive pulmonary vascular remodeling in idiopathic or familial PAH, their role in SLE-associated PAH remains unclear. What is the prevalence of rare variants in PAH-related genes in patients with SLE-associated PAH and how are these variants associated with clinical phenotypes and outcomes? Based on the Chinese SLE Treatment and Research Group PAH cohort, 241 patients with SLE-associated PAH were recruited and screened for rare deleterious variants in 12 definitive and 9 candidate PAH-related genes by whole exome sequencing. Clinical features, hemodynamic characteristics, and outcomes were compared between variant carriers and noncarriers. Another 87 patients with SLE-associated PAH were included as a genetic replication cohort. In the discovery cohort, 7.2% of patients carried rare variants in PAH-related genes, a higher trend than in the control cohort (4.5%; P = .085). This trend remained consistent in the independent validation cohort (8.5% vs 4.8%; P = .148) and reached statistical significance in the combined cohort analysis (7.4% vs 4.7%; P = .036). Variant carriers showed a significantly higher proportion of PAH as the onset symptom of SLE and significantly lower SLE disease activity. Carrying rare variants in PAH-related genes was identified as an independent prognostic factor of mortality (hazard ratio, 5.89; 95% CI, 1.56-22.27; P = .009). Our results show that rare variants in PAH-related genes are associated with a distinct vasculopathy phenotype and worse outcomes in patients with SLE-associated PAH, demonstrating the clinical implications of better risk stratification and personalized treatment strategies for patients with SLE-associated PAH.