Genetic variants in OSTN and common haplotypes are associated with increased residual pulmonary vascular obstructionGenetic factors and proteins linked to lung blockage after blood clots

Background and Aims: Residual pulmonary vascular obstruction (RPVO) defined as the persistence of thrombotic material within the pulmonary arteries several months after an acute pulmonary embolism (PE) is associated with an increased risk of severe complications, including recurrent events and chronic pulmonary hypertension. However, the genomic architecture underlying RPVO in unprovoked PE remains poorly understood, and this study aims to address this gap. Method: By leveraging genetic and imaging RPVO data from three independent cohorts totaling 586 unprovoked PE patients, we conducted a meta-analysis of genome wide association study (GWAS) of RPVO using a dedicated statistical method to handle the semi-continuous distribution of RPVO. The meta-GWAS was complemented by haplotype association analyses and transcriptome wide association studies as well as Mendelian Randomization (MR) approaches based on plasma metabolites and proteins. Results: Through meta-GWAS, we identified one locus, OSTN, associated with RPVO (lead variant rs59109356 associated with a ~2-fold increase of RPVO, p=3.92x10-8). A second locus, CCN4, previously reported to associate with pulmonary fibrosis, was also identified, with evidence of association approaching genome-wide significance (p=6.7x10-8). We also identified a common haplotype spanning over AHSG/HRG/KNG1 associated with a ~3-fold increase of RPVO (p=2.96x10-8). Using plasma protein-based MR, we demonstrated that one unit increase in genetically determined plasma levels of IL-1 R AcP encoding IL1RAP was associated with a 28% (p=1.32x10-6) reduction in RPVO. We also observed statistical evidence that the CCN4 (p=0.06) and IL1RAP (p=0.02) loci associate with the risk of PE recurrence in a sample of 1,617 unprovoked PE patients. Conclusions: By identifying novel molecular determinants of RPVO that map to loci involved in inflammatory pathways and vascular remodeling, our study provides evidence that inflammation is the predominant, and likely the key mechanism underlying RPVO, whereas impaired fibrinolysis appears to play a more limited role.