Multi-Omic Profiling In Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a rare but devastating condition with highly heterogeneous patient groups and clinical responses. Molecular profiling of blood can be used to better understand the underlying pathology. Combining the output from different analytical platforms has the potential to identify key signalling pathways. We combined transcriptomic, metabolomic and genomic analyses to investigate PAH in a UK PAH cohort. RNA sequencing was performed on whole blood samples from patients with PAH recruited as part of the UK National PAH Cohort study and age- and sex-matched healthy controls. A three-stage design of RNA discovery, RNA validation/model construction and model validation was used to define a set of discriminating RNAs. We performed survival analysis and Mendelian randomisation analysis using summary statistics from a PAH genome-wide association study. We identified 507 genes with differential expression in PAH patients compared to healthy controls. A LASSO model of 25 RNAs was able to distinguish PAH with 87% accuracy (AUC 95% CI: 0.791-0.945) in model validation and was also associated with long-term survival in PAH patients. The combination of RNA and metabolome profiles was best able to distinguish PAH from controls (p=0.00175). Mendelian randomisation detected an association between SMAD5 levels and PAH disease susceptibility (OR:0.317, 95%CI:0.129-0.776, p=0.012). We have identified a whole blood RNA signature of PAH, which includes RNAs relevant to disease pathogenesis, improves distinction of PAH by metabolomic profiles and identifies patients with poor clinical outcomes. Genetic variants associated with lower SMAD5 expression may increase susceptibility to PAH.