Association of Canonical Pathways With Length of Survival in Pulmonary Arterial Hypertension

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Abstract Pulmonary arterial hypertension (PAH) is a chronic, progressive disease without cure. Treatment can improve outcome, but informed predictions with clinical and genomic measurements can guide treatment and therapy choices. Previous research has focused on identifying clinical variables that could predict future outcomes. The current research aims to find genomic variants that can predict survival time. Whole genome sequencing was performed on stored samples from 325 PAH patients. We split samples into long survival and short survival using median, mean, and a strict definition where samples were included with Long survival greater than 7 years and Short survival with mortality less than 5. Variants were filtered for quality, assigned to genes, and filtered for function and population frequency. Genes are grouped based on Canonical Pathways defined in Ingenuity Pathway Analysis.Patients were 50% IPAH, 81% female, 97% european decent with a mean age of 54 at sample acquisition. Mean follow-up post sample acquisition was 5.4 years (range 0.6 to 9 years). For the strict definitions of long and short, mean long and short survival was 8.3 and 2.1 years, respectively. Of pathways containing more than one gene mutated in 3 or more samples, 31 pathways were associated with strict division of survival length using a fischer exact test. Bayesian network model generated for predicting Long or Short survival using the 31 identified pathways and has achieved high performance with AUC=0.75.An independent dataset curated by Triaxia was used for validation which provided 263 samples with a physician provided diagnosis of PAH and time to death survival data. Limiting to the same set of variants and using same long/short definitions, we identified 4 pathways associated with survival in the same direction (B cell Development, Cdc42 Signalling, Graft-versus-Host Disease signalling, and T Helper Cell Differentiation) possibly supporting the role that immune dysregulation plays a part in PAH pathogenesis. We identified pathways with biological relevance associated with a Long/Short survival time in patients with pulmonary arterial hypertension with the intentions of using a group of pathways as a model for prediction of outcome.

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