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AHA 2021: Association of Canonical Pathways with Length of Survival in Pulmonary Arterial Hypertension

Webb, A., An, H., Correa-Jaque, P., Lin, S., Liu, Z., Tiwari, H. K., Wiener, H., & Benza, R. L. “Abstract 11344: Association of Canonical Pathways with Length of Survival in Pulmonary Arterial Hypertension.” Circulation, vol. 144, no. Suppl_1, Nov. 2021, pp. A11344–A11344. 

Introduction: 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.

Methods: Whole genome sequencing was performed on stored samples from 221 PAH patients. 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

Results: Patient 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 years. 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, 29 pathways were associated with survival length. Biologically relevant pathways include Pentose Phosphate (p=0.005), IL-22 (p=0.006), Phospholipase C signaling (p=0.007), Endocannabinoid related pathways (p=0.01), and Thioredoxin pathway (p=0.015). A Neural network model based on the top pathways was constructed (figure) that predicted Long/Short survival.

Conclusions: We identified biologically relevant pathways associated with a Long/Short survival time in PAH patients. Our neural network model for predicting Long/Short survival using the 29 ident ified pathways and has achieved excellent performance.