`Blood Toxicogenomics Reveals Potential Biomarkers for Management of Idiosyncratic Drug-Induced Liver Injury

Rachel Church ^1,2 Benedict Anchang ³ Brian D Bennett ⁴ Pierre R. Bushel ³ Paul Brent Watkins ^2*

• ¹ University of North Carolina at Chapel Hill, Chapel Hill, United States
• ² Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
• ³ Biostatistics & Computational Biology, National Institute of Environmental Health Sciences, Research Triangle Park, United States
• ⁴ Integrative Bioinformatics Groups, National Institute of Environmental Health Sciences, Research Triangle Park, United States

Accurate diagnosis, assessment, and prognosis of idiosyncratic drug-induced liver injury (IDILI) is problematic, in part due to the shortcomings of traditional blood biomarkers. Studies in rodents and healthy volunteers have supported that RNA transcript changes in whole blood may address some of these shortcomings. In this study, we conducted RNA-Seq analysis on peripheral blood samples collected from 55 patients with acute IDILI and 17 patients with liver injuries not attributed to IDILI. Three differentially expressed genes (DEGs; CFD, SQLE, and INKA1) were identified as significantly associated with IDILI vs other liver injuries. No DEGs were identified comparing IDILI patients to the 5 patients with autoimmune hepatitis, suggesting possible common underlying mechanisms. Two genes (VMO1 and EFNA1) were significantly associated with hepatocellular injury compared to mixed/cholestatic injury. When patients with severe vs milder IDILI were compared, we identified over 500 DEGs. The top pathways identified from these DEGs had in common down regulation of multiple T-cell specific genes. Further analyses confirmed that these changes could largely be accounted for by a fall in the concentration of circulating T-cells during severe DILI, perhaps due to exhaustion or sequestration of these cells in the liver. Exploration of DEGs specific for the individual causal agents was largely unsuccessful, but isoniazid-induced IDILI demonstrated 25 DEGs compared to other non-isoniazid IDILI cases. Finally, among the 14 IDILI patients that had hepatocellular jaundice (i.e. Hy's Law cases), we identified 39 DEGs between the 4 patients with fatal or liver transplantation outcomes compared to those that recovered. These findings suggest the potential for blood-based transcriptomic biomarkers to aid in the diagnosis and prognostic stratification of IDILI.