Whole Genome Transciptome Co-Expression Network Analysis Identifies Pharmacogenetic Variation in Individual, Breed and Gender Drug Metabolism

Drug use in animal agriculture has received increased attention due to welfare concerns, food safety, and drug resistance. Therefore characterizing pathways resulting in variation across animals and/or inherent breed and sex differences in how they metabolize drugs is of importance. Our objective was to characterize networks and/or genes involved in metabolizing fenbendazole (FBZ) and flunixin meglumine (FLU). The population consisted of progeny that were derived from sires across four breeds (Duroc, Hampshire, Landrace and Yorkshire) that were mated to a common sow population. Progeny were randomly placed into groups: no drug (untreated), FLU or FBZ administered. An initial dose of FLU or FBZ was administered and blood collected over a 48-hour period to collect pharmacokinetic (PK) parameters and a second dose was given with animals sacrificed one hour later. Liver RNA-Seq transcriptome profiles from 20 animals with extreme PK profiles within each treatment group balanced across breed and sex were generated. Weighted gene co-expression network analysis identified 5 and 3 modules of co-expressed genes correlated (P-value <0.10; r >0.30) with PK parameters for FBZ and FLU, respectively. A portion of genes within modules for either FBZ or FLU with previously reported drug metabolism functions were differentially expressed across breed or sex (FDR <0.05) and included HSD17B2, CYP2A19, CYP4V2, CYP7A1, CYP2B22, CES2, MT1A, ABCC3 and GSTA1. The correlation between the differential connectivity of a gene between treated and untreated for FBZ and FLU was moderate (r =0.56). The current work has characterized modules and genes that impact drug metabolism.