Pharmacogenomics of Antiparasitic Drug Efficacy in Nigerian Cattle Breeds: SNP Discovery and Functional Validation

Pharmacogenomics examines how genetic variation influences individual responses to drugs, and its application in veterinary species has the potential to guide personalised treatment protocols and explain population-level variability in drug efficacy and adverse events. In Nigerian cattle, inter-breed pharmacokinetic differences for antiparasitic drugs have been observed empirically, but the underlying genetic determinants remain uncharacterised. This study conducted a genome-wide association and functional pharmacogenomics investigation of antiparasitic drug efficacy variation in White Fulani, N'Dama, Keteku, and Friesian crossbred cattle from multiple Nigerian states. Six hundred cattle were genotyped using the 50K Illumina BovineHD BeadChip. Pharmacokinetic phenotyping was performed using ivermectin, doramectin, and albendazole administered at standard doses, with sparse blood sampling and HPLC quantification of plasma concentrations. Ivermectin area under the curve variability was the primary pharmacokinetic endpoint for genome-wide association analysis. Candidate SNPs were validated in a replication cohort and prioritised candidates were functionally evaluated by in vitro CYP450 enzyme activity assays using liver microsomes and by CRISPR-Cas9 editing of candidate variants in bovine hepatocyte cell lines. Genome-wide association identified 12 significant SNPs on Bos taurus autosomes 2, 7, and 14 associated with ivermectin AUC variability, with the strongest association in a ABCB1 gene intron variant at p less than 5 x 10 to the minus 8 power. N'Dama cattle showed the highest frequency of the high-AUC allele, consistent with their previously observed longer drug half-lives. CRISPR-edited cells carrying the candidate variant showed 2.4-fold higher P-glycoprotein efflux activity. These findings provide first pharmacogenomic insights into antiparasitic drug disposition in Nigerian cattle breeds with major implications for breed-specific dosing optimisation. Keywords: pharmacogenomics, antiparasitic drugs, cattle breeds, SNP, ivermectin.