Allelic variation in CYP3A4 and PLB1 drives feed efficiency and immunometabolic resilience in beef cattle

Immunometabolic traits are increasingly recognized as key determinants of feed efficiency and resilience in beef cattle. This study aimed to identify functional genetic markers associated with these traits by integrating SNP genotyping and gene expression profiling. We evaluated genetic markers for feed efficiency and immunocompetence in 102 crossbred steers (217 ± 8.2 kg) fed a high-forage total mixed ration for 63 days, using GrowSafe8000 intake nodes to calculate residual feed intake (RFI). From the 20 most efficient (low-RFI) and 20 least efficient (high-RFI) animals, we genotyped three metabolic loci (CYP3A4 rs438103222, PLB1 rs456635825, CRAT rs876019788) and profiled blood mRNA levels of these, plus eight innate/adaptive immune genes. Logistic regression revealed that CYP3A4 and PLB1 polymorphisms, but not CRAT, were strongly associated with initial and final body weight, average daily gain, and feed intake: CYP3A4 A/A and PLB1 A-allele carriers achieved superior growth on reduced feed. Haplotype reconstruction across the three loci defined eight multi-SNP combinations, with the C-A-A haplotype enriched in low-RFI steers and combinations harboring CYP3A4 A and PLB1 A alleles linked to low RFI. Intriguingly, these favorable genotypes also overlapped with up-regulation of immune sensors and effectors (e.g., CD14, TLR4, TNF-α), indicating a coordinated metabolic-immune adaptation in efficient cattle. Collectively, our results validate CYP3A4 and PLB1 as high-impact quantitative trait nucleotides for marker-assisted selection aimed at simultaneously improving feed efficiency and immune resilience in beef production.