Candidate Pharmacogenomic and HLA Risk Alleles for Drug-Induced Liver Injury in Vietnamese Cancer Patients: A Pre-Specified Case-Control Study

Abstract Drug-induced liver injury (DILI) complicates chemotherapy, tyrosine kinase inhibitor (TKI), and immune checkpoint inhibitor treatment, yet no matched case-control study has examined germline risk factors for treatment-related DILI in a Southeast Asian population. We studied 101 RUCAM-adjudicated DILI cases and 101 matched controls, genotyped on a custom array (43,317 variants) enriched for HLA and pharmacogenes. We tested 90 candidate pharmacogenomic variants, HLA alleles by drug class, and CPIC actionable-allele burden, ran a genome-wide scan, and attempted to replicate the FOXO3 rs4946935-gefitinib association. No candidate variant, estimable HLA-by-drug-class cell (6 of 24), or genome-wide variant (9.12 million tested) reached significance. CPIC burden was not associated with DILI (OR 0.83, 95% CI 0.44-1.55), nor was the FOXO3-by-TKI interaction. The design detects only large-effect alleles at common frequencies. Results held across six sample subsets and, for candidate variants, two imputation panels. Larger collaborative studies are needed to detect moderate effects