Whole-exome sequencing reveals cumulative rare variant burden associated with susceptibility to anti-tuberculosis drug-induced liver injury in a Han Chinese cohort

Background Anti-tuberculosis drug-induced liver injury (AT-DILI) complicates 2-28% of tuberculosis treatments, limiting therapy and occasionally causing acute liver failure. Inter-individual susceptibility remains incompletely explained by known genetic factors. Methods We performed an integrated whole-exome sequencing (WES) analysis of an AT-DILI cohort, combining common variant association analysis, rare variant burden testing at the gene and pathway levels, and exploratory genotype–phenotype analyses. A matched sub-cohort was further analyzed for cis genetic–epigenetic associations between genetic variants and DNA methylation. Results Rare variant burden analysis prioritized PTGS1 as a candidate susceptibility gene (P SKAT-O = 4.58 × 10 -4 , Enrichment Ratio = 3.461), with an increased burden of rare functional variants observed among AT-DILI cases. Pathway-level burden analyses further indicated enrichment of biological processes related to xenobiotic metabolism, immune regulation, and cellular stress responses, including regulated cell death. A cis genetic–epigenetic association analysis in a matched sub-cohort (n = 28) identified a nominal association at the GPR132 locus, suggesting a potential relationship between genetic variation and DNA methylation. Furthermore, genotype–phenotype analyses showed that rare variant burden in S100A2 displayed nominal positive correlations with peak alanine aminotransferase (ALT) levels. Conclusion These findings provide an integrated characterization of candidate rare variant signals and associated biological processes in AT-DILI. The results prioritize PTGS1 and other candidate loci for further investigation and expand our understanding of potential genetic contributors to inter-individual variability in anti-tuberculosis treatment outcomes.