Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class i and II alleles
Background & Aims: Drug-induced liver injury (DILI), especially from antimicrobial agents, is an important cause of serious liver disease. Amoxicillin-clavulanate (AC) is a leading cause of idiosyncratic DILI, but little is understood about genetic susceptibility to this adverse reaction. Methods: We performed a genome-wide association study using 822,927 single nucleotide polymorphism (SNP) markers from 201 White European and US cases of DILI following AC administration (AC-DILI) and 532 population controls, matched for genetic background. Results: AC-DILI was associated with many loci in the major histocompatibility complex. The strongest effect was with an HLA class II SNP (rs9274407, P = 4.8 × 10-14), which correlated with rs3135388, a tag SNP of HLA-DRB1 (*)1501-DQB1 (*)0602 that was previously associated with AC-DILI. Conditioned on rs3135388, rs9274407 is still significant (P = 1.1 × 10-4). An independent association was observed in the class I region (rs2523822, P = 1.8 × 10-10), related to HLA-A (*)0201. The most significant class I and II SNPs showed statistical interaction (P =.0015). High-resolution HLA genotyping (177 cases and 219 controls) confirmed associations of HLA-A (*)0201 (P = 2 × 10-6) and HLA-DQB1 (*)0602 (P = 5 × 10-10) and their interaction (P =.005). Additional, population-dependent effects were observed in HLA alleles with nominal significance. In an analysis of autoimmune-related genes, rs2476601 in the gene PTPN22 was associated (P = 1.3 × 10-4). Conclusions: Class I and II HLA genotypes affect susceptibility to AC-DILI, indicating the importance of the adaptive immune response in pathogenesis. The HLA genotypes identified will be useful in studies of the pathogenesis of AC-DILI but have limited utility as predictive or diagnostic biomarkers because of the low positive predictive values.