Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles

Abstract

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.

Figure 1. AC-DILI genome-wide association results

Each point represents association analysis results for a single SNP with chromosome position on the x axis and -log₁₀ p-value on the y axis. All 201 DILI cases and 532 population controls were included in the analysis. SNPs with p-values smaller than 10⁻⁶ and 10⁻⁷ are highlighted in green and red, respectively. Panel A shows the results for the entire genome. Panels B to D show enlarged sections of the MHC region. Panel B is an enlargement of the results presented in A, panel C shows the analysis of each SNP in this chromosome region conditioned on the top class II SNP (rs9274407) and panel D analysis of each SNP conditioned on the top class I and II SNPs (rs9274407 and rs2523822). Positions of a range of MHC genes are shown in B to D.

Figure 2. Additional Q-Q plots for ADME and autoimmune genes

A shows a Q-Q plot for ADME genes and B a Q-Q plot for GWAS hits for autoimmune disease genes. The autoimmune disease SNPs studied related to type 1 diabetes, Crohn’s disease, celiac disease, systemic lupus erythematosus, ankylosing spondylitis, primary biliary cirrhosis, systemic sclerosis, juvenile arthritis and Grave’s disease. All show an association with at least one of these diseases with p ≤ 5×10^−8.

Figure 3. Relationship between HLA genotype and clinical parameters

A shows the relationship between HLA-B*1801 and peak ALT in Spanish cases and B a comparison of odds ratios for different liver damage patterns for HLA-B*1801 in Spanish cases and controls.