Genetic factors affecting antimicrobial-induced liver injury

Abstract

Flucloxacillin and co-amoxiclav are both associated with drug-induced liver injury (DILI). HLA genotype is an important predictor of DILI susceptibility but it is likely that non-HLA risk factors also contribute. This study aimed to characterise non-HLA risk factors in larger cohorts (155 flucloxacillin and 165 co-amoxiclav adjudicated cases) than previously. Drug causality of the cases was assessed using the RUCAM method which showed 88.1% of the cases were either highly probable or probable but 11.9% of them indicated a possible causality for the drug. Variants showing associations in previous candidate gene, genome-wide association and exome sequencing studies were genotyped to extend these findings. A SNP (rs2476601) in PTPN22, which encodes a protein involved in T-cell-receptor signalling had already been shown to be a risk factor for co-amoxiclav DILI. This was confirmed by genotyping co-amoxiclav DILI cases (n=99) (OR=2.74, 95% CI=1.58–4.77; P=4.1x10-4). There was also a significant effect for flucloxacillin DILI (OR=1.9, 95% CI=1.1–3.1; P=0.02). Exome sequencing performed previously on 66 UK co-amoxiclav DILI cases reported significant associations for several variants, including rs117511121 in IL12RB1 and rs145855109 in TPH1. Additional cases (n=99) were genotyped for rs117511121, confirming the association (OR 6.5, 95% CI=1.5-27.8; P=0.012). No association with IL12RB1 genotype was seen for flucloxacillin DILI. Functional analysis of IL12RB1 using reporter gene constructs revealed significantly lower luciferase activity for the variant constructs. The TPH1 variant was confirmed to be associated with co-amoxiclav DILI (n=99) (OR=14.73, 95% CI=2.94–73.92; P=0.013). Polymorphisms in the following genes showed no significant association with DILI due to either drug: FMO5, GPX1, GSTM1, GSTT1, HFE, KCNJ1, SHMT1, SLCO1B1, SOD2, ST6GAL1 and UGT1A1. The findings for PTPN22 and IL12RB1 confirm the relevance of T cell responses to co-amoxiclav DILI. Odds ratios of 17 for DILI risk can be calculated for individuals with the at risk HLA alleles (A*02:01 and DRB1*15:01) and the PTPN22 and IL12RB1 variants, assuming an additive model. PTPN22 is also relevant to flucloxacillin DILI but, though biologically plausible as a risk factor, appears minor compared with HLA-B*57:01.