HLA Alleles Influence the Clinical Signature of Amoxicillin-Clavulanate Hepatotoxicity

Abstract

Background and AimThe genotype-phenotype interaction in drug-induced liver injury (DILI) is a subject of growing interest. Previous studies have linked amoxicillin-clavulanate (AC) hepatotoxicity susceptibility to specific HLA alleles. In this study we aimed to examine potential associations between HLA class I and II alleles and AC DILI with regards to phenotypic characteristics, severity and time to onset in Spanish AC hepatotoxicity cases.MethodsHigh resolution genotyping of HLA loci A, B, C, DRB1 and DQB1 was performed in 75 AC DILI cases and 885 controls.ResultsThe distributions of class I alleles A*3002 (P/Pc = 2.6E-6/5E-5, OR 6.7) and B*1801 (P/Pc = 0.008/0.22, OR 2.9) were more frequently found in hepatocellular injury cases compared to controls. In addition, the presence of the class II allele combination DRB1*1501-DQB1*0602 (P/Pc = 5.1E-4/0.014, OR 3.0) was significantly increased in cholestatic/mixed cases. The A*3002 and/or B*1801 carriers were found to be younger (54 vs 65 years, P = 0.019) and were more frequently hospitalized than the DRB1*1501-DQB1*0602 carriers. No additional alleles outside those associated with liver injury patterns were found to affect potential severity as measured by Hy’s Law criteria. The phenotype frequencies of B*1801 (P/Pc = 0.015/0.42, OR 5.2) and DRB1*0301-DQB1*0201 (P/Pc = 0.0026/0.07, OR 15) were increased in AC DILI cases with delayed onset compared to those corresponding to patients without delayed onset, while the opposite applied to DRB1*1302-DQB1*0604 (P/Pc = 0.005/0.13, OR 0.07).ConclusionsHLA class I and II alleles influence the AC DILI signature with regards to phenotypic expression, latency presentation and severity in Spanish patients.

Drug-Induced Liver Injury

“…Several HLA genotypes, such as HLA-DRB1 * 15 and HLA-DRB1 * 06, have been shown to be more common in humans with amoxicillin-clavulanate-induced DILI, although this association is still strongly influenced by additional confounders, notably ethnicity. [21][22][23] The low positive predictive value of having any HLA allele, even one thought to predispose to DILI, is still too small to aid in the clinical prevention of DILI. 21 Genes involved in drug metabolism have also been studied in an attempt to understand the pathogenesis of idiosyncratic DILI.…”

Genome-Wide Association Studies for Idiosyncratic Drug-Induced Hepatotoxicity: Looking Back–Looking Forward to Next-Generation Innovation

“…Polymorphisms in the human major histocompatibility complex (MHC) gene cluster, referred to as the human leukocyte antigen (HLA), have been demonstrated to contribute to risk of developing idiosyncratic DIH . HLA alleles identified through CGASs include HLA-DQB1*02:01 and DQB1*05:05 for antituberculosis drugs (Chen et al, 2015b;Sharma et al, 2002); HLA-B*58:01 and DRB1*01:02 for nevirapine-containing antiretroviral regimens (Ostrov et al, 2012;Phillips et al, 2013); HLA-DRB1*15:01, DQB1*06:02, A*02:01, and DRB5*01:01 for AC (Andrade et al, 2004;Drago et al, 2014;Hautekeete et al, 1999;O'Donohue et al, 2000;Stephens et al, 2013), and HLA-A*33:01 for ticlopidine (Hirata et al, 2008)-induced DIH.…”

Drug Induced Liver Disease

“…Genetic variation at human leukocyte antigen (HLA) class I & II loci has been shown to be associated with amoxicillin-clavulanate DILD. The strongest association thus far identified is at a single nucleotide polymorphism in the gene encoding the class II HLA-DRB1* 1501-DQB1* 0602 allele [8,9]. Variations of genes for mitochondrial DNA polymerase gamma are associated with valproate hepatotoxicity [10].…”