Stephens, CamillaLópez-Nevot, Miguel-ÁngelRuiz-Cabello, FranciscoUlzurrun, EugeniaSoriano, GermánRomero-Gómez, ManuelMoreno-Casares, AntoniaLucena, M IsabelAndrade, Raul J2024-01-152024-01-152013-07http://hdl.handle.net/10668/1272http://hdl.handle.net/20.500.12105/17053BACKGROUND AND AIM: The 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. METHODS: High resolution genotyping of HLA loci A, B, C, DRB1 and DQB1 was performed in 75 AC DILI cases and 885 controls. RESULTS: The 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). CONCLUSIONS: HLA class I and II alleles influence the AC DILI signature with regards to phenotypic expression, latency presentation and severity in Spanish patients.engVoRhttps://creativecommons.org/licenses/by/4.0/Combinación Amoxicilina-Clavulanato de PotasioEnfermedad Hepática Inducida por DrogasPredisposición Genética a la EnfermedadHaplotiposFenotipoInmunidad AdaptativaAntibacterianosGenes Clase I del Complejo de Histocompatibilidad (MHC)Genes Clase II del Complejo de Histocompatibilidad (MHC)Antígenos HLA-AAntígenos HLA-DQAntígenos HLA-DRCadenas beta de HLA-DRFactores de riesgoEspañaAmoxicillin-Potassium Clavulanate CombinationDrug-Induced Liver InjuryGenetic Predisposition to DiseaseHaplotypesPhenotypeAdaptive ImmunityAnti-Bacterial AgentsGenes, MHC Class IGenes, MHC Class IIHLA-A AntigensHLA-DQ AntigensHLA-DR AntigensHLA-DR beta-ChainsRisk FactorsSpainAttribution 4.0 International2387451410.1371/journal.pone.00681111932-6203PloS Oneopen access