HLA alleles influence the clinical signature of amoxicillin-clavulanate hepatotoxicity

• Published in: PloS one Vol. 8; no. 7; p. e68111
• Main Authors: Stephens, Camilla, López-Nevot, Miguel-Ángel, Ruiz-Cabello, Francisco, Ulzurrun, Eugenia, Soriano, Germán, Romero-Gómez, Manuel, Moreno-Casares, Antonia, Lucena, M Isabel, Andrade, Raúl J
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09.07.2013; Public Library of Science (PLoS)
• Subjects: Adult; Aged; Alleles; Amoxicillin; Amoxicillin-Potassium Clavulanate Combination - toxicity; Anti-Bacterial Agents - toxicity; Antibiotics; Antigens; Bilirubin - metabolism; Carriers; Chemical and Drug Induced Liver Injury - genetics; Chemical and Drug Induced Liver Injury - metabolism; Clavulanate; Collaboration; Drb1 protein; Female; Genetic aspects; Genetic Association Studies; Genomes; Genotype; Genotyping; Hepatitis; Hepatology; Hepatotoxicity; Histocompatibility antigen HLA; Histocompatibility Antigens Class I - chemistry; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class II - chemistry; Histocompatibility Antigens Class II - genetics; HLA Antigens - chemistry; HLA Antigens - genetics; Hospitals; Humans; Injuries; International organizations; Latency; Liver; Liver diseases; Male; Medicine; Middle Aged; Patients; Penicillin; Phenotype; Spain
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0068111

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. High resolution genotyping of HLA loci A, B, C, DRB1 and DQB1 was performed in 75 AC DILI cases and 885 controls. 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). HLA class I and II alleles influence the AC DILI signature with regards to phenotypic expression, latency presentation and severity in Spanish patients.