@misc{10481/31146,
year = {2013},
url = {http://hdl.handle.net/10481/31146},
abstract = {[Background 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.},
organization = {This study was supported by the research grant Proyecto Excelencia P10-CTS-6470 and by the Agencia Española del Medicamento. CIBERehd and Red Genómica del Cancer are funded by Instituto de Salud Carlos III.},
publisher = {Public Library of Science (PLOS)},
keywords = {Alleles},
keywords = {Amino acid analysis},
keywords = {Arginine},
keywords = {Bilirubin},
keywords = {Damage mechanics},
keywords = {Genotyping},
keywords = {Phenotypes},
keywords = {Spain},
title = {HLA Alleles Influence the Clinical Signature of Amoxicillin-Clavulanate Hepatotoxicity},
author = {Stephens, Camilla and López Nevot, Miguel Ángel and Ruiz-Cabello, Francisco and Ulzurrun, Eugenia and Soriano, Germán and Romero-Gómez, Manuel and Moreno-Casares, Anonia and Lucena, María Isabel and Andrade, Raúl J.},
}