Autoantibody presentation in drug-induced liver injury and idiopathic autoimmune hepatitis: The influence of human leucocyte antigen alleles

Camilla Stephens, Agustin Castiella, Eva M. Gomez-Moreno, Pedro Otazua, Miguel Ángel López-Nevot, Eva Zapata, Aida Ortega-Alonso, Francisco Ruiz-Cabello, Inmaculada Medina-Cáliz, Mercedes Robles-Díaz, German Soriano, Eva Roman, Hacibe Hallal, José M. Moreno-Planas, Martin Prieto, Raúl J. Andrade, M. Isabel Lucena

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Abstract

© Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved. Objectives Positive autoantibody (AAB) titres are commonly encountered in autoimmune hepatitis (AIH) and in a proportion of drug-induced liver injury (DILI) patients. The underlying mechanism for selective AAB occurrence in DILI is unknown, but could be associated with variations in immune-Associated genes. Hence, we aimed to analyse human leucocyte antigen (HLA) allele compositions in DILI with positive (+) and negative (-) AAB titres and in AIH patients. Methods High-resolution genotyping of HLA class I (A, B, C) and II (DRB1, DQB1) loci was performed on 207 DILI and 50 idiopathic AIH patients and compared with 885 healthy Spanish controls. Results Compared with controls, HLA-B∗08:01 [44 vs. 9.7%, P=3.7E-13/corrected P-value (Pc) = 1.0E-11], C∗07:01 (46 vs. 24%, P=6.4E-04/Pc = 0.012), DRB1∗03:01 (58 vs. 21.5%, P=5.0E-09/Pc = 1.0E-07) and DQB1∗02:01 (56 vs. 22%, P=6.8E-08/Pc = 9.0E-07) were significantly more frequent in AIH patients. The HLA-A∗01:01 frequency was increased in the same population, but did not reach significance after Bonferroni's correction (34 vs. 19%, P = 0.02/Pc = 0.37). Fifty-eight of 207 DILI patients presented positive titres for at least one AAB (predominantly antinuclear antibody 76% and antismooth muscle antibody 28%). There was a tendency towards higher representation of DRB1∗14:01 and DQB1∗05:03 in DILI AAB+ compared with DILI AAB- (13.8 vs. 4.0%, P = 0.02/Pc = 0.5; 13.8 vs. 4.7%, P = 0.04/Pc = 0.5). Conclusion The presence of HLA alleles B∗08:01, C∗07:01, DRB1∗03:01, DQB1∗02:01 and possibly A∗01:01 enhances the risk of AIH (type 1) in Spanish patients. These alleles form part of the ancestral haplotype 8.1. HLA-DRB1∗14:01 and DQB1∗05:03 could potentially increase the risk of positive AAB (particularly antinuclear antibody) in Spanish DILI patients.
Original languageEnglish
Pages (from-to)414-422
JournalPharmacogenetics and Genomics
Volume26
Issue number9
DOIs
Publication statusPublished - 1 Sep 2016

Keywords

  • hepatotoxicity
  • human immune system
  • liver disease
  • major histocompatibility complex
  • pharmacogenetics

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    Stephens, C., Castiella, A., Gomez-Moreno, E. M., Otazua, P., López-Nevot, M. Á., Zapata, E., Ortega-Alonso, A., Ruiz-Cabello, F., Medina-Cáliz, I., Robles-Díaz, M., Soriano, G., Roman, E., Hallal, H., Moreno-Planas, J. M., Prieto, M., Andrade, R. J., & Isabel Lucena, M. (2016). Autoantibody presentation in drug-induced liver injury and idiopathic autoimmune hepatitis: The influence of human leucocyte antigen alleles. Pharmacogenetics and Genomics, 26(9), 414-422. https://doi.org/10.1097/FPC.0000000000000230