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Killer Immunoglobulin-Like Receptor Profiles Are not Associated with Risk of Amoxicillin-Clavulanate–Induced Liver Injury in Spanish Patients

Natural killer cells are an integral part of the immune system and represent a large proportion of the lymphocyte population in the liver. The activity of these cells is regulated by various cell surface receptors, such as killer Ig-like receptors (KIR) that bind to human leukocyte antigen (HLA) cla...

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Autores principales: Stephens, Camilla, Moreno-Casares, Antonia, López-Nevot, Miguel-Ángel, García-Cortés, Miren, Medina-Cáliz, Inmaculada, Hallal, Hacibe, Soriano, German, Roman, Eva, Ruiz-Cabello, Francisco, Romero-Gomez, Manuel, Lucena, M. Isabel, Andrade, Raúl J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4999432/
https://www.ncbi.nlm.nih.gov/pubmed/27616993
http://dx.doi.org/10.3389/fphar.2016.00280
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author Stephens, Camilla
Moreno-Casares, Antonia
López-Nevot, Miguel-Ángel
García-Cortés, Miren
Medina-Cáliz, Inmaculada
Hallal, Hacibe
Soriano, German
Roman, Eva
Ruiz-Cabello, Francisco
Romero-Gomez, Manuel
Lucena, M. Isabel
Andrade, Raúl J.
author_facet Stephens, Camilla
Moreno-Casares, Antonia
López-Nevot, Miguel-Ángel
García-Cortés, Miren
Medina-Cáliz, Inmaculada
Hallal, Hacibe
Soriano, German
Roman, Eva
Ruiz-Cabello, Francisco
Romero-Gomez, Manuel
Lucena, M. Isabel
Andrade, Raúl J.
author_sort Stephens, Camilla
collection PubMed
description Natural killer cells are an integral part of the immune system and represent a large proportion of the lymphocyte population in the liver. The activity of these cells is regulated by various cell surface receptors, such as killer Ig-like receptors (KIR) that bind to human leukocyte antigen (HLA) class I ligands on the target cell. The composition of KIR receptors has been suggested to influence the development of specific diseases, in particularly autoimmune diseases, cancer and reproductive diseases. The role played in idiosyncratic drug-induced liver injury (DILI) is currently unknown. In this study, we examined KIR gene profiles and HLA class I polymorphisms in amoxicillin-clavulanate (AC) DILI patients in search for potential risk associations. One hundred and two AC DILI patients and 226 controls were genotyped for the presence or absence of 16 KIR loci, including the two pseudogenes 2DP1 and 3DP1. No significant differences were found in the distribution of individual KIRs between patients and controls, which were comparable to previously reported KIR data from ethnically similar cohorts. The 21.6 and 21.2% of the patients and controls, respectively, were homozygous haplotype A carriers, while 78.4 and 78.8%, respectively, contained at least one B haplotype (Bx). The genotypes translated into 27 (AC DILI) and 46 (controls) different gene profiles, with 19 being present in both groups. The most frequent Bx gene profile containing KIRs 2DS2, 2DL2, 2DL3, 2DP1, 2DL1, 3DL1, 2DS4, 3DL2, 3DL3, 2DL4, and 3PD1 was present in 16% of the DILI patients and 14% of the controls. The distribution of HLA class I epitopes did not differ significantly between AC DILI patients and controls. The most frequent receptor-ligand combinations in the DILI patients were 2DL3 + epitope C1 (67%) and 3DL1 + Bw4 motif (67%), while 2DL1 + epitope C2 (69%) and 3DL1 + Bw4 motif (69%) predominated in the controls. This is to our knowledge the first analysis of KIR receptor-HLA ligand associations in DILI, although our findings do not support evidence of these genetic variations playing a major role in AC DILI development.
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spelling pubmed-49994322016-09-09 Killer Immunoglobulin-Like Receptor Profiles Are not Associated with Risk of Amoxicillin-Clavulanate–Induced Liver Injury in Spanish Patients Stephens, Camilla Moreno-Casares, Antonia López-Nevot, Miguel-Ángel García-Cortés, Miren Medina-Cáliz, Inmaculada Hallal, Hacibe Soriano, German Roman, Eva Ruiz-Cabello, Francisco Romero-Gomez, Manuel Lucena, M. Isabel Andrade, Raúl J. Front Pharmacol Pharmacology Natural killer cells are an integral part of the immune system and represent a large proportion of the lymphocyte population in the liver. The activity of these cells is regulated by various cell surface receptors, such as killer Ig-like receptors (KIR) that bind to human leukocyte antigen (HLA) class I ligands on the target cell. The composition of KIR receptors has been suggested to influence the development of specific diseases, in particularly autoimmune diseases, cancer and reproductive diseases. The role played in idiosyncratic drug-induced liver injury (DILI) is currently unknown. In this study, we examined KIR gene profiles and HLA class I polymorphisms in amoxicillin-clavulanate (AC) DILI patients in search for potential risk associations. One hundred and two AC DILI patients and 226 controls were genotyped for the presence or absence of 16 KIR loci, including the two pseudogenes 2DP1 and 3DP1. No significant differences were found in the distribution of individual KIRs between patients and controls, which were comparable to previously reported KIR data from ethnically similar cohorts. The 21.6 and 21.2% of the patients and controls, respectively, were homozygous haplotype A carriers, while 78.4 and 78.8%, respectively, contained at least one B haplotype (Bx). The genotypes translated into 27 (AC DILI) and 46 (controls) different gene profiles, with 19 being present in both groups. The most frequent Bx gene profile containing KIRs 2DS2, 2DL2, 2DL3, 2DP1, 2DL1, 3DL1, 2DS4, 3DL2, 3DL3, 2DL4, and 3PD1 was present in 16% of the DILI patients and 14% of the controls. The distribution of HLA class I epitopes did not differ significantly between AC DILI patients and controls. The most frequent receptor-ligand combinations in the DILI patients were 2DL3 + epitope C1 (67%) and 3DL1 + Bw4 motif (67%), while 2DL1 + epitope C2 (69%) and 3DL1 + Bw4 motif (69%) predominated in the controls. This is to our knowledge the first analysis of KIR receptor-HLA ligand associations in DILI, although our findings do not support evidence of these genetic variations playing a major role in AC DILI development. Frontiers Media S.A. 2016-08-26 /pmc/articles/PMC4999432/ /pubmed/27616993 http://dx.doi.org/10.3389/fphar.2016.00280 Text en Copyright © 2016 Stephens, Moreno-Casares, López-Nevot, García-Cortés, Medina-Cáliz, Hallal, Soriano, Roman, Ruiz-Cabello, Romero-Gomez, Lucena and Andrade. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Stephens, Camilla
Moreno-Casares, Antonia
López-Nevot, Miguel-Ángel
García-Cortés, Miren
Medina-Cáliz, Inmaculada
Hallal, Hacibe
Soriano, German
Roman, Eva
Ruiz-Cabello, Francisco
Romero-Gomez, Manuel
Lucena, M. Isabel
Andrade, Raúl J.
Killer Immunoglobulin-Like Receptor Profiles Are not Associated with Risk of Amoxicillin-Clavulanate–Induced Liver Injury in Spanish Patients
title Killer Immunoglobulin-Like Receptor Profiles Are not Associated with Risk of Amoxicillin-Clavulanate–Induced Liver Injury in Spanish Patients
title_full Killer Immunoglobulin-Like Receptor Profiles Are not Associated with Risk of Amoxicillin-Clavulanate–Induced Liver Injury in Spanish Patients
title_fullStr Killer Immunoglobulin-Like Receptor Profiles Are not Associated with Risk of Amoxicillin-Clavulanate–Induced Liver Injury in Spanish Patients
title_full_unstemmed Killer Immunoglobulin-Like Receptor Profiles Are not Associated with Risk of Amoxicillin-Clavulanate–Induced Liver Injury in Spanish Patients
title_short Killer Immunoglobulin-Like Receptor Profiles Are not Associated with Risk of Amoxicillin-Clavulanate–Induced Liver Injury in Spanish Patients
title_sort killer immunoglobulin-like receptor profiles are not associated with risk of amoxicillin-clavulanate–induced liver injury in spanish patients
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4999432/
https://www.ncbi.nlm.nih.gov/pubmed/27616993
http://dx.doi.org/10.3389/fphar.2016.00280
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