Camilla Stephens1, 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. 1. aUnidad de Gestión Clínica de Enfermedades Digestivas, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, CIBERehd, Málaga bServicio de Digestivo, Hospital Mendaro cServicio de Digestivo, Hospital Mondragón, Guipúzcoa dDepartamento de Bioquímica y Biología Molecular III/Inmunología, Instituto de Investigación Biosanitario de Granada, Hospital Universitario Virgen de las Nieves, Universidad de Granada, Granada eServicio de Gastroenterología, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, CIBERehd fEscola Universitària d'Infermeria EUI-Sant Pau, Universitat Autònoma de Barcelona, Barcelona gServicio de Aparato Digestivo, Hospital Morales Meseguer, Murcia hServicio de Digestivo, Complejo Hospitalario Universitario de Albacete, Albacete iUnidad de Hepatología, Servicio de Aparato Digestivo, Hospital Universitari i Politècnic La Fe, CIBERehd, Valencia, Spain.
Abstract
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.
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.
Authors: Aurelio A Moya-García; Andrés González-Jiménez; Fernando Moreno; Camilla Stephens; María Isabel Lucena; Juan A G Ranea Journal: Genes (Basel) Date: 2022-07-21 Impact factor: 4.141