title: Autoantibody presentation in drug-induced liver injury and idiopathic autoimmune hepatitis: the influence of human leucocyte antigen alleles.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.affiliation: 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.
authors.forename: Camilla
authors.initials: C
authors.lastname: Stephens
authors.forename: Agustin
authors.initials: A
authors.lastname: Castiella
authors.forename: Eva M
authors.initials: EM
authors.lastname: Gomez-Moreno
authors.forename: Pedro
authors.initials: P
authors.lastname: Otazua
authors.forename: Miguel-Ángel
authors.initials: MÁ
authors.lastname: López-Nevot
authors.forename: Eva
authors.initials: E
authors.lastname: Zapata
authors.forename: Aida
authors.initials: A
authors.lastname: Ortega-Alonso
authors.forename: Francisco
authors.initials: F
authors.lastname: Ruiz-Cabello
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Medina-Cáliz
authors.forename: Mercedes
authors.initials: M
authors.lastname: Robles-Díaz
authors.forename: German
authors.initials: G
authors.lastname: Soriano
authors.forename: Eva
authors.initials: E
authors.lastname: Roman
authors.forename: Hacibe
authors.initials: H
authors.lastname: Hallal
authors.forename: José M
authors.initials: JM
authors.lastname: Moreno-Planas
authors.forename: Martin
authors.initials: M
authors.lastname: Prieto
authors.forename: Raúl J
authors.initials: RJ
authors.lastname: Andrade
authors.forename: M Isabel
authors.initials: MI
authors.lastname: Lucena
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001323:Autoantibodies / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000276:immunology*; D005260:Female; D020022:Genetic Predisposition to Disease; D019693:Hepatitis, Autoimmune / Q000235:genetics / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D013030:Spain; D044465:White People / Q000235:genetics
chemical_list: D001323:Autoantibodies; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II