title: Selected ABCB1, ABCB4 and ABCC2 polymorphisms do not enhance the risk of drug-induced hepatotoxicity in a Spanish cohort.
abstract: OBJECTIVE
  Flawed ABC transporter functions may contribute to increased risk of drug-induced liver injury (DILI). We aimed to analyse the influence of genetic variations in ABC transporters on the risk of DILI development and clinical presentations in a large Spanish DILI cohort.
  
  
  METHODS
  A total of ten polymorphisms in ABCB1 (1236T>C, 2677G>T,A, 3435T>C), ABCB4 (1954A>G) and ABCC2 (-1774G>del, -1549A>G, -24C>T, 1249G>A, 3972C>T and 4544G>A) were genotyped using Taqman 5' allelic discrimination assays or sequencing in 141 Spanish DILI patients and 161 controls. The influence of specific genotypes, alleles and haplotypes on the risk of DILI development and clinical presentations was analysed.
  
  
  RESULTS
  None of the individual polymorphisms or haplotypes was found to be associated with DILI development. Carriers homozygous for the ABCC2 -1774del allele were however only found in DILI patients. Hence, this genotype could potentially be associated with increased risk, though its low frequency in our Spanish cohort prevented a final conclusion. Furthermore, carriers homozygous for the ABCC2 -1774G/-1549A/-24T/1249G/3972T/4544G haplotype were found to have a higher propensity for total bilirubin elevations when developing DILI.
  
  
  CONCLUSIONS
  Our findings do not support a role for the analysed polymorphisms in the ABCB1, ABCB4 and ABCC2 transporter genes in DILI development in Spanish patients. The ABCC2 -1774deldel genotype was however restricted to DILI cases and could potentially contribute to enhanced DILI susceptibility.
authors.affiliation: S Farmacología Clínica and UGC de Gastroenterología y Hepatología, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Ulzurrun
authors.affiliation: S Farmacología Clínica and UGC de Gastroenterología y Hepatología, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
authors.forename: Camilla
authors.initials: C
authors.lastname: Stephens
authors.affiliation: Departamento de Bioquímica y Biología Molecular III/Inmunología, Hospital Universitario Virgen de las Nieves, Universidad de Granada, Granada, Spain; Instituto de Investigación Biosanitario de Granada, Granada, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Ruiz-Cabello
authors.affiliation: S Farmacología Clínica and UGC de Gastroenterología y Hepatología, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Robles-Diaz
authors.affiliation: Departamento de Bioquímica y Biología Molecular III/Inmunología, Hospital Universitario Virgen de las Nieves, Universidad de Granada, Granada, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Saenz-López
authors.affiliation: Servicio de Aparato Digestivo, Hospital Morales Meseguer, Murcia, Spain.
authors.forename: Hacibe
authors.initials: H
authors.lastname: Hallal
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain; Servicio de Gastroenterología, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: German
authors.initials: G
authors.lastname: Soriano
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain; Servicio de Gastroenterología, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain; Escola Universitària d'Infermeria EUI-Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Roman
authors.affiliation: Unidad de Gestión Clínica de Farmacia, Hospital Torrecárdenas, Almería, Spain.
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Fernandez
authors.affiliation: S Farmacología Clínica and UGC de Gastroenterología y Hepatología, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
authors.forename: M Isabel
authors.initials: MI
authors.lastname: Lucena
authors.affiliation: S Farmacología Clínica and UGC de Gastroenterología y Hepatología, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
authors.forename: Raúl J
authors.initials: RJ
authors.lastname: Andrade
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001663:Bilirubin / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics*; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic; D012307:Risk Factors; D013030:Spain; D055815:Young Adult
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D001663:Bilirubin; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C513055:ABCB1 protein, human; C000715087:ABCC2 protein, human; C095122:multidrug resistance protein 3
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