Selected ABCB1, ABCB4 and ABCC2 polymorphisms do not enhance the risk of drug-induced hepatotoxicity in a Spanish cohort

• Published in: PloS one Vol. 9; no. 4; p. e94675
• Main Authors: Ulzurrun, Eugenia, Stephens, Camilla, Ruiz-Cabello, Francisco, Robles-Diaz, Mercedes, Saenz-López, Pablo, Hallal, Hacibe, Soriano, German, Roman, Eva, Fernandez, M Carmen, Lucena, M Isabel, Andrade, Raúl J
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.04.2014; Public Library of Science (PLoS)
• Subjects: ABC transporter; Adolescent; Adult; Aged; Aged, 80 and over; Alleles; ATP Binding Cassette Transporter, Sub-Family B - genetics; Bile; Bilirubin; Bilirubin - blood; Biology and Life Sciences; Carrier proteins; Carriers; Chemical and Drug Induced Liver Injury - genetics; Development and progression; Female; Genetic aspects; Genetic diversity; Genetic polymorphisms; Genomics; Genotype; Genotypes; Haplotypes; Health risks; Hepatotoxicity; Homozygote; Humans; Injury analysis; Linkage Disequilibrium; Liver; Liver diseases; Male; Medicine and Health Sciences; Middle Aged; Multidrug Resistance-Associated Proteins - genetics; Patients; Physiological aspects; Polymorphism, Genetic; Research and Analysis Methods; Risk; Risk Factors; Spain; Young Adult; Spain
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0094675

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. 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. 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. 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.