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oai:riuma.uma.es:10630/402692026-02-03T10:57:40Zcom_10630_2254col_10630_37953

Susceptibility to Amoxicillin-Clavulanate-Induced Liver Injury is Influenced by Multiple HLA Class I and II Alleles Lucena-González, María Isabel Molokhia, Mariam Shen, Y Urban, TJ Aithal, Guruprasad P. Andrade-Bellido, Raúl Jesús Day, CP Ruiz-Cabello, Francisco Donaldson, PT Stephens, Camilla Munir, Pirmohamed Romero-Gomez, Manuel Navarro, JM Fontana, Robert J. Miller, M Groome, M Bondon-Guitton, E Conforti, A Stricker, BHC Carvajal, Alfonso Ibanez, L Yue, Qun-Ying Eichelbaum, Michel Floratos, Aris Pe’er, Itsik Daly, Mark J Goldstein, David B Dillon, John F Nelson, Matthew R Watkins, Paul B Daly, Ann K Hepatotoxicidad Medicamentos - Efectos secundarios Farmacogenética Background & Aims: Drug-induced liver injury (DILI), especially from antimicrobial agents, is an important cause of serious liver disease. Amoxicillin-clavulanate (AC) is a leading cause of idiosyncratic DILI, but little is understood about genetic susceptibility to this adverse reaction. Methods: We performed a genome-wide association study using 822,927 singlenucleotide polymorphism (SNP) markers from 201 White European and US cases of ACDILI and 532 population controls, matched for genetic background. Results: AC-DILI was associated with many loci in the major histocompatibility complex. The strongest effect was with a human leukocyte antigen (HLA) class II SNP (rs9274407, P=4.8×10−14), which correlated with rs3135388, a tag SNP of HLADRB1*1501-DQB1*0602 that was previously associated with AC-DILI. Conditioned on rs3135388, rs9274407 is still significant (P=1.1×10−4). An independent association was observed in the class I region (rs2523822, P=1.8×10−10), related to HLA-A*0201. The most significant class I and II SNPs showed statistical interaction (P=0.0015). Highresolution HLA genotyping (177 cases and 219 controls) confirmed associations of HLAA*0201 (P=2×10−6) and HLA-DQB1*0602 (P=5×10−10), and their interaction (P=0.005). Additional, population-dependent effects were observed in HLA alleles with nominal significance. In an analysis of auto-immunerelated genes, rs2476601 in the gene PTPN22 was associated (P=1.3×10−4). Conclusions: Class I and II HLA genotypes affect susceptibility to AC-DILI, indicating the importance of the adaptive immune response in pathogenesis. The HLA genotypes identified will be useful in studies of the pathogenesis of AC-DILI, but have limited utility as predictive or diagnostic biomarkers because of the low positive-predictive values 2025-10-16T09:31:59Z 2025-10-16T09:31:59Z 2025-10-16T09:31:59Z 2011-07 journal article Lucena MI, Molokhia M, Shen Y, Urban TJ, Aithal GP, Andrade RJ, Day CP, Ruiz-Cabello F, Donaldson PT, Stephens C, Pirmohamed M, Romero-Gomez M, Navarro JM, Fontana RJ, Miller M, Groome M, Bondon-Guitton E, Conforti A, Stricker BHC, Carvajal A, Ibanez L, Yue QY, Eichelbaum M, Floratos A, Pe'er I, Daly MJ, Goldstein DB, Dillon JF, Nelson MR, Watkins PB, Daly AK; Spanish DILI Registry; EUDRAGENE; DILIN; DILIGEN; International SAEC. Susceptibility to Amoxicillin-Clavulanate-Induced Liver Injury is Influenced by Multiple HLA Class I and II Alleles. Gastroenterology 2011 Jul;41(1):338-347 https://hdl.handle.net/10630/40269 10.1053/j.gastro.2011.04.001 eng http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 Internacional Elsevier