RT Journal Article
T1 Susceptibility to Amoxicillin-Clavulanate-Induced Liver Injury is Influenced by Multiple HLA Class I and II Alleles
A1 Lucena-González, María Isabel
A1 Molokhia, Mariam
A1 Shen, Y
A1 Urban, TJ
A1 Aithal, Guruprasad P.
A1 Andrade-Bellido, Raúl Jesús
A1 Day, CP
A1 Ruiz-Cabello, Francisco
A1 Donaldson, PT
A1 Stephens, Camilla
A1 Munir, Pirmohamed
A1 Romero-Gomez, Manuel
A1 Navarro, JM
A1 Fontana, Robert J.
A1 Miller, M
A1 Groome, M
A1 Bondon-Guitton, E
A1 Conforti, A
A1 Stricker, BHC
A1 Carvajal, Alfonso
A1 Ibanez, L
A1 Yue, Qun-Ying
A1 Eichelbaum, Michel
A1 Floratos, Aris
A1 Pe’er, Itsik
A1 Daly, Mark J
A1 Goldstein, David B
A1 Dillon, John F
A1 Nelson, Matthew R
A1 Watkins, Paul B
A1 Daly, Ann K
K1 Hepatotoxicidad
K1 Medicamentos - Efectos secundarios
K1 Farmacogenética
AB Background & Aims: Drug-induced liver injury (DILI), especially from antimicrobialagents, is an important cause of serious liver disease. Amoxicillin-clavulanate (AC) is aleading cause of idiosyncratic DILI, but little is understood about genetic susceptibilityto 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.
AB Results: AC-DILI was associated with many loci in the major histocompatibilitycomplex. 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 onrs3135388, rs9274407 is still significant (P=1.1×10−4). An independent association wasobserved in the class I region (rs2523822, P=1.8×10−10), related to HLA-A*0201. Themost 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 withnominal significance. In an analysis of auto-immunerelated genes, rs2476601 in the genePTPN22 was associated (P=1.3×10−4).
AB Conclusions: Class I and II HLA genotypes affect susceptibility to AC-DILI, indicatingthe importance of the adaptive immune response in pathogenesis. The HLA genotypesidentified will be useful in studies of the pathogenesis of AC-DILI, but have limited utilityas predictive or diagnostic biomarkers because of the low positive-predictive values
PB Elsevier
YR 2011
FD 2011-07
LK https://hdl.handle.net/10630/40269
UL https://hdl.handle.net/10630/40269
LA eng
NO 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
NO https://openpolicyfinder.jisc.ac.uk/id/publication/4770
DS RIUMA. Repositorio Institucional de la Universidad de Málaga
RD 19 ene 2026