RT info:eu-repo/semantics/article
T1 Susceptibility to Amoxicillin-Clavulanate-Induced Liver Injury Is Influenced by Multiple HLA Class I and II Alleles
A1 Lucena, M. Isabel
A1 Molokhia, Mariam
A1 Shen, Yufeng
A1 Urban, Thomas J.
A1 Aithad, Guruprasad P.
A1 Andrade, Raúl J
A1 Day, Christopher P.
A1 Ruiz Cabello, Francisco
A1 Donaldson, Peter T.
A1 Stephens, Camilla
A1 Pirmohamed, Munir
A1 Romero Gómez, Manuel
A1 Navarro, José María
A1 Fontana, Roberto J.
A1 Miller, Michael
A1 Groome, Max
A1 Bondon-Guitton, Emmanuelle
A1 Conforti, Anita
A1 Stricker, Bruno H.C.
A1 Carvajal García-Pando, Alfonso
A1 Ibánez, Luisa
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 Amoxicilina - Efectos secundarios
AB Background & AimsDrug-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.MethodsWe performed a genome-wide association study using 822,927 single-nucleotide polymorphism (SNP) markers from 201 White European and US cases of AC-DILI and 532 population controls, matched for genetic background.ResultsAC-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 HLA-DRB1*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). High-resolution HLA genotyping (177 cases and 219 controls) confirmed associations of HLA-A*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).ConclusionsClass 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.
PB WB Saunders
SN 0016-5085
YR 2011
FD 2011
LK http://uvadoc.uva.es/handle/10324/8577
UL http://uvadoc.uva.es/handle/10324/8577
LA spa
NO Gastroenterology. 2011 Jul; 141(1): 338–347
NO Producción Científica
DS UVaDOC
RD 22-nov-2024