Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles.
Gastroenterology
; 141(1): 338-47, 2011 Jul.
Article
em En
| MEDLINE
| ID: mdl-21570397
ABSTRACT
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 single nucleotide polymorphism (SNP) markers from 201 White European and US cases of DILI following AC administration (AC-DILI) 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 an 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=.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=.005). Additional, population-dependent effects were observed in HLA alleles with nominal significance. In an analysis of autoimmune-related 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Genes MHC Classe I
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Genes MHC da Classe II
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Combinação Amoxicilina e Clavulanato de Potássio
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Polimorfismo de Nucleotídeo Único
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Doença Hepática Induzida por Substâncias e Drogas
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Imunidade Adaptativa
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Antibacterianos
Tipo de estudo:
Clinical_trials
/
Etiology_studies
/
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Limite:
Aged
/
Aged80
/
Female
/
Humans
/
Male
/
Middle aged
País/Região como assunto:
America do norte
/
Europa
Idioma:
En
Revista:
Gastroenterology
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Espanha