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JOURNAL ARTICLE
MULTICENTER STUDY

Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles

M Isabel Lucena, Mariam Molokhia, Yufeng Shen, Thomas J Urban, Guruprasad P Aithal, Raúl J Andrade, Christopher P Day, Francisco Ruiz-Cabello, Peter T Donaldson, Camilla Stephens, Munir Pirmohamed, Manuel Romero-Gomez, Jose Maria Navarro, Robert J Fontana, Michael Miller, Max Groome, Emmanuelle Bondon-Guitton, Anita Conforti, Bruno H C Stricker, Alfonso Carvajal, Luisa Ibanez, Qun-Ying Yue, Michel Eichelbaum, Aris Floratos, Itsik Pe'er, Mark J Daly, David B Goldstein, John F Dillon, Matthew R Nelson, Paul B Watkins, Ann K Daly
Gastroenterology 2011, 141 (1): 338-47
21570397

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.

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