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, Raul 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 CarvajalLuisa 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, Int SAEC, EUDRAGENE, Spanish DILI Registry, DILIGEN, DILIN

    Research output: Contribution to journalArticlepeer-review

    379 Citations (Scopus)


    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 X 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 X 10(-4)). An independent association was observed in the class I region (rs2523822, P = 1.8 X 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 X 10(-6)) and HLA-DQB1*0602 (P = 5 X 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 X 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.

    Original languageEnglish
    Pages (from-to)338-347
    Number of pages10
    Issue number1
    Publication statusPublished - 2011


    • Hepatotoxicity
    • Genome-Wide Association Study
    • GWAS
    • Pharmacogenomics


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