HLA-B5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin

Ann K. Daly, Peter T. Donaldson, Pallav Bhatnagar, Yufeng Shen, Itsik Pe'er, Aris Floratos, Mark J. Daly, David B. Goldstein, Sally John, Matthew R. Nelson, Julia Graham, B. Kevin Park, John F. Dillon, William Bernal, Heather J. Cordell, Munir Pirmohamed, Guruprasad P. Aithal, Christopher P. Day

    Research output: Contribution to journalLetter

    698 Citations (Scopus)

    Abstract

    Drug-induced liver injury (DILI) is an important cause of serious liver disease. The antimicrobial agent flucloxacillin is a common cause of DILI, but the genetic basis for susceptibility remains unclear. We conducted a genome-wide association (GWA) study using 866,399 markers in 51 cases of flucloxacillin DILI and 282 controls matched for sex and ancestry. The GWA showed an association peak in the major histocompatibility complex (MHC) region with the strongest association (P = 8.7 × 10 -33) seen for rs2395029[G], a marker in complete linkage disequilibrium (LD) with HLA-B*5701. Further MHC genotyping, which included 64 flucloxacillin-tolerant controls, confirmed the association with HLA-B5701 (OR = 80.6, P = 9.0 × 10 -19). The association was replicated in a second cohort of 23 cases. In HLA-B*5701 carrier cases, rs10937275 in ST6GAL1 on chromosome 3 also showed genome-wide significance (OR = 4.1, P = 1.4 × 10 -8). These findings provide new insights into the mechanism of flucloxacillin DILI and have the potential to substantially improve diagnosis of this serious disease.

    Original languageEnglish
    Pages (from-to)816-819
    Number of pages4
    JournalNature Genetics
    Volume41
    Issue number7
    DOIs
    Publication statusPublished - 1 Jul 2009

    Fingerprint

    Floxacillin
    Chemical and Drug Induced Liver Injury
    Genotype
    HLA-B Antigens
    Major Histocompatibility Complex
    Genome
    Chromosomes, Human, Pair 3
    Genome-Wide Association Study
    Linkage Disequilibrium
    Genetic Predisposition to Disease
    Anti-Infective Agents
    Liver Diseases

    Cite this

    Daly, A. K., Donaldson, P. T., Bhatnagar, P., Shen, Y., Pe'er, I., Floratos, A., ... Day, C. P. (2009). HLA-B5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nature Genetics, 41(7), 816-819. https://doi.org/10.1038/ng.379
    Daly, Ann K. ; Donaldson, Peter T. ; Bhatnagar, Pallav ; Shen, Yufeng ; Pe'er, Itsik ; Floratos, Aris ; Daly, Mark J. ; Goldstein, David B. ; John, Sally ; Nelson, Matthew R. ; Graham, Julia ; Park, B. Kevin ; Dillon, John F. ; Bernal, William ; Cordell, Heather J. ; Pirmohamed, Munir ; Aithal, Guruprasad P. ; Day, Christopher P. / HLA-B5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. In: Nature Genetics. 2009 ; Vol. 41, No. 7. pp. 816-819.
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    abstract = "Drug-induced liver injury (DILI) is an important cause of serious liver disease. The antimicrobial agent flucloxacillin is a common cause of DILI, but the genetic basis for susceptibility remains unclear. We conducted a genome-wide association (GWA) study using 866,399 markers in 51 cases of flucloxacillin DILI and 282 controls matched for sex and ancestry. The GWA showed an association peak in the major histocompatibility complex (MHC) region with the strongest association (P = 8.7 × 10 -33) seen for rs2395029[G], a marker in complete linkage disequilibrium (LD) with HLA-B*5701. Further MHC genotyping, which included 64 flucloxacillin-tolerant controls, confirmed the association with HLA-B5701 (OR = 80.6, P = 9.0 × 10 -19). The association was replicated in a second cohort of 23 cases. In HLA-B*5701 carrier cases, rs10937275 in ST6GAL1 on chromosome 3 also showed genome-wide significance (OR = 4.1, P = 1.4 × 10 -8). These findings provide new insights into the mechanism of flucloxacillin DILI and have the potential to substantially improve diagnosis of this serious disease.",
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    Daly, AK, Donaldson, PT, Bhatnagar, P, Shen, Y, Pe'er, I, Floratos, A, Daly, MJ, Goldstein, DB, John, S, Nelson, MR, Graham, J, Park, BK, Dillon, JF, Bernal, W, Cordell, HJ, Pirmohamed, M, Aithal, GP & Day, CP 2009, 'HLA-B5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin', Nature Genetics, vol. 41, no. 7, pp. 816-819. https://doi.org/10.1038/ng.379

    HLA-B5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. / Daly, Ann K.; Donaldson, Peter T.; Bhatnagar, Pallav; Shen, Yufeng; Pe'er, Itsik; Floratos, Aris; Daly, Mark J.; Goldstein, David B.; John, Sally; Nelson, Matthew R.; Graham, Julia; Park, B. Kevin; Dillon, John F.; Bernal, William; Cordell, Heather J.; Pirmohamed, Munir; Aithal, Guruprasad P.; Day, Christopher P.

    In: Nature Genetics, Vol. 41, No. 7, 01.07.2009, p. 816-819.

    Research output: Contribution to journalLetter

    TY - JOUR

    T1 - HLA-B∗5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin

    AU - Daly, Ann K.

    AU - Donaldson, Peter T.

    AU - Bhatnagar, Pallav

    AU - Shen, Yufeng

    AU - Pe'er, Itsik

    AU - Floratos, Aris

    AU - Daly, Mark J.

    AU - Goldstein, David B.

    AU - John, Sally

    AU - Nelson, Matthew R.

    AU - Graham, Julia

    AU - Park, B. Kevin

    AU - Dillon, John F.

    AU - Bernal, William

    AU - Cordell, Heather J.

    AU - Pirmohamed, Munir

    AU - Aithal, Guruprasad P.

    AU - Day, Christopher P.

    N1 - Copyright 2009 Elsevier B.V., All rights reserved.

    PY - 2009/7/1

    Y1 - 2009/7/1

    N2 - Drug-induced liver injury (DILI) is an important cause of serious liver disease. The antimicrobial agent flucloxacillin is a common cause of DILI, but the genetic basis for susceptibility remains unclear. We conducted a genome-wide association (GWA) study using 866,399 markers in 51 cases of flucloxacillin DILI and 282 controls matched for sex and ancestry. The GWA showed an association peak in the major histocompatibility complex (MHC) region with the strongest association (P = 8.7 × 10 -33) seen for rs2395029[G], a marker in complete linkage disequilibrium (LD) with HLA-B*5701. Further MHC genotyping, which included 64 flucloxacillin-tolerant controls, confirmed the association with HLA-B5701 (OR = 80.6, P = 9.0 × 10 -19). The association was replicated in a second cohort of 23 cases. In HLA-B*5701 carrier cases, rs10937275 in ST6GAL1 on chromosome 3 also showed genome-wide significance (OR = 4.1, P = 1.4 × 10 -8). These findings provide new insights into the mechanism of flucloxacillin DILI and have the potential to substantially improve diagnosis of this serious disease.

    AB - Drug-induced liver injury (DILI) is an important cause of serious liver disease. The antimicrobial agent flucloxacillin is a common cause of DILI, but the genetic basis for susceptibility remains unclear. We conducted a genome-wide association (GWA) study using 866,399 markers in 51 cases of flucloxacillin DILI and 282 controls matched for sex and ancestry. The GWA showed an association peak in the major histocompatibility complex (MHC) region with the strongest association (P = 8.7 × 10 -33) seen for rs2395029[G], a marker in complete linkage disequilibrium (LD) with HLA-B*5701. Further MHC genotyping, which included 64 flucloxacillin-tolerant controls, confirmed the association with HLA-B5701 (OR = 80.6, P = 9.0 × 10 -19). The association was replicated in a second cohort of 23 cases. In HLA-B*5701 carrier cases, rs10937275 in ST6GAL1 on chromosome 3 also showed genome-wide significance (OR = 4.1, P = 1.4 × 10 -8). These findings provide new insights into the mechanism of flucloxacillin DILI and have the potential to substantially improve diagnosis of this serious disease.

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    U2 - 10.1038/ng.379

    DO - 10.1038/ng.379

    M3 - Letter

    VL - 41

    SP - 816

    EP - 819

    JO - Nature Genetics

    JF - Nature Genetics

    SN - 1061-4036

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    Daly AK, Donaldson PT, Bhatnagar P, Shen Y, Pe'er I, Floratos A et al. HLA-B5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nature Genetics. 2009 Jul 1;41(7):816-819. https://doi.org/10.1038/ng.379