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 journalArticle

    264 Citations (Scopus)

    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 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
    JournalGastroenterology
    Volume141
    Issue number1
    DOIs
    Publication statusPublished - 2011

    Keywords

    • Hepatotoxicity
    • Genome-Wide Association Study
    • GWAS
    • Pharmacogenomics
    • WHOLE-GENOME ASSOCIATION
    • JAPANESE PATIENTS
    • UNITED-STATES
    • HEPATOTOXICITY
    • POPULATION
    • GENOTYPE
    • DISEASE
    • COMBINATION
    • HEPATITIS
    • GENETICS

    Cite this

    Lucena, M. I., Molokhia, M., Shen, Y., Urban, T. J., Aithal, G. P., Andrade, R. J., ... Int SAEC, EUDRAGENE, Spanish DILI Registry, DILIGEN, DILIN (2011). Susceptibility to Amoxicillin-Clavulanate-Induced Liver Injury Is Influenced by Multiple HLA Class I and II Alleles. Gastroenterology, 141(1), 338-347. https://doi.org/10.1053/j.gastro.2011.04.001
    Lucena, M. Isabel ; Molokhia, Mariam ; Shen, Yufeng ; Urban, Thomas J. ; Aithal, Guruprasad P. ; Andrade, Raul J. ; Day, Christopher P. ; Ruiz-Cabello, Francisco ; Donaldson, Peter T. ; Stephens, Camilla ; Pirmohamed, Munir ; Romero-Gomez, Manuel ; Navarro, Jose Maria ; Fontana, Robert J. ; Miller, Michael ; Groome, Max ; Bondon-Guitton, Emmanuelle ; Conforti, Anita ; Stricker, Bruno H. C. ; Carvajal, Alfonso ; Ibanez, Luisa ; Yue, Qun-Ying ; Eichelbaum, Michel ; Floratos, Aris ; Pe'er, Itsik ; Daly, Mark J. ; Goldstein, David B. ; Dillon, John F. ; Nelson, Matthew R. ; Watkins, Paul B. ; Daly, Ann K. ; Int SAEC, EUDRAGENE, Spanish DILI Registry, DILIGEN, DILIN. / Susceptibility to Amoxicillin-Clavulanate-Induced Liver Injury Is Influenced by Multiple HLA Class I and II Alleles. In: Gastroenterology. 2011 ; Vol. 141, No. 1. pp. 338-347.
    @article{950cc08781244dafae5258becfa507fe,
    title = "Susceptibility to Amoxicillin-Clavulanate-Induced Liver Injury Is Influenced by Multiple HLA Class I and II Alleles",
    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 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.",
    keywords = "Hepatotoxicity, Genome-Wide Association Study, GWAS, Pharmacogenomics, WHOLE-GENOME ASSOCIATION, JAPANESE PATIENTS, UNITED-STATES, HEPATOTOXICITY, POPULATION, GENOTYPE, DISEASE, COMBINATION, HEPATITIS, GENETICS",
    author = "Lucena, {M. Isabel} and Mariam Molokhia and Yufeng Shen and Urban, {Thomas J.} and Aithal, {Guruprasad P.} and Andrade, {Raul J.} and Day, {Christopher P.} and Francisco Ruiz-Cabello and Donaldson, {Peter T.} and Camilla Stephens and Munir Pirmohamed and Manuel Romero-Gomez and Navarro, {Jose Maria} and Fontana, {Robert J.} and Michael Miller and Max Groome and Emmanuelle Bondon-Guitton and Anita Conforti and Stricker, {Bruno H. C.} and Alfonso Carvajal and Luisa Ibanez and Qun-Ying Yue and Michel Eichelbaum and Aris Floratos and Itsik Pe'er and Daly, {Mark J.} and Goldstein, {David B.} and Dillon, {John F.} and Nelson, {Matthew R.} and Watkins, {Paul B.} and Daly, {Ann K.} and {Int SAEC, EUDRAGENE, Spanish DILI Registry, DILIGEN, DILIN}",
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    pages = "338--347",
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    Lucena, MI, Molokhia, M, Shen, Y, Urban, TJ, Aithal, GP, Andrade, RJ, Day, CP, Ruiz-Cabello, F, Donaldson, PT, Stephens, C, Pirmohamed, M, Romero-Gomez, M, Navarro, JM, Fontana, RJ, Miller, M, Groome, M, Bondon-Guitton, E, Conforti, A, Stricker, BHC, Carvajal, A, Ibanez, L, Yue, Q-Y, Eichelbaum, M, Floratos, A, Pe'er, I, Daly, MJ, Goldstein, DB, Dillon, JF, Nelson, MR, Watkins, PB, Daly, AK & Int SAEC, EUDRAGENE, Spanish DILI Registry, DILIGEN, DILIN 2011, 'Susceptibility to Amoxicillin-Clavulanate-Induced Liver Injury Is Influenced by Multiple HLA Class I and II Alleles', Gastroenterology, vol. 141, no. 1, pp. 338-347. https://doi.org/10.1053/j.gastro.2011.04.001

    Susceptibility to Amoxicillin-Clavulanate-Induced Liver Injury Is Influenced by Multiple HLA Class I and II Alleles. / Lucena, M. Isabel; Molokhia, Mariam; Shen, Yufeng; Urban, Thomas J.; Aithal, Guruprasad P.; Andrade, Raul J.; Day, Christopher P.; Ruiz-Cabello, Francisco; Donaldson, Peter T.; Stephens, Camilla; Pirmohamed, Munir; Romero-Gomez, Manuel; Navarro, Jose Maria ; Fontana, Robert J.; Miller, Michael; Groome, Max; Bondon-Guitton, Emmanuelle; Conforti, Anita; Stricker, Bruno H. C.; Carvajal, Alfonso; Ibanez, Luisa; Yue, Qun-Ying; Eichelbaum, Michel; Floratos, Aris; Pe'er, Itsik; Daly, Mark J.; Goldstein, David B.; Dillon, John F.; Nelson, Matthew R.; Watkins, Paul B.; Daly, Ann K.; Int SAEC, EUDRAGENE, Spanish DILI Registry, DILIGEN, DILIN.

    In: Gastroenterology, Vol. 141, No. 1, 2011, p. 338-347.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Susceptibility to Amoxicillin-Clavulanate-Induced Liver Injury Is Influenced by Multiple HLA Class I and II Alleles

    AU - Lucena, M. Isabel

    AU - Molokhia, Mariam

    AU - Shen, Yufeng

    AU - Urban, Thomas J.

    AU - Aithal, Guruprasad P.

    AU - Andrade, Raul J.

    AU - Day, Christopher P.

    AU - Ruiz-Cabello, Francisco

    AU - Donaldson, Peter T.

    AU - Stephens, Camilla

    AU - Pirmohamed, Munir

    AU - Romero-Gomez, Manuel

    AU - Navarro, Jose Maria

    AU - Fontana, Robert J.

    AU - Miller, Michael

    AU - Groome, Max

    AU - Bondon-Guitton, Emmanuelle

    AU - Conforti, Anita

    AU - Stricker, Bruno H. C.

    AU - Carvajal, Alfonso

    AU - Ibanez, Luisa

    AU - Yue, Qun-Ying

    AU - Eichelbaum, Michel

    AU - Floratos, Aris

    AU - Pe'er, Itsik

    AU - Daly, Mark J.

    AU - Goldstein, David B.

    AU - Dillon, John F.

    AU - Nelson, Matthew R.

    AU - Watkins, Paul B.

    AU - Daly, Ann K.

    AU - Int SAEC, EUDRAGENE, Spanish DILI Registry, DILIGEN, DILIN

    N1 - Times Cited: 28

    PY - 2011

    Y1 - 2011

    N2 - 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.

    AB - 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.

    KW - Hepatotoxicity

    KW - Genome-Wide Association Study

    KW - GWAS

    KW - Pharmacogenomics

    KW - WHOLE-GENOME ASSOCIATION

    KW - JAPANESE PATIENTS

    KW - UNITED-STATES

    KW - HEPATOTOXICITY

    KW - POPULATION

    KW - GENOTYPE

    KW - DISEASE

    KW - COMBINATION

    KW - HEPATITIS

    KW - GENETICS

    U2 - 10.1053/j.gastro.2011.04.001

    DO - 10.1053/j.gastro.2011.04.001

    M3 - Article

    C2 - 21570397

    VL - 141

    SP - 338

    EP - 347

    JO - Gastroenterology

    JF - Gastroenterology

    SN - 0016-5085

    IS - 1

    ER -