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 Carvajal; Luisa Ibanez; Qun-Ying Yue; Michel Eichelbaum; Aris Floratos; Itsik Pe&apos;er; Mark J. Daly; David B. Goldstein; John F. Dillon; Matthew R. Nelson; Paul B. Watkins; Ann K. Daly

doi:10.1053/j.gastro.2011.04.001

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

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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 language	English
Pages (from-to)	338 - 347
Number of pages	10
Journal	Gastroenterology
Volume	141
Issue number	1
DOIs	https://doi.org/10.1053/j.gastro.2011.04.001
Publication status	Published - Jul 2011

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Lucena, M. I., Molokhia, M., Shen, Y., Urban, T. J., Aithal, G. P., Andrade, R. J., Day, C. P., Ruiz-Cabello, F., Donaldson, P. T., Stephens, C., Pirmohamed, M., Romero-Gomez, M., Maria Navarro, J., Fontana, R. J., Miller, M., Groome, M., Bondon-Guitton, E., Conforti, A., Stricker, B. H. C., ... Daly, A. K. (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

@article{9578f374dd3544e98bd01743bf356d91,

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.",

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 {Maria Navarro}, Jose 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.}",

year = "2011",

month = jul,

doi = "10.1053/j.gastro.2011.04.001",

language = "English",

volume = "141",

pages = "338 -- 347",

journal = "Gastroenterology",

issn = "1528-0012",

publisher = "WB Saunders",

number = "1",

}

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, Maria Navarro, J, 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 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

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 - Maria Navarro, Jose

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.

PY - 2011/7

Y1 - 2011/7

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.

U2 - 10.1053/j.gastro.2011.04.001

DO - 10.1053/j.gastro.2011.04.001

M3 - Article

SN - 1528-0012

VL - 141

SP - 338

EP - 347

JO - Gastroenterology

JF - Gastroenterology

IS - 1

ER -

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

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