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'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

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

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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 - 2011

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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., Navarro, J. M., Fontana, R. J., Miller, M., Groome, M., Bondon-Guitton, E., Conforti, A., Stricker, B. H. C., ... 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

@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}",

note = "Times Cited: 28",

year = "2011",

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

language = "English",

volume = "141",

pages = "338--347",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders",

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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

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

SN - 0016-5085

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

Abstract

Keywords

UN SDGs

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