Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study

International Drug-Induced Liver Injury Consortium, Drug-Induced Liver Injury Network Investigators, and International Serious Adverse Events Consortium

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

Background & Aims We performed a genome-wide association study (GWAS) to identify genetic risk factors for drug-induced liver injury (DILI) from licensed drugs without previously reported genetic risk factors. Methods We performed a GWAS of 862 persons with DILI and 10,588 population-matched controls. The first set of cases was recruited before May 2009 in Europe (n = 137) and the United States (n = 274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the United States, and South America. For the GWAS, we included only cases with patients of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze HLA genes and single nucleotide polymorphisms. After the discovery analysis was concluded, we validated our findings using data from 283 European patients with diagnosis of DILI associated with various drugs. Results We associated DILI with rs114577328 (a proxy for A*33:01 a HLA class I allele; odds ratio [OR], 2.7; 95% confidence interval [CI], 1.9−3.8; P = 2.4 × 10−8) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6−2.5; P = 9.7 × 10−9). The association with A*33:01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A*33:01 was significant genome wide for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 was associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the lipopolysaccharide-responsive vesicle trafficking, beach and anchor containing gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6−2.7; P = 4.8 × 10−9). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR, 5.4; 95% CI, 3.0−9.5; P = 7.1 × 10−9). We validated the association between A*33:01 terbinafine- and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224. Conclusions In a GWAS of persons of European descent with DILI, we associated HLA-A*33:01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non−drug-specific risk factors.

Original languageEnglish (US)
Pages (from-to)1078-1089
Number of pages12
JournalGastroenterology
Volume152
Issue number5
DOIs
StatePublished - Apr 1 2017

Fingerprint

Chemical and Drug Induced Liver Injury
Liver
Wounds and Injuries
Pharmaceutical Preparations
Genes
terbinafine
Genome-Wide Association Study
Chromosomes, Human, Pair 2
Odds Ratio
Confidence Intervals
Fenofibrate
Ticlopidine
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Floxacillin
Chromosomes, Human, Pair 18
Sertraline
Clavulanic Acid
HLA-A Antigens

Keywords

  • Anti-Fungal Agent
  • Liver Damage
  • Medication
  • Side Effect

ASJC Scopus subject areas

  • Gastroenterology

Cite this

International Drug-Induced Liver Injury Consortium, Drug-Induced Liver Injury Network Investigators, and International Serious Adverse Events Consortium (2017). Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study. Gastroenterology, 152(5), 1078-1089. https://doi.org/10.1053/j.gastro.2016.12.016

Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study. / International Drug-Induced Liver Injury Consortium, Drug-Induced Liver Injury Network Investigators, and International Serious Adverse Events Consortium.

In: Gastroenterology, Vol. 152, No. 5, 01.04.2017, p. 1078-1089.

Research output: Contribution to journalArticle

International Drug-Induced Liver Injury Consortium, Drug-Induced Liver Injury Network Investigators, and International Serious Adverse Events Consortium 2017, 'Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study', Gastroenterology, vol. 152, no. 5, pp. 1078-1089. https://doi.org/10.1053/j.gastro.2016.12.016
International Drug-Induced Liver Injury Consortium, Drug-Induced Liver Injury Network Investigators, and International Serious Adverse Events Consortium. Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study. Gastroenterology. 2017 Apr 1;152(5):1078-1089. https://doi.org/10.1053/j.gastro.2016.12.016
International Drug-Induced Liver Injury Consortium, Drug-Induced Liver Injury Network Investigators, and International Serious Adverse Events Consortium. / Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study. In: Gastroenterology. 2017 ; Vol. 152, No. 5. pp. 1078-1089.
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abstract = "Background & Aims We performed a genome-wide association study (GWAS) to identify genetic risk factors for drug-induced liver injury (DILI) from licensed drugs without previously reported genetic risk factors. Methods We performed a GWAS of 862 persons with DILI and 10,588 population-matched controls. The first set of cases was recruited before May 2009 in Europe (n = 137) and the United States (n = 274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the United States, and South America. For the GWAS, we included only cases with patients of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze HLA genes and single nucleotide polymorphisms. After the discovery analysis was concluded, we validated our findings using data from 283 European patients with diagnosis of DILI associated with various drugs. Results We associated DILI with rs114577328 (a proxy for A*33:01 a HLA class I allele; odds ratio [OR], 2.7; 95{\%} confidence interval [CI], 1.9−3.8; P = 2.4 × 10−8) and with rs72631567 on chromosome 2 (OR, 2.0; 95{\%} CI, 1.6−2.5; P = 9.7 × 10−9). The association with A*33:01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A*33:01 was significant genome wide for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 was associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the lipopolysaccharide-responsive vesicle trafficking, beach and anchor containing gene) and only hepatocellular DILI (OR, 2.1; 95{\%} CI, 1.6−2.7; P = 4.8 × 10−9). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR, 5.4; 95{\%} CI, 3.0−9.5; P = 7.1 × 10−9). We validated the association between A*33:01 terbinafine- and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224. Conclusions In a GWAS of persons of European descent with DILI, we associated HLA-A*33:01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non−drug-specific risk factors.",
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TY - JOUR

T1 - Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study

AU - International Drug-Induced Liver Injury Consortium, Drug-Induced Liver Injury Network Investigators, and International Serious Adverse Events Consortium

AU - Nicoletti, Paola

AU - Aithal, Guruprasad P.

AU - Bjornsson, Einar S.

AU - Andrade, Raul J.

AU - Sawle, Ashley

AU - Arrese, Marco

AU - Barnhart, Huiman X.

AU - Bondon-Guitton, Emmanuelle

AU - Hayashi, Paul H.

AU - Bessone, Fernando

AU - Carvajal, Alfonso

AU - Cascorbi, Ingolf

AU - Cirulli, Elizabeth T.

AU - Chalasani, Naga

AU - Conforti, Anita

AU - Coulthard, Sally A.

AU - Daly, Mark J.

AU - Day, Christopher P.

AU - Dillon, John F.

AU - Fontana, Robert J.

AU - Grove, Jane I.

AU - Hallberg, Pär

AU - Hernández, Nelia

AU - Ibáñez, Luisa

AU - Kullak-Ublick, Gerd A.

AU - Laitinen, Tarja

AU - Larrey, Dominique

AU - Lucena, M. Isabel

AU - Maitland-van der Zee, Anke H.

AU - Martin, Jennifer H.

AU - Molokhia, Mariam

AU - Pirmohamed, Munir

AU - Powell, Elizabeth E.

AU - Qin, Shengying

AU - Serrano, Jose

AU - Stephens, Camilla

AU - Stolz, Andrew

AU - Wadelius, Mia

AU - Watkins, Paul B.

AU - Floratos, Aris

AU - Shen, Yufeng

AU - Nelson, Matthew R.

AU - Urban, Thomas J.

AU - Daly, Ann K.

PY - 2017/4/1

Y1 - 2017/4/1

N2 - Background & Aims We performed a genome-wide association study (GWAS) to identify genetic risk factors for drug-induced liver injury (DILI) from licensed drugs without previously reported genetic risk factors. Methods We performed a GWAS of 862 persons with DILI and 10,588 population-matched controls. The first set of cases was recruited before May 2009 in Europe (n = 137) and the United States (n = 274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the United States, and South America. For the GWAS, we included only cases with patients of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze HLA genes and single nucleotide polymorphisms. After the discovery analysis was concluded, we validated our findings using data from 283 European patients with diagnosis of DILI associated with various drugs. Results We associated DILI with rs114577328 (a proxy for A*33:01 a HLA class I allele; odds ratio [OR], 2.7; 95% confidence interval [CI], 1.9−3.8; P = 2.4 × 10−8) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6−2.5; P = 9.7 × 10−9). The association with A*33:01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A*33:01 was significant genome wide for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 was associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the lipopolysaccharide-responsive vesicle trafficking, beach and anchor containing gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6−2.7; P = 4.8 × 10−9). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR, 5.4; 95% CI, 3.0−9.5; P = 7.1 × 10−9). We validated the association between A*33:01 terbinafine- and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224. Conclusions In a GWAS of persons of European descent with DILI, we associated HLA-A*33:01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non−drug-specific risk factors.

AB - Background & Aims We performed a genome-wide association study (GWAS) to identify genetic risk factors for drug-induced liver injury (DILI) from licensed drugs without previously reported genetic risk factors. Methods We performed a GWAS of 862 persons with DILI and 10,588 population-matched controls. The first set of cases was recruited before May 2009 in Europe (n = 137) and the United States (n = 274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the United States, and South America. For the GWAS, we included only cases with patients of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze HLA genes and single nucleotide polymorphisms. After the discovery analysis was concluded, we validated our findings using data from 283 European patients with diagnosis of DILI associated with various drugs. Results We associated DILI with rs114577328 (a proxy for A*33:01 a HLA class I allele; odds ratio [OR], 2.7; 95% confidence interval [CI], 1.9−3.8; P = 2.4 × 10−8) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6−2.5; P = 9.7 × 10−9). The association with A*33:01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A*33:01 was significant genome wide for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 was associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the lipopolysaccharide-responsive vesicle trafficking, beach and anchor containing gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6−2.7; P = 4.8 × 10−9). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR, 5.4; 95% CI, 3.0−9.5; P = 7.1 × 10−9). We validated the association between A*33:01 terbinafine- and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224. Conclusions In a GWAS of persons of European descent with DILI, we associated HLA-A*33:01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non−drug-specific risk factors.

KW - Anti-Fungal Agent

KW - Liver Damage

KW - Medication

KW - Side Effect

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