A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury

Drug-Induced Liver Injury Network (DILIN) investigators, International DILI consortium (iDILIC)

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Background & Aims: We performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility. Methods: We performed a genome-wide association study of 2048 individuals with DILI (cases) and 12,429 individuals without (controls). Our analysis included subjects of European (1806 cases and 10,397 controls), African American (133 cases and 1,314 controls), and Hispanic (109 cases and 718 controls) ancestry. We analyzed DNA from 113 Icelandic cases and 239,304 controls to validate our findings. Results: We associated idiosyncratic DILI with rs2476601, a nonsynonymous polymorphism that encodes a substitution of tryptophan with arginine in the protein tyrosine phosphatase, nonreceptor type 22 gene (PTPN22) (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.28–1.62; P = 1.2 × 10 –9 and replicated the finding in the validation set (OR 1.48; 95% CI 1.09–1.99; P =.01). The minor allele frequency showed the same effect size (OR > 1) among ethnic groups. The strongest association was with amoxicillin and clavulanate-associated DILI in persons of European ancestry (OR 1.62; 95% CI 1.32–1.98; P = 4.0 × 10 –6 ; allele frequency = 13.3%), but the polymorphism was associated with DILI of other causes (OR 1.37; 95% CI 1.21–1.56; P = 1.5 × 10 –6 ; allele frequency = 11.5%). Among amoxicillin- and clavulanate-associated cases of European ancestry, rs2476601 doubled the risk for DILI among those with the HLA risk alleles A*02:01 and DRB1*15:01. Conclusions: In a genome-wide association study, we identified rs2476601 in PTPN22 as a non-HLA variant that associates with risk of liver injury caused by multiple drugs and validated our finding in a separate cohort. This variant has been associated with increased risk of autoimmune diseases, providing support for the concept that alterations in immune regulation contribute to idiosyncratic DILI.

Original languageEnglish (US)
Pages (from-to)1707-1716.e2
JournalGastroenterology
Volume156
Issue number6
DOIs
StatePublished - May 1 2019

Fingerprint

Chemical and Drug Induced Liver Injury
Protein Tyrosine Phosphatases
Odds Ratio
Genes
Gene Frequency
Confidence Intervals
Clavulanic Acid
Genome-Wide Association Study
Amoxicillin
Multiple Trauma
Hispanic Americans
Ethnic Groups
Tryptophan
African Americans
Autoimmune Diseases
Arginine
Alleles
Liver
DNA
Pharmaceutical Preparations

Keywords

  • Amino Acid Change
  • GWAS
  • Inflammation
  • Mutation

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Drug-Induced Liver Injury Network (DILIN) investigators, & International DILI consortium (iDILIC) (2019). A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury. Gastroenterology, 156(6), 1707-1716.e2. https://doi.org/10.1053/j.gastro.2019.01.034

A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury. / Drug-Induced Liver Injury Network (DILIN) investigators; International DILI consortium (iDILIC).

In: Gastroenterology, Vol. 156, No. 6, 01.05.2019, p. 1707-1716.e2.

Research output: Contribution to journalArticle

Drug-Induced Liver Injury Network (DILIN) investigators & International DILI consortium (iDILIC) 2019, 'A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury', Gastroenterology, vol. 156, no. 6, pp. 1707-1716.e2. https://doi.org/10.1053/j.gastro.2019.01.034
Drug-Induced Liver Injury Network (DILIN) investigators, International DILI consortium (iDILIC). A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury. Gastroenterology. 2019 May 1;156(6):1707-1716.e2. https://doi.org/10.1053/j.gastro.2019.01.034
Drug-Induced Liver Injury Network (DILIN) investigators ; International DILI consortium (iDILIC). / A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury. In: Gastroenterology. 2019 ; Vol. 156, No. 6. pp. 1707-1716.e2.
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abstract = "Background & Aims: We performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility. Methods: We performed a genome-wide association study of 2048 individuals with DILI (cases) and 12,429 individuals without (controls). Our analysis included subjects of European (1806 cases and 10,397 controls), African American (133 cases and 1,314 controls), and Hispanic (109 cases and 718 controls) ancestry. We analyzed DNA from 113 Icelandic cases and 239,304 controls to validate our findings. Results: We associated idiosyncratic DILI with rs2476601, a nonsynonymous polymorphism that encodes a substitution of tryptophan with arginine in the protein tyrosine phosphatase, nonreceptor type 22 gene (PTPN22) (odds ratio [OR] 1.44; 95{\%} confidence interval [CI] 1.28–1.62; P = 1.2 × 10 –9 and replicated the finding in the validation set (OR 1.48; 95{\%} CI 1.09–1.99; P =.01). The minor allele frequency showed the same effect size (OR > 1) among ethnic groups. The strongest association was with amoxicillin and clavulanate-associated DILI in persons of European ancestry (OR 1.62; 95{\%} CI 1.32–1.98; P = 4.0 × 10 –6 ; allele frequency = 13.3{\%}), but the polymorphism was associated with DILI of other causes (OR 1.37; 95{\%} CI 1.21–1.56; P = 1.5 × 10 –6 ; allele frequency = 11.5{\%}). Among amoxicillin- and clavulanate-associated cases of European ancestry, rs2476601 doubled the risk for DILI among those with the HLA risk alleles A*02:01 and DRB1*15:01. Conclusions: In a genome-wide association study, we identified rs2476601 in PTPN22 as a non-HLA variant that associates with risk of liver injury caused by multiple drugs and validated our finding in a separate cohort. This variant has been associated with increased risk of autoimmune diseases, providing support for the concept that alterations in immune regulation contribute to idiosyncratic DILI.",
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TY - JOUR

T1 - A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury

AU - Drug-Induced Liver Injury Network (DILIN) investigators

AU - International DILI consortium (iDILIC)

AU - Cirulli, Elizabeth T.

AU - Nicoletti, Paola

AU - Abramson, Karen

AU - Andrade, Raul J.

AU - Bjornsson, Einar S.

AU - Chalasani, Naga

AU - Fontana, Robert J.

AU - Hallberg, Pär

AU - Li, Yi Ju

AU - Lucena, M. Isabel

AU - Long, Nanye

AU - Molokhia, Mariam

AU - Nelson, Matthew R.

AU - Odin, Joseph A.

AU - Pirmohamed, Munir

AU - Rafnar, Thorunn

AU - Serrano, Jose

AU - Stefánsson, Kári

AU - Stolz, Andrew

AU - Daly, Ann K.

AU - Aithal, Guruprasad P.

AU - Watkins, Paul B.

AU - Bessone, Fernando

AU - Bjornsson, Einar

AU - Cascorbi, Ingolf

AU - Dillon, John F.

AU - Day, Christopher P.

AU - Hallberg, Par

AU - Hernández, Nelia

AU - Ibanez, Luisa

AU - Kullak-Ublick, Gerd A.

AU - Laitinen, Tarja

AU - Larrey, Dominique

AU - Maitland-van der Zee, Anke

AU - Martin, Jennifer H.

AU - Menzies, Dick

AU - Qin, Shengying

AU - Wadelius, Mia

PY - 2019/5/1

Y1 - 2019/5/1

N2 - Background & Aims: We performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility. Methods: We performed a genome-wide association study of 2048 individuals with DILI (cases) and 12,429 individuals without (controls). Our analysis included subjects of European (1806 cases and 10,397 controls), African American (133 cases and 1,314 controls), and Hispanic (109 cases and 718 controls) ancestry. We analyzed DNA from 113 Icelandic cases and 239,304 controls to validate our findings. Results: We associated idiosyncratic DILI with rs2476601, a nonsynonymous polymorphism that encodes a substitution of tryptophan with arginine in the protein tyrosine phosphatase, nonreceptor type 22 gene (PTPN22) (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.28–1.62; P = 1.2 × 10 –9 and replicated the finding in the validation set (OR 1.48; 95% CI 1.09–1.99; P =.01). The minor allele frequency showed the same effect size (OR > 1) among ethnic groups. The strongest association was with amoxicillin and clavulanate-associated DILI in persons of European ancestry (OR 1.62; 95% CI 1.32–1.98; P = 4.0 × 10 –6 ; allele frequency = 13.3%), but the polymorphism was associated with DILI of other causes (OR 1.37; 95% CI 1.21–1.56; P = 1.5 × 10 –6 ; allele frequency = 11.5%). Among amoxicillin- and clavulanate-associated cases of European ancestry, rs2476601 doubled the risk for DILI among those with the HLA risk alleles A*02:01 and DRB1*15:01. Conclusions: In a genome-wide association study, we identified rs2476601 in PTPN22 as a non-HLA variant that associates with risk of liver injury caused by multiple drugs and validated our finding in a separate cohort. This variant has been associated with increased risk of autoimmune diseases, providing support for the concept that alterations in immune regulation contribute to idiosyncratic DILI.

AB - Background & Aims: We performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility. Methods: We performed a genome-wide association study of 2048 individuals with DILI (cases) and 12,429 individuals without (controls). Our analysis included subjects of European (1806 cases and 10,397 controls), African American (133 cases and 1,314 controls), and Hispanic (109 cases and 718 controls) ancestry. We analyzed DNA from 113 Icelandic cases and 239,304 controls to validate our findings. Results: We associated idiosyncratic DILI with rs2476601, a nonsynonymous polymorphism that encodes a substitution of tryptophan with arginine in the protein tyrosine phosphatase, nonreceptor type 22 gene (PTPN22) (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.28–1.62; P = 1.2 × 10 –9 and replicated the finding in the validation set (OR 1.48; 95% CI 1.09–1.99; P =.01). The minor allele frequency showed the same effect size (OR > 1) among ethnic groups. The strongest association was with amoxicillin and clavulanate-associated DILI in persons of European ancestry (OR 1.62; 95% CI 1.32–1.98; P = 4.0 × 10 –6 ; allele frequency = 13.3%), but the polymorphism was associated with DILI of other causes (OR 1.37; 95% CI 1.21–1.56; P = 1.5 × 10 –6 ; allele frequency = 11.5%). Among amoxicillin- and clavulanate-associated cases of European ancestry, rs2476601 doubled the risk for DILI among those with the HLA risk alleles A*02:01 and DRB1*15:01. Conclusions: In a genome-wide association study, we identified rs2476601 in PTPN22 as a non-HLA variant that associates with risk of liver injury caused by multiple drugs and validated our finding in a separate cohort. This variant has been associated with increased risk of autoimmune diseases, providing support for the concept that alterations in immune regulation contribute to idiosyncratic DILI.

KW - Amino Acid Change

KW - GWAS

KW - Inflammation

KW - Mutation

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