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

Publication ,  Journal Article
Cirulli, ET; Nicoletti, P; Abramson, K; Andrade, RJ; Bjornsson, ES; Chalasani, N; Fontana, RJ; Hallberg, P; Li, YJ; Lucena, MI; Long, N ...
Published in: Gastroenterology
May 2019

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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Published In

Gastroenterology

DOI

EISSN

1528-0012

Publication Date

May 2019

Volume

156

Issue

6

Start / End Page

1707 / 1716.e2

Location

United States

Related Subject Headings

  • White People
  • Risk Factors
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22
  • Polymorphism, Single Nucleotide
  • Mutation, Missense
  • Middle Aged
  • Male
  • Humans
  • Hispanic or Latino
  • HLA-DRB1 Chains
 

Citation

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Cirulli, E. T., Nicoletti, P., Abramson, K., Andrade, R. J., Bjornsson, E. S., Chalasani, N., … 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
Cirulli, Elizabeth T., Paola Nicoletti, Karen Abramson, Raul J. Andrade, Einar S. Bjornsson, Naga Chalasani, Robert J. Fontana, et al. “A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury.Gastroenterology 156, no. 6 (May 2019): 1707-1716.e2. https://doi.org/10.1053/j.gastro.2019.01.034.
Cirulli ET, Nicoletti P, Abramson K, Andrade RJ, Bjornsson ES, Chalasani N, et al. A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury. Gastroenterology. 2019 May;156(6):1707-1716.e2.
Cirulli, Elizabeth T., et al. “A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury.Gastroenterology, vol. 156, no. 6, May 2019, pp. 1707-1716.e2. Pubmed, doi:10.1053/j.gastro.2019.01.034.
Cirulli ET, Nicoletti P, Abramson K, Andrade RJ, Bjornsson ES, Chalasani N, Fontana RJ, Hallberg P, Li YJ, Lucena MI, Long N, Molokhia M, Nelson MR, Odin JA, Pirmohamed M, Rafnar T, Serrano J, Stefánsson K, Stolz A, Daly AK, Aithal GP, Watkins PB, 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;156(6):1707-1716.e2.
Journal cover image

Published In

Gastroenterology

DOI

EISSN

1528-0012

Publication Date

May 2019

Volume

156

Issue

6

Start / End Page

1707 / 1716.e2

Location

United States

Related Subject Headings

  • White People
  • Risk Factors
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22
  • Polymorphism, Single Nucleotide
  • Mutation, Missense
  • Middle Aged
  • Male
  • Humans
  • Hispanic or Latino
  • HLA-DRB1 Chains