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

Authors

Elizabeth T. Cirulli

Paola Nicoletti

Karen Abramson

Raul J. Andrade

Einar S. Bjornsson

Naga Chalasani

Robert J. Fontana

Hallberg

Yi Ju Li

M Isabel Lucena

Nanye Long

Mariam Molokhia

Matthew R. Nelson

Joseph A. Odin

Munir Pirmohamed

Thorunn Rafnar

Jose Serrano

Kari Stefansson

Andrew Stolz

Ann K. Daly

Paul B. Watkins



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, non- receptor type 22 gene (PTPN22) (odds ratio [OR], 1.44; 95% CI, 1.28–1.62; P=1.2x10–9 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=4.0x10-6; allele frequency=13.3%), but the polymorphism was associated with DILI of other causes (OR, 1.37; 95% CI, 1.21–1.56; P= 1.5x10–6; 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.

Citation

Cirulli, E. T., Nicoletti, P., Abramson, K., Andrade, R. J., Bjornsson, E. S., Chalasani, N., …Watkins, P. B. (2019). A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury. Gastroenterology,

Journal Article Type Article
Acceptance Date Jan 13, 2019
Online Publication Date Jan 18, 2019
Publication Date 2019-05
Deposit Date Jan 31, 2019
Publicly Available Date Jan 19, 2020
Publisher Elsevier
Peer Reviewed Peer Reviewed
Keywords Amino acid change; GWAS; Mutation; Inflammation
Public URL https://nottingham-repository.worktribe.com/output/1507903
Publisher URL https://www.sciencedirect.com/science/article/pii/S0016508519300940?via%3Dihub

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