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

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Authors
Cirulli, Elizabeth T
Nicoletti, Paola
Abramson, Karen
Andrade, Raul J
Bjornsson, Einar S
Chalasani, Naga
Fontana, Robert J
Hallberg, Pär
Li, Yi Ju
Lucena, M Isabel
Long, Nanye
Molokhia, Mariam
Nelson, Matthew R
Odin, Joseph A
Pirmohamed, Munir
Rafnar, Thorunn
Serrano, Jose
Stefánsson, Kári
Stolz, Andrew
Daly, Ann K
Aithal, Guruprasad P
Watkins, Paul B
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Issue Date
2019-05

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Citation
A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury. 2019, 156(6):1707-1716 Gastroenterology
Abstract
We performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility. 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. 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 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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Additional Links
https://www.sciencedirect.com/science/article/pii/S0016508519300940
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511989/
ae974a485f413a2113503eed53cd6c53
10.1053/j.gastro.2019.01.034
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