Elizabeth T. Cirulli
A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury
Cirulli, Elizabeth T.; Nicoletti, Paola; Abramson, Karen; Andrade, Raul J.; Bjornsson, Einar S.; Chalasani, Naga; Fontana, Robert J.; Hallberg, P�r; Li, Yi Ju; Lucena, M Isabel; Long, Nanye; Molokhia, Mariam; Nelson, Matthew R.; Odin, Joseph A.; Pirmohamed, Munir; Rafnar, Thorunn; Serrano, Jose; Stefansson, Kari; Stolz, Andrew; Daly, Ann K.; Aithal, Guruprasad P.; Watkins, Paul B.
Authors
Paola Nicoletti
Karen Abramson
Raul J. Andrade
Einar S. Bjornsson
Naga Chalasani
Robert J. Fontana
P�r 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
GURUPRASAD AITHAL Guru.Aithal@nottingham.ac.uk
Professor of Hepatology
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 |
Print ISSN | 0016-5085 |
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 |
Contract Date | Jan 31, 2019 |
Files
Supplment For Ptpn22 Manuscript Final
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2018 5 Ptpn22 Rev Final Notrack
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