Publication: A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury.
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Identifiers
Date
2019-01-13
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
Advisors
Journal Title
Journal ISSN
Volume Title
Publisher
Elsevier
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 × 10-9 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. 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.
Description
MeSH Terms
Adult
Black or african american
Amoxicillin
Anti-bacterial agents
Case-control studies
Chemical and drug induced liver injury
Clavulanic acid
Female
Gene frequency
Genome-wide association study
HLA-A2 antigen
HLA-DRB1 chains
Hispanic or latino
Humans
Male
Middle aged
Mutation, missense
Polymorphism, single nucleotide
Protein tyrosine phosphatase, non-Receptor type 22
Risk factors
White people
Black or african american
Amoxicillin
Anti-bacterial agents
Case-control studies
Chemical and drug induced liver injury
Clavulanic acid
Female
Gene frequency
Genome-wide association study
HLA-A2 antigen
HLA-DRB1 chains
Hispanic or latino
Humans
Male
Middle aged
Mutation, missense
Polymorphism, single nucleotide
Protein tyrosine phosphatase, non-Receptor type 22
Risk factors
White people
DeCS Terms
Amoxicilina
Antibacterianos
Antígeno HLA-A2
Cadenas HLA-DRB1
Estudio de asociación del genoma completo
Frecuencia de los genes
Mutación missense
Polimorfismo de nucleótido simple
Ácido clavulánico
Antibacterianos
Antígeno HLA-A2
Cadenas HLA-DRB1
Estudio de asociación del genoma completo
Frecuencia de los genes
Mutación missense
Polimorfismo de nucleótido simple
Ácido clavulánico
CIE Terms
Keywords
Amino Acid Change, GWAS, Inflammation, Mutation
Citation
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