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A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury
Duke Univ, Duke Ctr Appl Genom & Precis Med, Durham, NC USA.
Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, One Gustave Levy Pl, New York, NY 10029 USA;Sema4, Stamford, CT USA.
Duke Univ, Duke Mol Physiol Inst, Durham, NC USA.
Univ Malaga, Hosp Univ Virgen de la Victoria, Ctr Invest Biomed Red Enfermedades Hepat & Digest, UGC Digest,Inst Invest Biomed Malaga IBIMA, Malaga, Spain;Univ Malaga, IBIMA Hosp Univ Virgen de la Victoria, Malaga, Spain;CIBERehd, Madrid, Spain.
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2019 (English)In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 156, no 6, p. 1707-1716Article in journal (Refereed) Published
Abstract [en]

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 x 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 x 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 x 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.

Place, publisher, year, edition, pages
W B SAUNDERS CO-ELSEVIER INC , 2019. Vol. 156, no 6, p. 1707-1716
Keywords [en]
Amino Acid Change, GWAS, Mutation, Inflammation
National Category
Gastroenterology and Hepatology
Identifiers
URN: urn:nbn:se:uu:diva-382821DOI: 10.1053/j.gastro.2019.01.034ISI: 000464659200032PubMedID: 30664875OAI: oai:DiVA.org:uu-382821DiVA, id: diva2:1313709
Funder
Swedish Research Council, 521-2011-2440Swedish Society of Medicine, 2008-21619Swedish Heart Lung Foundation, 20120557Available from: 2019-05-06 Created: 2019-05-06 Last updated: 2019-05-06Bibliographically approved

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Hallberg, PärWadelius, Mia

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