期刊
GASTROENTEROLOGY
卷 156, 期 6, 页码 1707-+出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2019.01.034
关键词
Amino Acid Change; GWAS; Mutation; Inflammation
资金
- National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (NIH) [U01-DK065176, U01-DK065201, U01-DK065184, U01-DK065211, U01DK065193, U01-DK065238, U01-DK083023, U01-DK083027, U01-DK082992, U01-DK083020, U01-DK100928]
- CTSA [UL1 RR025761, UL1 RR025747, UL1 UL1 RR024986]
- International Serious Adverse Events Consortium
- Abbott
- Amgen
- Daiichi-Sankyo
- GlaxoSmithKline
- Merck
- Novartis
- Pfizer
- Roche
- Sanofi-Aventis
- Takeda
- Wellcome Trust
- National Institute for Health Research (NIHR) Nottingham Digestive Diseases Biomedical Research Unit at the Nottingham University Hospitals NHS Trust
- University of Nottingham
- EC 5th Framework program [QLRI-CT-2002-02757]
- Spanish Medicine Agency
- Fondo Europeo de Desarrollo Regional - FEDER [FIS PI16_01748, PI15_01440]
- Instituto de Salud Carlos III
- Swedish Medical Products Agency
- Swedish Society of Medicine [2008-21619]
- Swedish Research Council [521-2011-2440]
- Swedish Heart and Lung Foundation [20120557]
- National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London
- MRC [MR/N005953/1, MR/L006758/1] Funding Source: UKRI
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.
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