Genome-wide Association Study of Methotrexate-Induced Liver Injury in Rheumatoid Arthritis Patients.

Autor: Eektimmerman F; Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.; Department of Clinical Pharmacy, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands., Swen JJ; Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands., den Broeder AA; Department of Rheumatology, Radboudumc and Sint Maartenskliniek, Nijmegen, The Netherlands., Hazes JMW; Department of Rheumatology, ErasmusMC, University Medical Center Rotterdam, Rotterdam, The Netherlands., Kurreeman FS; Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands., Verstappen SMM; Division of Musculoskeletal and Dermatological Sciences, Centre for Epidemiology Versus Arthritis, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.; NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK., Nair N; NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.; Division of Musculoskeletal Sciences, Centre for Genetics and Genomics Versus Arthritis, The University of Manchester, Manchester, UK., Pawlik A; Department of Physiology, Pomeranian Medical University, Szczecin, Poland., Nurmohamed MT; Amsterdam Rheumatology and Immunology Center, Amsterdam, The Netherlands., Dolžan V; Faculty of Medicine, Institute of Biochemistry and Molecular Genetics, University of Ljubljana, Ljubljana, Slovenia., Böhringer S; Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands., Allaart CF; Department of Rheumatology, Leiden University Medical Centre, Leiden, The Netherlands., Guchelaar HJ; Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
Jazyk: angličtina
Zdroj: Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 2023 Apr; Vol. 113 (4), pp. 916-923. Date of Electronic Publication: 2023 Feb 20.
DOI: 10.1002/cpt.2858
Abstrakt: Hepatotoxicity is a serious adverse drug reaction related to methotrexate (MTX). However, the cause of drug-induced liver injury (DILI) is still unclear and unpredictable. Genetic risk factors may predispose for MTX-DILI. Therefore, we conducted a nested case-control genome-wide association study to explore genetic risk factors associated with MTX-DILI. Seven international groups contributed blood samples and data of patients with rheumatoid arthritis who used MTX. MTX-DILI was defined as an alanine aminotransferase (ALT) level of at least three times the upper limit of normal (ULN), to increase contrast controls ALT levels did not raise above two times the ULN. Per study site, control subjects and patients with MTX-DILI (ratio 3:1) were matched for age, gender, and duration of MTX use. Patients were genotyped using Illumina GSA MD-24v1-0 and data were imputed using the 1000 Genomes reference panel. Single-nucleotide polymorphisms (SNPs) were analyzed using an additive genetic model, corrected for sex, country, and age. A P-value of ≤ 5 × 10 -8 was considered significant, whereas a  P-value of ≤ 5 × 10 -6 was considered suggestive. A total of 108 MTX-DILI cases and 311 controls were included for association analysis. None of the SNPs were significantly associated with MTX-DILI. However, we found seven suggestive genetic variants associated with MTX-DILI (P-values 7.43 × 10 -8 to 4.86 × 10 -6 ). Of those, five SNPs were in the intronic protein-coding regions of FTCDNL1, BCOR, FGF14, RBMS3, and PFDN4/DOK5. Investigation of candidates SPATA9 (rs72783407), PLCG2 (rs60427389), RAVER2 (rs72675408), JAK1 (rs72675451), PTPN2 (rs2476601), MTHFR C677T (rs1801133), and into the HLA region did not show significant findings. No genetic variants associated with MTX-DILI were found, whereas suggestive SNPs need further investigation.
(© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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