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

被引：3

作者：

Eektimmerman, Frank ^{[1
,2
]}

Swen, Jesse J. J. ^{[1
]}

den Broeder, Alfons A. A. ^{[3
]}

Hazes, Johanna M. W. ^{[4
]}

Kurreeman, Fina S. S. ^{[5
]}

Verstappen, Suzanne M. M. ^{[6
,7
]}

Nair, Nisha ^{[7
,8
]}

Pawlik, Andrzej ^{[9
]}

Nurmohamed, Mike T. T. ^{[10
]}

Dolzan, Vita ^{[11
]}

Bohringer, Stefan ^{[12
]}

Allaart, Cornelia F. F. ^{[5
]}

Guchelaar, Henk-Jan ^{[1
]}

机构：

[1] Leiden Univ, Dept Clin Pharm & Toxicol, Med Ctr, Leiden, Netherlands

[2] Canisius Wilhelmina Hosp, Dept Clin Pharm, Nijmegen, Netherlands

[3] Dept Rheumatol, Radboudumc & Sint Maartenskliniek, Nijmegen, Netherlands

[4] Univ Med Ctr Rotterdam, Dept Rheumatol, ErasmusMC, Rotterdam, Netherlands

[5] Leiden Univ, Dept Rheumatol, Med Ctr, Leiden, Netherlands

[6] Univ Manchester, Fac Biol Med & Hlth, Ctr Epidemiol Versus Arthrit, Div Musculoskeletal & Dermatol Sci, Manchester, England

[7] Manchester Univ NHS Fdn Trust, NIHR Manchester Biomed Res Ctr, Manchester Acad Hlth Sci Ctr, Manchester, England

[8] Univ Manchester, Ctr Genet & Genom Versus Arthrit, Div Musculoskeletal Sci, Manchester, England

[9] Pomeranian Med Univ, Dept Physiol, Szczecin, Poland

[10] Amsterdam Rheumatol & Immunol Ctr, Amsterdam, Netherlands

[11] Univ Ljubljana, Inst Biochem & Mol Genet, Fac Med, Ljubljana, Slovenia

[12] Leiden Univ, Dept Med Stat & Bioinformat, Med Ctr, Leiden, Netherlands

来源：

CLINICAL PHARMACOLOGY & THERAPEUTICS | 2023年 / 113卷 / 04期

关键词：

RISK-FACTORS; HEPATOTOXICITY; STRATEGIES; THERAPY;

D O I：

10.1002/cpt.2858

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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 x 10(-8) was considered significant, whereas a P-value of <= 5 x 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 x 10(-8) to 4.86 x 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.

引用

页码：916 / 923

页数：8

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