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Genome-wide association study of methotrexate-induced liver injury in rheumatoid arthritis patients
Eektimmerman, Frank ...
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 rheumatoid arthritis patients who used MTX. MTX-induced DILI was defined as an ALT level of at least 3X the upper limit of normal (ULN), to increase contrast controls ALT levels did not raise above 2X ULN. Per study site, control and MTX DILI patients (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 1000Genomes reference panel. SNPs were analyzed using an additive genetic model, corrected for sex, country, and age. A p-value of ≤5x10-8 was considered significant, while a p-value of ≤5x10-6 was considered suggestive. A total of 104 MTX-induced DILI cases and 315 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-value 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, while suggestive SNPs need further investigation.
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