TY - JOUR
T1 - Genome-wide Association Study of Methotrexate-Induced Liver Injury in Rheumatoid Arthritis Patients
AU - Eektimmerman, Frank
AU - Swen, Jesse J.
AU - den Broeder, Alfons A.
AU - Hazes, Johanna M. W.
AU - Kurreeman, Fina S.
AU - Verstappen, Suzanne M. M.
AU - Nair, Nisha
AU - Pawlik, Andrzej
AU - Nurmohamed, Mike T.
AU - Dolžan, Vita
AU - Böhringer, Stefan
AU - Allaart, Cornelia F.
AU - Guchelaar, Henk-Jan
N1 - Funding Information:
No funding was received for this work. The authors would like to thank Yavuz Ariyurek for his technical advice concerning performing the GWAS. In addition, we show our gratitude to Jip Linthorst for the preliminary research for causes of DILI and to Renée Baak-Pablo, Daniëlle Klootwijk, and Rowena Schaap for the preparation of the GWAS.
Funding Information:
S. Verstappen and N. Nair are supported by Versus Arthritis (grant numbers 20385 and 20380) and the NIHR Manchester Biomedical Research Centre, UK. All other authors declared no competing interests for this work.
Publisher Copyright:
© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
PY - 2023/4
Y1 - 2023/4
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85148366554
U2 - 10.1002/cpt.2858
DO - 10.1002/cpt.2858
M3 - Article
C2 - 36708065
SN - 0009-9236
VL - 113
SP - 916
EP - 923
JO - Clinical pharmacology and therapeutics
JF - Clinical pharmacology and therapeutics
IS - 4
ER -