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

Frank Eektimmerman; Jesse J. Swen; Alfons A. den Broeder; Johanna M.W. Hazes; Fina S. Kurreeman; Suzanne M.M. Verstappen; Nisha Nair; Andrzej Pawlik; Mike T. Nurmohamed; Vita Dolžan; Stefan Böhringer; Cornelia F. Allaart; Henk Jan Guchelaar

doi:10.1002/cpt.2858

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

Frank Eektimmerman, Jesse J. Swen, Alfons A. den Broeder, Johanna M.W. Hazes, Fina S. Kurreeman, Suzanne M.M. Verstappen, Nisha Nair, Andrzej Pawlik, Mike T. Nurmohamed, Vita Dolžan, Stefan Böhringer, Cornelia F. Allaart, Henk Jan Guchelaar^*

^*Corresponding author for this work

Rheumatology

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

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.

Original language	English
Pages (from-to)	916-923
Number of pages	8
Journal	Clinical Pharmacology and Therapeutics
Volume	113
Issue number	4
Early online date	27 Jan 2023
DOIs	https://doi.org/10.1002/cpt.2858
Publication status	Published - Apr 2023

Bibliographical note

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.

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Genome-wide Association Study of Methotrexate-Induced Liver Injury in Rheumatoid Arthritis PatientsFinal published version, 1.12 MBLicence: CC BY-NC

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Eektimmerman, F., Swen, J. J., den Broeder, A. A., Hazes, J. M. W., Kurreeman, F. S., Verstappen, S. M. M., Nair, N., Pawlik, A., Nurmohamed, M. T., Dolžan, V., Böhringer, S., Allaart, C. F., & Guchelaar, H. J. (2023). Genome-wide Association Study of Methotrexate-Induced Liver Injury in Rheumatoid Arthritis Patients. Clinical Pharmacology and Therapeutics, 113(4), 916-923. https://doi.org/10.1002/cpt.2858

@article{30064d00d00c40fa9329d975d5f3e83c,

title = "Genome-wide Association Study of Methotrexate-Induced Liver Injury in Rheumatoid Arthritis Patients",

abstract = "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.",

author = "Frank Eektimmerman and Swen, {Jesse J.} and {den Broeder}, {Alfons A.} and Hazes, {Johanna M.W.} and Kurreeman, {Fina S.} and Verstappen, {Suzanne M.M.} and Nisha Nair and Andrzej Pawlik and Nurmohamed, {Mike T.} and Vita Dol{\v z}an and Stefan B{\"o}hringer and Allaart, {Cornelia F.} and Guchelaar, {Henk Jan}",

note = "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 Ren{\'e}e Baak-Pablo, Dani{\"e}lle 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: {\textcopyright} 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.",

year = "2023",

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language = "English",

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pages = "916--923",

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Eektimmerman, F, Swen, JJ, den Broeder, AA, Hazes, JMW, Kurreeman, FS, Verstappen, SMM, Nair, N, Pawlik, A, Nurmohamed, MT, Dolžan, V, Böhringer, S, Allaart, CF & Guchelaar, HJ 2023, 'Genome-wide Association Study of Methotrexate-Induced Liver Injury in Rheumatoid Arthritis Patients', Clinical Pharmacology and Therapeutics, vol. 113, no. 4, pp. 916-923. https://doi.org/10.1002/cpt.2858

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.

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

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