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Identification of SNPs associated with methotrexate treatment outcomes in patients with early rheumatoid arthritis

Methotrexate is one of the cornerstones of rheumatoid arthritis (RA) therapy. Genetic factors or single nucleotide polymorphisms (SNPs) are responsible for 15%–30% of the variation in drug response. Identification of clinically effective SNP biomarkers for predicting methotrexate (MTX) sensitivity h...

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Autores principales: Kolan, Shrikant S., Li, Gaoyang, Grimolizzi, Franco, Sexton, Joe, Goll, Guro, Kvien, Tore K., Sundlisæter, Nina Paulshus, Zucknick, Manuela, Lillegraven, Siri, Haavardsholm, Espen A., Skålhegg, Bjørn Steen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9714492/
https://www.ncbi.nlm.nih.gov/pubmed/36467057
http://dx.doi.org/10.3389/fphar.2022.1075603
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author Kolan, Shrikant S.
Li, Gaoyang
Grimolizzi, Franco
Sexton, Joe
Goll, Guro
Kvien, Tore K.
Sundlisæter, Nina Paulshus
Zucknick, Manuela
Lillegraven, Siri
Haavardsholm, Espen A.
Skålhegg, Bjørn Steen
author_facet Kolan, Shrikant S.
Li, Gaoyang
Grimolizzi, Franco
Sexton, Joe
Goll, Guro
Kvien, Tore K.
Sundlisæter, Nina Paulshus
Zucknick, Manuela
Lillegraven, Siri
Haavardsholm, Espen A.
Skålhegg, Bjørn Steen
author_sort Kolan, Shrikant S.
collection PubMed
description Methotrexate is one of the cornerstones of rheumatoid arthritis (RA) therapy. Genetic factors or single nucleotide polymorphisms (SNPs) are responsible for 15%–30% of the variation in drug response. Identification of clinically effective SNP biomarkers for predicting methotrexate (MTX) sensitivity has been a challenge. The aim of this study was to explore the association between the disease related outcome of MTX treatment and 23 SNPs in 8 genes of the MTX pathway, as well as one pro-inflammatory related gene in RA patients naïve to MTX. Categorical outcomes such as Disease Activity Score (DAS)-based European Alliance of Associations for Rheumatology (EULAR) non-response at 4 months, The American College of Rheumatology and EULAR (ACR/EULAR) non-remission at 6 months, and failure to sustain MTX monotherapy from 12 to 24 months were assessed, together with continuous outcomes of disease activity, joint pain and fatigue. We found that the SNPs rs1801394 in the MTRR gene, rs408626 in DHFR gene, and rs2259571 in AIF-1 gene were significantly associated with disease activity relevant continuous outcomes. Additionally, SNP rs1801133 in the MTHFR gene was identified to be associated with improved fatigue. Moreover, associations with p values at uncorrected significance level were found in SNPs and different categorical outcomes: 1) rs1476413 in the MTHFR gene and rs3784864 in ABCC1 gene are associated with ACR/EULAR non-remission; 2) rs1801133 in the MTHFR gene is associated with EULAR response; 3) rs246240 in the ABCC1 gene, rs2259571 in the AIF-1 gene, rs2274808 in the SLC19A1 gene and rs1476413 in the MTHFR gene are associated with failure to MTX monotherapy after 12–24 months. The results suggest that SNPs in genes associated with MTX activity may be used to predict MTX relevant-clinical outcomes in patients with RA.
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spelling pubmed-97144922022-12-02 Identification of SNPs associated with methotrexate treatment outcomes in patients with early rheumatoid arthritis Kolan, Shrikant S. Li, Gaoyang Grimolizzi, Franco Sexton, Joe Goll, Guro Kvien, Tore K. Sundlisæter, Nina Paulshus Zucknick, Manuela Lillegraven, Siri Haavardsholm, Espen A. Skålhegg, Bjørn Steen Front Pharmacol Pharmacology Methotrexate is one of the cornerstones of rheumatoid arthritis (RA) therapy. Genetic factors or single nucleotide polymorphisms (SNPs) are responsible for 15%–30% of the variation in drug response. Identification of clinically effective SNP biomarkers for predicting methotrexate (MTX) sensitivity has been a challenge. The aim of this study was to explore the association between the disease related outcome of MTX treatment and 23 SNPs in 8 genes of the MTX pathway, as well as one pro-inflammatory related gene in RA patients naïve to MTX. Categorical outcomes such as Disease Activity Score (DAS)-based European Alliance of Associations for Rheumatology (EULAR) non-response at 4 months, The American College of Rheumatology and EULAR (ACR/EULAR) non-remission at 6 months, and failure to sustain MTX monotherapy from 12 to 24 months were assessed, together with continuous outcomes of disease activity, joint pain and fatigue. We found that the SNPs rs1801394 in the MTRR gene, rs408626 in DHFR gene, and rs2259571 in AIF-1 gene were significantly associated with disease activity relevant continuous outcomes. Additionally, SNP rs1801133 in the MTHFR gene was identified to be associated with improved fatigue. Moreover, associations with p values at uncorrected significance level were found in SNPs and different categorical outcomes: 1) rs1476413 in the MTHFR gene and rs3784864 in ABCC1 gene are associated with ACR/EULAR non-remission; 2) rs1801133 in the MTHFR gene is associated with EULAR response; 3) rs246240 in the ABCC1 gene, rs2259571 in the AIF-1 gene, rs2274808 in the SLC19A1 gene and rs1476413 in the MTHFR gene are associated with failure to MTX monotherapy after 12–24 months. The results suggest that SNPs in genes associated with MTX activity may be used to predict MTX relevant-clinical outcomes in patients with RA. Frontiers Media S.A. 2022-11-17 /pmc/articles/PMC9714492/ /pubmed/36467057 http://dx.doi.org/10.3389/fphar.2022.1075603 Text en Copyright © 2022 Kolan, Li, Grimolizzi, Sexton, Goll, Kvien, Sundlisæter, Zucknick, Lillegraven, Haavardsholm and Skålhegg. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Kolan, Shrikant S.
Li, Gaoyang
Grimolizzi, Franco
Sexton, Joe
Goll, Guro
Kvien, Tore K.
Sundlisæter, Nina Paulshus
Zucknick, Manuela
Lillegraven, Siri
Haavardsholm, Espen A.
Skålhegg, Bjørn Steen
Identification of SNPs associated with methotrexate treatment outcomes in patients with early rheumatoid arthritis
title Identification of SNPs associated with methotrexate treatment outcomes in patients with early rheumatoid arthritis
title_full Identification of SNPs associated with methotrexate treatment outcomes in patients with early rheumatoid arthritis
title_fullStr Identification of SNPs associated with methotrexate treatment outcomes in patients with early rheumatoid arthritis
title_full_unstemmed Identification of SNPs associated with methotrexate treatment outcomes in patients with early rheumatoid arthritis
title_short Identification of SNPs associated with methotrexate treatment outcomes in patients with early rheumatoid arthritis
title_sort identification of snps associated with methotrexate treatment outcomes in patients with early rheumatoid arthritis
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9714492/
https://www.ncbi.nlm.nih.gov/pubmed/36467057
http://dx.doi.org/10.3389/fphar.2022.1075603
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