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Genetic Polymorphisms of GGH and ABCC2 Are Associated with Methotrexate Intolerance in Patients with Rheumatoid Arthritis

Objective: to identify new single-nucleotide polymorphisms (SNPs) in genes encoding proteins involved in methotrexate (MTX) metabolism and to evaluate the associations of these SNPs with MTX toxicity or intolerance in a southern Spanish cohort of patients with rheumatoid arthritis (RA). Methods: An...

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Autores principales: Escudero-Contreras, Alejandro, López-Medina, Clementina, Collantes-Estévez, Eduardo, Ortega-Castro, Rafaela, Calvo-Gutiérrez, Jerusalem, Mena-Vázquez, Natalia, Panero-Lamothe, Blanca, Manzanares-Martín, Bárbara, Cáliz-Cáliz, Rafael, Jiménez-Morales, Alberto, Ruiz-Jiménez, Mayte, Font-Ugalde, Pilar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8472669/
https://www.ncbi.nlm.nih.gov/pubmed/34575187
http://dx.doi.org/10.3390/jcm10184070
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author Escudero-Contreras, Alejandro
López-Medina, Clementina
Collantes-Estévez, Eduardo
Ortega-Castro, Rafaela
Calvo-Gutiérrez, Jerusalem
Mena-Vázquez, Natalia
Panero-Lamothe, Blanca
Manzanares-Martín, Bárbara
Cáliz-Cáliz, Rafael
Jiménez-Morales, Alberto
Ruiz-Jiménez, Mayte
Font-Ugalde, Pilar
author_facet Escudero-Contreras, Alejandro
López-Medina, Clementina
Collantes-Estévez, Eduardo
Ortega-Castro, Rafaela
Calvo-Gutiérrez, Jerusalem
Mena-Vázquez, Natalia
Panero-Lamothe, Blanca
Manzanares-Martín, Bárbara
Cáliz-Cáliz, Rafael
Jiménez-Morales, Alberto
Ruiz-Jiménez, Mayte
Font-Ugalde, Pilar
author_sort Escudero-Contreras, Alejandro
collection PubMed
description Objective: to identify new single-nucleotide polymorphisms (SNPs) in genes encoding proteins involved in methotrexate (MTX) metabolism and to evaluate the associations of these SNPs with MTX toxicity or intolerance in a southern Spanish cohort of patients with rheumatoid arthritis (RA). Methods: An observational, retrospective, and multicenter study was conducted at three participating hospitals in southern Spain. The main variable was intolerance to MTX (i.e., bDMARD monotherapy), defined as an interruption of treatment due to adverse events or toxicity. Patients being treated with MTX and bDMARDs (combined treatment) at the time of the study visit were considered “tolerant” of MTX. Ten polymorphisms were selected for sequencing in our patients according to a literature review. Each polymorphism was classified according to three possible genotypes (e.g., two homozygous (AA or GG) and one heterozygous (AG)), and the association of these combinations with MTX intolerance was evaluated. Results: A total of 227 patients were included in the final analysis (107 intolerant of MTX and 120 tolerant). A significant association was observed between MTX intolerance and the GGH-T401C AA/AG genotype (OR 2.13, 95% CI 1.06–4.29) in comparison with the GG genotype. On the other hand, an inverse association was observed between the ABCC2-C24T TT/TC genotype and intolerance to MTX (OR 0.59, 95% CI 0.35–1.00) in comparison with the CC genotype. Conclusion: This study provides new data on the association between genetic polymorphisms and MTX intolerance, which may contribute to the development of new biomarkers and personalized medicine in patients with RA.
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spelling pubmed-84726692021-09-28 Genetic Polymorphisms of GGH and ABCC2 Are Associated with Methotrexate Intolerance in Patients with Rheumatoid Arthritis Escudero-Contreras, Alejandro López-Medina, Clementina Collantes-Estévez, Eduardo Ortega-Castro, Rafaela Calvo-Gutiérrez, Jerusalem Mena-Vázquez, Natalia Panero-Lamothe, Blanca Manzanares-Martín, Bárbara Cáliz-Cáliz, Rafael Jiménez-Morales, Alberto Ruiz-Jiménez, Mayte Font-Ugalde, Pilar J Clin Med Article Objective: to identify new single-nucleotide polymorphisms (SNPs) in genes encoding proteins involved in methotrexate (MTX) metabolism and to evaluate the associations of these SNPs with MTX toxicity or intolerance in a southern Spanish cohort of patients with rheumatoid arthritis (RA). Methods: An observational, retrospective, and multicenter study was conducted at three participating hospitals in southern Spain. The main variable was intolerance to MTX (i.e., bDMARD monotherapy), defined as an interruption of treatment due to adverse events or toxicity. Patients being treated with MTX and bDMARDs (combined treatment) at the time of the study visit were considered “tolerant” of MTX. Ten polymorphisms were selected for sequencing in our patients according to a literature review. Each polymorphism was classified according to three possible genotypes (e.g., two homozygous (AA or GG) and one heterozygous (AG)), and the association of these combinations with MTX intolerance was evaluated. Results: A total of 227 patients were included in the final analysis (107 intolerant of MTX and 120 tolerant). A significant association was observed between MTX intolerance and the GGH-T401C AA/AG genotype (OR 2.13, 95% CI 1.06–4.29) in comparison with the GG genotype. On the other hand, an inverse association was observed between the ABCC2-C24T TT/TC genotype and intolerance to MTX (OR 0.59, 95% CI 0.35–1.00) in comparison with the CC genotype. Conclusion: This study provides new data on the association between genetic polymorphisms and MTX intolerance, which may contribute to the development of new biomarkers and personalized medicine in patients with RA. MDPI 2021-09-09 /pmc/articles/PMC8472669/ /pubmed/34575187 http://dx.doi.org/10.3390/jcm10184070 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Escudero-Contreras, Alejandro
López-Medina, Clementina
Collantes-Estévez, Eduardo
Ortega-Castro, Rafaela
Calvo-Gutiérrez, Jerusalem
Mena-Vázquez, Natalia
Panero-Lamothe, Blanca
Manzanares-Martín, Bárbara
Cáliz-Cáliz, Rafael
Jiménez-Morales, Alberto
Ruiz-Jiménez, Mayte
Font-Ugalde, Pilar
Genetic Polymorphisms of GGH and ABCC2 Are Associated with Methotrexate Intolerance in Patients with Rheumatoid Arthritis
title Genetic Polymorphisms of GGH and ABCC2 Are Associated with Methotrexate Intolerance in Patients with Rheumatoid Arthritis
title_full Genetic Polymorphisms of GGH and ABCC2 Are Associated with Methotrexate Intolerance in Patients with Rheumatoid Arthritis
title_fullStr Genetic Polymorphisms of GGH and ABCC2 Are Associated with Methotrexate Intolerance in Patients with Rheumatoid Arthritis
title_full_unstemmed Genetic Polymorphisms of GGH and ABCC2 Are Associated with Methotrexate Intolerance in Patients with Rheumatoid Arthritis
title_short Genetic Polymorphisms of GGH and ABCC2 Are Associated with Methotrexate Intolerance in Patients with Rheumatoid Arthritis
title_sort genetic polymorphisms of ggh and abcc2 are associated with methotrexate intolerance in patients with rheumatoid arthritis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8472669/
https://www.ncbi.nlm.nih.gov/pubmed/34575187
http://dx.doi.org/10.3390/jcm10184070
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