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

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Date

2021-09-09

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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

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MDPI
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Abstract

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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Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans
Medical Subject Headings::Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 2-Ring::Pteridines::Pterins::Aminopterin::Methotrexate
Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Variation::Polymorphism, Genetic::Polymorphism, Single Nucleotide
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Case-Control Studies::Retrospective Studies
Medical Subject Headings::Geographical Locations::Geographic Locations::Europe::Spain
Medical Subject Headings::Diseases::Musculoskeletal Diseases::Rheumatic Diseases::Arthritis, Rheumatoid
Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genotype
Medical Subject Headings::Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Nucleotides
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Evaluation Studies as Topic::Clinical Trials as Topic::Multicenter Studies as Topic

DeCS Terms

Genética
Biomarcadores
Polimorfismo genético
Genotipo
Artritis Reumatoide

CIE Terms

Keywords

Methotrexate, Rheumatoid arthritis, Genetics, Biomarkers, Metotrexato, Genetic polymorphisms, Genotype

Citation

Escudero-Contreras A, López-Medina C, Collantes-Estévez E, Ortega-Castro R, Calvo-Gutiérrez J, Mena-Vázquez N, et al. Genetic Polymorphisms of GGH and ABCC2 Are Associated with Methotrexate Intolerance in Patients with Rheumatoid Arthritis. J Clin Med. 2021 Sep 9;10(18):4070