<i>SLC19A1</i>
            80G Allele as a Biomarker of Methotrexate-Related Gastrointestinal Toxicity in Portuguese Rheumatoid Arthritis Patients

Lima, Áurea; Bernardes, Miguel; Sousa, Hugo; Azevedo, Rita; Costa, Lúcia; Ventura, Francisco; Seabra, Vítor; Medeiros, Rui

doi:10.2217/pgs.13.244

Cited by 34 publications

(23 citation statements)

References 52 publications

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“…The occurrence of MTX-related toxicity was registered at each visit and, according to severity, MTX dose was adjusted or discontinued. Folic acid supplementation was prescribed to all patients for the prevention of toxicity occurrence and their regular compliance was registered [7] , [25] , [26] . Other concomitant drugs, such as corticosteroids and non-steroidal anti-inflammatories (NSAIDs) were allowed during the study.…”

Section: Methodsmentioning

confidence: 99%

“…Methotrexate (MTX) is the cornerstone for rheumatoid arthritis (RA) treatment and is the most widely used disease-modifying antirheumatic drug (DMARD) in newly diagnosed patients [1] , [2] . Despite its cost-effectiveness, therapeutic outcome is variable mainly concerning to MTX clinical response and/or development of MTX-related toxicity [3] – [7] . MTX is an antifolate drug with important anti-inflammatory and antiproliferative effects, partly achieved by the intracellular inhibition of thymidylate synthase (TS) [8] – [10] .…”

Section: Introductionmentioning

confidence: 99%

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Role of Key TYMS Polymorphisms on Methotrexate Therapeutic Outcome in Portuguese Rheumatoid Arthritis Patients

et al. 2014

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BackgroundTherapeutic outcome of rheumatoid arthritis (RA) patients treated with methotrexate (MTX) can be modulated by thymidylate synthase (TS) levels, which may be altered by genetic polymorphisms in TS gene (TYMS). This study aims to elucidate the influence of TYMS polymorphisms in MTX therapeutic outcome (regarding both clinical response and toxicity) in Portuguese RA patients.MethodsClinicopathological data from 233 Caucasian RA patients treated with MTX were collected, outcomes were defined and patients were genotyped for the following TYMS polymorphisms: 1) 28 base pairs (bp) variable number tandem repeat (rs34743033); 2) single nucleotide polymorphism C>G (rs2853542); and 3) 6 bp sequence deletion (1494del6, rs34489327). Chi-square and binary logistic regression analyses were performed, using genotype and haplotype-based approaches.ResultsConsidering TYMS genotypes, 3R3R (p = 0.005, OR = 2.34), 3RC3RG (p = 0.016, OR = 3.52) and 6bp− carriers (p = 0.011, OR = 1.96) were associated with non-response to MTX. Multivariate analysis confirmed the increased risk for non-response to MTX in 6bp− carriers (p = 0.016, OR = 2.74). Data demonstrated that TYMS polymorphisms were in linkage disequilibrium (p<0.00001). Haplotype multivariate analysis revealed that haplotypes harboring both 3R and 6bp− alleles were associated with non-response to MTX. Regarding MTX-related toxicity, no statistically significant differences were observed in relation to TYMS genotypes and haplotypes.ConclusionOur study reveals that TYMS polymorphisms could be important to help predicting clinical response to MTX in RA patients. Despite the potential of these findings, translation into clinical practice needs larger studies to confirm these evidences.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Role of Key TYMS Polymorphisms on Methotrexate Therapeutic Outcome in Portuguese Rheumatoid Arthritis Patients

et al. 2014

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“…Sin embargo, el OR de 1,540(IC95%; 0,871-2,719) indica bajo riesgo de padecer LLA, aunque no se descartaría la probabilidad de ser responsable en parte, de la aparición de eventos adversos mediados por MTX, tal como lo reportó Owen et al (13). El polimorfismo SLC19A1 (rs2838956) se encontró en un importante número de pacientes con HT y HM; lo cual favorecería la posible presentación de reacciones gastro-intestinales adversas por MTX, como se ha asociado en población portuguesa (22,23). Además, los SNPs de SLC19A1 pudieran estar asociados a riesgos tóxicos en pacientes tratados con altas dosis de MTX tal como lo indica Faganel et al (24).…”

Section: Discussionunclassified

Impacto de polimorfismos genéticos de la vía metabólica del metotrexato sobre la sobrevida de niños mexicanos con leucemia linfoblástica aguda (LLA)

Zaruma‐Torres

Lares‐Asseff

Reyes-Espinoza

et al. 2015

Vitae

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RESUMENAntecedentes: La leucemia linfoblástica aguda (LLA) es un padecimiento oncológico importante en la población pediátrica mexicana, cuya base genética pudiera modificar la efectividad de la quimioterapia del antifolato metotrexato (MTX) y el tiempo de sobrevida libre de enfermedad y la sobrevida total. Objetivo: Determinar la asociación de 10 polimorfismos genéticos de la vía del folato: en transportadores celulares (COL18A1, SLC19A1, ABCB1 y ABCC5) y las enzimas folilpoliglutamil sintetasa (FPGS) y xantina oxidasa (XO), con la sobrevida de los niños con leucemia linfoblástica aguda. Métodos: En el Centro Estatal de Cancerología de Durango-México, se estudiaron 39 niños con leucemia linfoblástica aguda tratados con MTX y 102 controles sin la enfermedad, a quienes mediante qPCR, se les determinaron 10 polimorfismos en la vía del folato. Durante 5 años de seguimiento se determinó la sobrevida libre de enfermedad y la sobrevida total, y su relación con su genotipo. Resultados: Cuatro polimorfismos no estuvieron en equilibrio de Hardy-Weinberg COL18A1(rs2274808), ABCC5(rs9838667 y rs3792585) y XO(rs17011368). Únicamente el rs17011368 de XO se asoció con riesgo de estar presente en los pacientes con leucemia linfoblástica aguda cuyo OR fue 9.771 p=0,001). El FPGS (rs1544105) afectó la sobrevida libre de enfermedad y la sobrevida total (Log Rank p<0.05). Conclusiones: El polimorfismo (rs17011368) de la XO presentó riesgo para leucemia linfoblástica aguda; así mismo, se encontró una asociación importante entre los portadores del polimorfismo FPGS (rs1544105) que modificaría la sobrevidas de los pacientes tratados con MTX.Palabras clave: Metotrexato, xantina oxidasa, supervivencia, leucemia linfoblástica, genotipo. ABSTRACTBackground: Acute lymphoblastic leukemia (ALL) is a major cancer disease in Mexican pediatric population, were the genotype could affect the effectiveness of chemotherapy in which the methotrexate (MTX) is involved and consequently the time of disease free survival and overall survival. Objective: Determine the association of 10 genetic polymorphisms of the folate pathway: in cellular carriers SLC19A1, ABCB1 and ABCC5) and in enzymes such as folylpolyglutamate synthetase (FPGS) and xanthine oxidase (XO), with survival of children with acute lymphoblastic leukemia. Methods: Thirtynine children with acute lymphoblastic leukemia from the State Cancer Center in Durango (Mexico) treated with MTX and 102 healthy controls, were qPCR analyzed for 10 polymorphisms in the folate pathway. During 5 years of follow up, the disease-free survival and overall survival rates were investigated in relation with their genotypes. Results: Four polymorphisms were not found in Hardy-Weinberg Equilibrium COL18A1 (rs2274808), ABCC5 (rs9838667 and rs3792585) and XO (rs170113685). Only XO (rs170113685) was associated with risk of being present in patients with ALL whose odds ratio was 9.771 (95% 4.974-19.196, p=0.001). The polymorphism rs1544105 for FPGS affected disease free survival and overall survival (Log Rank tes...

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“…En RFC/SLC19A1, los pacientes que portan el alelo G en G80A (rs1051266) tienen una captación intracelular de MTX menor en comparación con los que portan el alelo A, lo cual llevaría a menor eficacia 17,43 . Un estudio reciente realizado en población portuguesa sugiere mayor toxicidad gastrointestinal temprana en los portadores del alelo G, la cual se reduce significativamente con el suplemento de ácido fólico 54 . En un estudio realizado con población del Treatment of Early Aggressive Rheumatoid Arthritis se encontró asociación de variantes en el gen SLC22A2 con una mejor respuesta al MTX 55 .…”

Section: Características Poblacionales Polimorfismos Y Genotiposunclassified

Farmacogenética del metotrexato en artritis reumatoide. Revisión sistemática

Restrepo

Giraldo

Londoño

et al. 2016

Revista Colombiana de Reumatología

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SLC19A1 80G Allele as a Biomarker of Methotrexate-Related Gastrointestinal Toxicity in Portuguese Rheumatoid Arthritis Patients

Abstract: SLC19A1 G80A genotyping may be a useful tool for clinicians to identify patients at higher risk for developing gastrointestinal toxicity related to MTX treatment.

Cited by 34 publications

References 52 publications

Role of Key TYMS Polymorphisms on Methotrexate Therapeutic Outcome in Portuguese Rheumatoid Arthritis Patients

Role of Key TYMS Polymorphisms on Methotrexate Therapeutic Outcome in Portuguese Rheumatoid Arthritis Patients

Impacto de polimorfismos genéticos de la vía metabólica del metotrexato sobre la sobrevida de niños mexicanos con leucemia linfoblástica aguda (LLA)

Farmacogenética del metotrexato en artritis reumatoide. Revisión sistemática

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