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Vol. 13. Num. 6.November - December 2017
Pages 311-370
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Vol. 13. Num. 6.November - December 2017
Pages 311-370
Original Article
DOI: 10.1016/j.reumae.2016.08.004
Impact of Genetic Variants of ATP Binding Cassette B1, AICAR Transformylase/IMP Cyclohydrolase, Folyl-polyglutamate Synthetase, and Methylenetetrahydrofolate Reductase on Methotrexate Toxicity
Impacto de variantes genéticas del transportador de membrana que une ATP B1, la aicar transformilasa/IMP ciclohidrolasa, la folilpoliglutamatosintetasa y la metilen-tetrahidrofolatorreductasa en la toxicidad de metotrexato
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Luis Sala-Icardoa, Amalia Lamanab, Ana María Ortizb, Elena García Lorenzob, Pablo Moreno Fresnedab, Rosario García-Vicuñab, Isidoro González-Álvarob,
Corresponding author
isidoro.ga@ser.es

Corresponding author.
a Servicio de Reumatología, Hospital Universitario de Torrejón de Ardoz, Torrejón de Ardoz, Madrid, Spain
b Servicio de Reumatología, Hospital Universitario La Princesa, Madrid, Spain
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Figures (1)
Tables (4)
Table 1. Baseline Characteristics of the Patients.
Table 2. Multivariate Analysis of the Effect of Different Variables on Glutamate Pyruvate Transaminase in Patients With Early Rheumatoid Arthritis.
Table 3. Multivariate Analysis of the Effect of the Different Factors on the Levels of Hematologic Variables in Visits of Patients With Early Rheumatoid Arthritis Who Were Being Treated With Methotrexate.
Table 4. Multivariate Analysis of the Factors That Influence the Methotrexate Dose Administered to Patients With Early Rheumatoid Arthritis (n=208).
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Abstract
Objective

To analyze the effect of single nucleotide polymorphisms (SNPs) with well-known functional impact of methylenetetrahydrofolate reductase (MTHFR; rs1801131 and rs1801133), the membrane transporter ABCB1 (rs1045642), the AICAR transformylase/IMP cyclohydrolase (ATIC; rs2372536) and folyl-polyglutamate synthetase (FPGS; rs1544105), on liver and bone marrow toxicity of methotrexate (MTX).

Patients and methods

We analyzed 1415 visits from 350 patients of the PEARL (Princesa Early Arthritis Register Longitudinal) study: (732 with MTX, 683 without MTX). The different SNPs were genotyped using specific TaqMan probes (Applied Biosystems). Multivariate analyzes were performed using generalized linear models in which the dependent variables were the levels of serum alanine aminotransferase (liver toxicity), leukocytes, platelets or hemoglobin (hematologic toxicity) and adjusted for clinical variables (disease activity, etc.), analytical (renal function, etc.), sociodemographic (age, sex, etc.) and genetic variants of MTHFR, ABCB1, ATIC and FPGS. The effect of these variables on the MTX doses prescribed throughout follow-up was also analyzed through multivariate analysis nested by visit and patient.

Results

When taking MTX, those patients carrying the CC genotype of rs1045642 in ABCB1 showed significantly higher GPT levels (7.1±2.0U/L; P<.001). Carrying at least one G allele of rs1544105 in FPGS was associated with lower leukocyte (−0.67±0.32; 0.038), hemoglobin (−0.34±0.11g/dL; P=.002), and platelet (−11.8±4.7; P=.012) levels. The presence of the G allele of rs1544105 in FPGS, and the T allele of rs1801133 in MTHFR, was significantly associated with the use of lower doses of MTX.

Discussion

Our data suggest that genotyping functional variants in FGPS and MTHFR enzymes and the transporter ABCB1 could help to identify patients with increased risk of MTX toxicity.

Keywords:
Rheumatoid arthritis
Methotrexate
Toxicity
Single nucleotide polymorphism
Resumen
Objetivo

Analizar el efecto de polimorfismos de nucleótido único (SNPs) de la metilen-tetrahidrofolatorreductasa (MTHFR; rs1801131 y rs1801133), el transportador de membrana que une ATP B1 (ABCB1; rs1045642), la aicartransformilasa/IMP ciclohidrolasa (ATIC; rs2372536) y la folilpoliglutamatosintetasa (FPGS; rs1544105) en la toxicidad hepática y medular de metotrexato (MTX).

Pacientes y métodos

Se analizaron 1.415 visitas (732 con MTX, 683 sin MTX) de 350 pacientes del Princesa Early Arthritis Register Longytudinal study. El genotipo de los diferentes SNP se determinó mediante sondas TaqMan (Applied Biosystems). Se realizaron análisis multivariables mediante modelos lineales generalizados en los que las variables dependientes fueron los niveles séricos de transaminasa glutámico-pirúvica (toxicidad hepática), leucocitos, plaquetas o hemoglobina (toxicidad hematológica) y se ajustaron por variables clínicas (actividad de la enfermedad, etc.), analíticas (función renal, etc.), sociodemográficas (edad, sexo, etc.) y las variantes genéticas de MTHFR, ABCB1, ATIC y FPGS. También se analizaron las variables que influyeron en las dosis de MTX administradas a lo largo del seguimiento.

Resultados

Cuando recibían MTX los portadores del genotipo CC del SNP rs1045642 de ABCB1 presentaron niveles significativamente mayores de GPT (7,1±2,0U/l; p<0,001). Los portadores de al menos un alelo G de rs1544105 en FPGS presentaron niveles significativamente menores de leucocitos (−0,67±0,32; 0,038), hemoglobina (−0,34±0,11g/dl; p=0,002) y de plaquetas (−11,8±4,7; p=0,012). La presencia del alelo G de rs1544105 (FPGS) y T de rs1801133 (MTHFR) se asoció, de forma aditiva y significativa, al uso de menores dosis de MTX.

Discusión

Nuestros datos sugieren que variantes genéticas de las enzimas FGPS y MTHFR, y del transportador ABCB1, podrían ayudar a detectar pacientes con mayor riesgo de toxicidad por MTX.

Palabras clave:
Artritis reumatoide
Metotrexato
Toxicidad
Polimorfismos de nucleótido único

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