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THU0242 Effect of Genetic Variants in Proteins of the Folic Acid Metabolic Pathways in the Toxicity of Methotrexate
  1. I. Gonzalez-Alvaro1,
  2. A. Lamana1,
  3. A. M. Ortiz1,
  4. R. Garcia-Vicuña1
  1. 1Rheumatology, Hospital U La Princesa. IIS La Princesa, Madrid, Spain

Abstract

Background The study of genetic variants of enzymes in the metabolic pathways of folic acid has provided conflicting results regarding toxicity or clinical response to methotrexate (MTX). There are several reasons for this lack of reproducibility: the origin of populations studied, differences in the definition of non-responder or presence of toxicity, as well as prejudice either in patients or physician which can bias the decision to discontinue MTX.

Objectives To analyze the effect of functional genetic variants of methylen-tetrahydrofolate reductase (MTHFR; rs1801131 y rs1801133), the membrane transporter ABCB1 (rs1045642), the AICAR transformylase/IMP ciclohydrolase (ATIC; rs2372536) and folil polyglutamate synthetase (FPGS; rs1544105) on GPT/ALT, leukocytes, platelets and hemoglobin (Hb) levels in patients with early arthritis (EA) exposed to MTX.

Methods We analyzed a total of 1034 visits (511 with MTX, 523 without MTX) from 287 patients (77% female; median age at disease onset: 54 years [interquartile range: 43 – 67]) of our EA register. Sociodemographic, clinical, laboratory and therapeutic data were systematically collected at baseline, 6, 12, 24 and 60 months. SNP genotyping was performed through specific TaqMan probes (Applyed Biosystem). We performed a multivariate analysis for each of the four dependent variables (GPT/ALT, leukocytes, platelets and Hb) through generalized linear models using the “glm” command of Stata12. The statistical significance was set at p<0.0125 due to multiple comparisons. However, all those variables with p<0.15 were maintained in the multivariable models.

Results The table shows results of the statistical analysis when MTX was used:

Conclusions Our data suggest that genetic variants of MTHFR and ABCB1 for hepatotoxicity and FGPS for haematologic toxicity may be more important than other factors such as MTX dose, age and renal function, although there is probably an indication bias with these two later variables.

Disclosure of Interest None Declared

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