TY - JOUR T1 - Impact of Genetic Variants of ATP Binding Cassette B1, AICAR Transformylase/IMP Cyclohydrolase, Folyl-polyglutamate Synthetase, and Methylenetetrahydrofolate Reductase on Methotrexate Toxicity JO - Reumatología Clínica (English Edition) T2 - AU - Sala-Icardo,Luis AU - Lamana,Amalia AU - Ortiz,Ana María AU - García Lorenzo,Elena AU - Moreno Fresneda,Pablo AU - García-Vicuña,Rosario AU - González-Álvaro,Isidoro SN - 21735743 M3 - 10.1016/j.reumae.2016.08.004 DO - 10.1016/j.reumae.2016.08.004 UR - https://reumatologiaclinica.org/en-impact-genetic-variants-atp-binding-articulo-S217357431730120X AB - ObjectiveTo 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 methodsWe 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. ResultsWhen 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. DiscussionOur 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. ER -