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Single nucleotide polymorphisms associated with methotrexate-induced nausea in juvenile idiopathic arthritis

  • Kyvsgaard, Nini1
  • Mikkelsen, Torben Stamm1
  • Als, Thomas D.2
  • Christensen, Anne Estmann3
  • Corydon, Thomas J.2, 4
  • Herlin, Troels1
  • 1 Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N, 8200, Denmark , Aarhus N (Denmark)
  • 2 Aarhus University, Aarhus, Denmark , Aarhus (Denmark)
  • 3 H.C. Andersen’s Children’s Hospital, Odense University Hospital, Odense, Denmark , Odense (Denmark)
  • 4 Aarhus University Hospital, Aarhus, Denmark , Aarhus (Denmark)
Published Article
Pediatric Rheumatology
Springer Science and Business Media LLC
Publication Date
Apr 01, 2021
DOI: 10.1186/s12969-021-00539-9
Springer Nature


BackgroundContext: Methotrexate (MTX) is a cornerstone in the treatment of juvenile idiopathic arthritis (JIA). MTX treatment is commonly associated with nausea. Large inter-individual variation exists in the level of MTX-induced nausea, possibly due to genetic factors.Purpose: To investigate whether MTX-induced nausea was associated with single nucleotide polymorphisms (SNPs) in genes encoding MTX-transporter proteins, a MTX metabolizing enzyme and a nausea receptor.FindingsMethods: Children aged ≥9 years treated with MTX for JIA were eligible. MTX-induced nausea was registered by the children’s completion of a nausea diary (min. 7 days) and the parents’ completion of the MTX intolerance severity score (MISS). The selected SNPs were: SLCO1B1 (rs4149056; rs4149081), SLCO1B3 (rs2117032), SLC19A1 (rs1051266), ABCC2 (rs2273697; rs3740066; rs717620), ABCB1 (rs2032582; rs1045642), MTHFR (rs1801131, rs1801133), HTR3A (rs1062613; rs1985242; rs1176713) and HTR3B (rs1176744).Result: Enrolled were 121 JIA patients (82 girls: 39 boys) with a median age of 13.3 years (IQR: 11.3–15.1). The median MTX dose was 9.7 mg/m2/week (IQR: 9.0–10.9). The median MTX treatment duration prior to enrolment was 340 days (IQR: 142–766). The SNP analysis was available for 119 patients. MTX intolerance was associated with the genotype distribution of rs1801133 (MTHFR) (p = 0.02). There was no additive effect of the minor alleles for any of the selected SNPs, nor any significant haplotype associations.ConclusionSummary: MTX-induced nausea may be influenced by genetic polymorphisms in a MTX metabolizing enzyme (rs1801133; MTHFR).Implications: Further analyses involving inclusion of larger cohorts are needed to understand the impact of SNPs on MTX-induced nausea in JIA.

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