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

Background 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.Context: 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.FindingsPurpose: Children aged >= 9years treated with MTX for JIA were eligible. MTX-induced nausea was registered by the children's completion of a nausea diary (min. 7days) and the parents' completion of the MTX intolerance severity score (MISS). The selected SNPs were: (rs4149056; rs4149081), (rs2117032), (rs1051266), (rs2273697; rs3740066; rs717620), (rs2032582; rs1045642), (rs1801131, rs1801133), (rs1062613; rs1985242; rs1176713) and (rs1176744).Methods:SLCO1B1SLCO1B3SLC19A1ABCC2ABCB1MTHFRHTR3AHTR3B Enrolled were 121 JIA patients (82 girls: 39 boys) with a median age of 13.3years (IQR: 11.3-15.1). The median MTX dose was 9.7mg/m2/week (IQR: 9.0-10.9). The median MTX treatment duration prior to enrolment was 340days (IQR: 142-766). The SNP analysis was available for 119 patients. MTX intolerance was associated with the genotype distribution of rs1801133 () (=0.02). There was no additive effect of the minor alleles for any of the selected SNPs, nor any significant haplotype associations.ConclusionResult:MTHFRp MTX-induced nausea may be influenced by genetic polymorphisms in a MTX metabolizing enzyme (rs1801133; MTHFR).Summary:Implications: Further analyses involving inclusion of larger cohorts are needed to understand the impact of SNPs on MTX-induced nausea in JIA.