Methotrexate-Induced Nausea in JIA May Be Influenced by Genetic Polymorphisms in MTX-Metabolizing Enzyme

methotrexate syringe
Researchers assessed whether methotrexate-induced nausea in JIA was associated with single-nucleotide polymorphisms in genes encoding MTX transporter proteins.

Genetic polymorphisms in a methotrexate (MTX)-metabolizing enzyme may have a significant impact on MTX-induced nausea in patients with juvenile idiopathic arthritis (JIA), according to study results published in Pediatric RheumatologyOnline Journal.

Methotrexate has a key role in the treatment of children with JIA; however, nausea is a common adverse event associated with MTX treatment. Previous studies have suggested that variation in the level of enterohepatic circulation may be responsible for the large inter-individual variation in the level of MTX-induced nausea in JIA.

In the current study, the researchers aimed at determining the association between MTX-induced nausea with selected single-nucleotide polymorphisms (SNPs) in genes encoding to MTX transporter proteins – the MTHFR enzyme, a MTX-metabolizing enzyme, and the 5-HT3-receptor, a nausea receptor – in children with JIA.

The study sample included 121 children (82 girls; median age, 13.3 years) who received treatment with MTX for JIA. All participants completed a nausea diary that included questions regarding nausea and the timely relation to MTX (child-assessed phenotype). Parents of the patients completed the Danish adaption of the MTX intolerance severity score (the parent-assessed phenotype) on the day of enrollment and focused on the child’s current state of MTX intolerance.

Data on the SNP analysis were available for 119 patients. There was a significant association between the SNP rs1801133 in the MTHFR enzyme and the parent-assessed phenotype (P =.02); but not for the child-assessed phenotype. No significant associations were found between the SNPs in the 5-HT3-receptor or MTX transporter protein and the phenotype subgroups.

“MTX-induced nausea may be influenced by SNPs in the MTHFR enzyme (rs1801133). Our data [do] not support an association between MTX-induced nausea and the remaining selected SNPs in genes encoding MTX transporter proteins or the 5-HT3 nausea receptor,” the researchers concluded.


Kyvsgaard N, Mikkelsen TS, Als TD, Christensen AE, Corydon TJ, Herlin T. Single nucleotide polymorphisms associated with methotrexate-induced nausea in juvenile idiopathic arthritis. Pediatr Rheumatol Online J. 2021;19(1):51. doi:10.1186/s12969-021-00539-9