Single Nucleotide Polymorphisms Associated with Methotrexate-induced Nausea in Juvenile Idiopathic Arthritis

Abstract

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). Results: 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. Conclusion Summary: 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.

SLCO1B1 *15 allele is associated with methotrexate‐induced nausea in pediatric patients with inflammatory bowel disease

“…Kyvsgaard et al recently found that the rs4149056 SNP in the SLCO1B1*5 and *15 alleles was not associated with MTX-induced nausea in a sample of 121 pediatric patients with JIA, but did find an association with the rs1801133 SNP in MTHFR that we did not investigate in this study. 23 Our sample size of 202 patients is one of the largest for a retrospective cohort study of MTX intolerance. However, there are some limitations to this study.…”

“…Kyvsgaard et al recently found that the rs4149056 SNP in the SLCO1B1 *5 and *15 alleles was not associated with MTX‐induced nausea in a sample of 121 pediatric patients with JIA, but did find an association with the rs1801133 SNP in MTHFR that we did not investigate in this study. 23 …”