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

Nini Kyvsgaard¹, Torben Stamm Mikkelsen², Thomas D Als³

¹Pediatric and Adolescent Medicine, Department of Clinical Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark. nini.kyvsgaard@rm.dk.

Pediatric Rheumatology Online Journal

|April 2, 2021

Abstract

Background:

Context: 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.

Findings:

Methods: 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.

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.

Keywords:

JIA Juvenile idiopathic arthritis MTX Methotrexate SNPs Single nucleotide polymorphisms

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