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. 2021 Apr 1;19(1):51.
doi: 10.1186/s12969-021-00539-9.

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

Nini Kyvsgaard  1 , Torben Stamm Mikkelsen  2 , Thomas D Als  3 , Anne Estmann Christensen  4 , Thomas J Corydon  3   5 , Troels Herlin  2
Affiliations

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

Nini Kyvsgaard et al. Pediatr Rheumatol Online J. .

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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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Illustration of methotrexate transporter proteins in the liver. MTX; Methotrexate. SLCO1B1, SLCO1B3, SLC19A1, ABCC2 and ABCB1; Methotrexate transporter proteins
Fig. 2
Fig. 2
Illustration of the intracellular effects of methotrexate-polyglutamates including the role of the MTHFR enzyme. dUMP; deoxyuridine monophosphate. dTMP; deoxythymidine monophosphate. TYMS; thymidylate synthase. MTX-PG; methotrexate polyglutamates. DHFR; dihydrofolate reductase. DHF; dihydrofolate. THF; tetrahydrofolate. 5-CH3-THF; 5-methyltetrahydrofolate. 5,10-CH2-THF; 5,10-methylenetetrahydrofolate. MTHFR; methylenetetrahydrofolate reductase. ATIC; AICAR formyltransferase. AICAR; 5-aminoimidazole 4-carboxamide ribonucleotide. FAICAR; 10-formyl AICAR. IMP; inosine monophosphate. AMP; adenosine monophosphate
Fig. 3
Fig. 3
Illustration of pathways mediating methotrexate-induced nausea. 5-HT3-receptor; 5-hydroxytryptamine type 3 receptor. D2-receptor; Dopamine type 2 receptor. NK1-receptor; Neurokinin type 1 receptor. MTX; Methotrexate
Fig. 4
Fig. 4
Flowchart of the enrollment and exclusion of patients. MTX; Methotrexate. MISS; Methotrexate intolerance severity score. SNP; Single nucleotide polymorphism
See this image and copyright information in PMC

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