This preprint is under consideration at Pediatric Rheumatology. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
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Short Report
Nini Kyvsgaard
Aarhus Universitetshospital
Corresponding Author
ORCiD: https://orcid.org/0000-0001-9490-1333
License:
This work is licensed under a CC BY 4.0 License. Read Full License
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).
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.
Keywords
JIA, Juvenile idiopathic arthritis, SNPs, Single nucleotide polymorphisms, MTX, Methotrexate
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On 17 Nov, 2020
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Received 08 Nov, 2020
Review #8 received
Received 08 Nov, 2020
Review #5 received
Received 07 Nov, 2020
Review #6 received
Received 07 Nov, 2020
Reviewer #8 agreed
On 28 Oct, 2020
Reviewer #6 agreed
On 27 Oct, 2020
Reviewer #7 agreed
On 27 Oct, 2020
Reviewer #5 agreed
On 26 Oct, 2020
Review #2 received
Received 26 Oct, 2020
Review #3 received
Received 25 Oct, 2020
Review #1 received
Received 24 Oct, 2020
Reviewer #4 agreed
On 16 Oct, 2020
Review #4 received
Received 16 Oct, 2020
Reviewer #2 agreed
On 13 Oct, 2020
Reviewer #3 agreed
On 13 Oct, 2020
Reviewers invited
Invitations sent on 12 Oct, 2020
Reviewer #1 agreed
On 12 Oct, 2020
Editor assigned
On 17 Aug, 2020
Submission checks complete
On 16 Aug, 2020
Editor invited
On 16 Aug, 2020
First submitted
On 14 Aug, 2020
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This preprint is under consideration at Pediatric Rheumatology. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Short Report
Nini Kyvsgaard
Aarhus Universitetshospital
Corresponding Author
ORCiD: https://orcid.org/0000-0001-9490-1333
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 2
Posted 05 Jan, 2021
No community comments so far
Editor assigned
On 16 Dec, 2020
Submission checks complete
On 16 Dec, 2020
Editor invited
On 16 Dec, 2020
No comments provided
Editorial decision: Major revision
On 17 Nov, 2020
Review #7 received
Received 08 Nov, 2020
Review #8 received
Received 08 Nov, 2020
Review #5 received
Received 07 Nov, 2020
Review #6 received
Received 07 Nov, 2020
Reviewer #8 agreed
On 28 Oct, 2020
Reviewer #6 agreed
On 27 Oct, 2020
Reviewer #7 agreed
On 27 Oct, 2020
Reviewer #5 agreed
On 26 Oct, 2020
Review #2 received
Received 26 Oct, 2020
Review #3 received
Received 25 Oct, 2020
Review #1 received
Received 24 Oct, 2020
Reviewer #4 agreed
On 16 Oct, 2020
Review #4 received
Received 16 Oct, 2020
Reviewer #2 agreed
On 13 Oct, 2020
Reviewer #3 agreed
On 13 Oct, 2020
Reviewers invited
Invitations sent on 12 Oct, 2020
Reviewer #1 agreed
On 12 Oct, 2020
Editor assigned
On 17 Aug, 2020
Submission checks complete
On 16 Aug, 2020
Editor invited
On 16 Aug, 2020
First submitted
On 14 Aug, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
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).
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.
Figure 1
Figure 2
Figure 3
Figure 4
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