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Folic acid pathway single nucleotide polymorphisms associated with methotrexate significant adverse events in United States veterans with rheumatoid arthritis.
Clin Exp Rheumatol 2014 May-Jun; 32(3):324-32CE

Abstract

OBJECTIVES

Methotrexate (MTX) is the cornerstone medication in the treatment of rheumatoid arthritis (RA). We examined whether single nucleotide polymorphisms (SNPs) in enzymes of the folic acid pathway (folylpoly-gamma-glutamate synthetase [FPGS], gamma-glutamyl hydrolase [GGH], and methylenetetrahydrofolate reductase [MTHFR]) associate with significant adverse events (SigAE).

METHODS

Patients (n=319) enrolled in the Veterans Affairs RA (VARA) registry taking MTX were genotyped for HLA-DRB1-SE and the following SNPs: FPGS (rs7033913, rs10760503, rs10106), GGH (12548933, rs7010484, rs4617146, rs719235, rs11988534), MTHFR (rs1801131, rs1801133). AE were abstracted from the medical record using a structured instrument. SigAE were defined as an AE leading to MTX discontinuation. Covariates included: age, gender, race, RA antibody status, tobacco, RA disease duration between diagnosis and MTX course, Charlson-Deyo comorbidity index, glucocorticoids, use of prior RA medications, and mean 4-variable disease activity score. Cox regression was performed to determine factors associated with time-to-SigAE. A p-value ≤ 0.005 established significance in the final model.

RESULTS

The presence of ≥ 1 copy of the minor allele in MTHFR rs1801131 was associated with an increased hazard ratio (HR) of SigAE (HR 3.05, 95% CI 1.48-6.29, p-value 0.003 and HR 3.88, 95% CI 1.62-9.28, p-value 0.002 for heterozygotes and homozygotes for the minor allele, respectively). An interaction term, between FPGS rs7033913 heterozygotes and GGH rs11988534 homozygotes for the minor allele, had a p-value <0.0001.

CONCLUSIONS

RA subjects taking MTX may have decreased time-to-SigAE with ≥ 1 copy of the minor allele in MTHFR rs1801131. Further investigation is warranted, as these SNPs may indicate susceptibility to MTX toxicity.

Authors+Show Affiliations

Denver Health and Hospital Authority, Denver; University of Colorado School of Medicine, Aurora, CO, USA. lisa.davis@ucdenver.edu.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24447348

Citation

Davis, L A., et al. "Folic Acid Pathway Single Nucleotide Polymorphisms Associated With Methotrexate Significant Adverse Events in United States Veterans With Rheumatoid Arthritis." Clinical and Experimental Rheumatology, vol. 32, no. 3, 2014, pp. 324-32.
Davis LA, Polk B, Mann A, et al. Folic acid pathway single nucleotide polymorphisms associated with methotrexate significant adverse events in United States veterans with rheumatoid arthritis. Clin Exp Rheumatol. 2014;32(3):324-32.
Davis, L. A., Polk, B., Mann, A., Wolff, R. K., Kerr, G. S., Reimold, A. M., ... Caplan, L. (2014). Folic acid pathway single nucleotide polymorphisms associated with methotrexate significant adverse events in United States veterans with rheumatoid arthritis. Clinical and Experimental Rheumatology, 32(3), pp. 324-32.
Davis LA, et al. Folic Acid Pathway Single Nucleotide Polymorphisms Associated With Methotrexate Significant Adverse Events in United States Veterans With Rheumatoid Arthritis. Clin Exp Rheumatol. 2014;32(3):324-32. PubMed PMID: 24447348.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Folic acid pathway single nucleotide polymorphisms associated with methotrexate significant adverse events in United States veterans with rheumatoid arthritis. AU - Davis,L A, AU - Polk,B, AU - Mann,A, AU - Wolff,R K, AU - Kerr,G S, AU - Reimold,A M, AU - Cannon,G W, AU - Mikuls,T R, AU - Caplan,L, Y1 - 2014/01/20/ PY - 2013/04/27/received PY - 2013/11/14/accepted PY - 2014/1/23/entrez PY - 2014/1/23/pubmed PY - 2014/8/13/medline SP - 324 EP - 32 JF - Clinical and experimental rheumatology JO - Clin. Exp. Rheumatol. VL - 32 IS - 3 N2 - OBJECTIVES: Methotrexate (MTX) is the cornerstone medication in the treatment of rheumatoid arthritis (RA). We examined whether single nucleotide polymorphisms (SNPs) in enzymes of the folic acid pathway (folylpoly-gamma-glutamate synthetase [FPGS], gamma-glutamyl hydrolase [GGH], and methylenetetrahydrofolate reductase [MTHFR]) associate with significant adverse events (SigAE). METHODS: Patients (n=319) enrolled in the Veterans Affairs RA (VARA) registry taking MTX were genotyped for HLA-DRB1-SE and the following SNPs: FPGS (rs7033913, rs10760503, rs10106), GGH (12548933, rs7010484, rs4617146, rs719235, rs11988534), MTHFR (rs1801131, rs1801133). AE were abstracted from the medical record using a structured instrument. SigAE were defined as an AE leading to MTX discontinuation. Covariates included: age, gender, race, RA antibody status, tobacco, RA disease duration between diagnosis and MTX course, Charlson-Deyo comorbidity index, glucocorticoids, use of prior RA medications, and mean 4-variable disease activity score. Cox regression was performed to determine factors associated with time-to-SigAE. A p-value ≤ 0.005 established significance in the final model. RESULTS: The presence of ≥ 1 copy of the minor allele in MTHFR rs1801131 was associated with an increased hazard ratio (HR) of SigAE (HR 3.05, 95% CI 1.48-6.29, p-value 0.003 and HR 3.88, 95% CI 1.62-9.28, p-value 0.002 for heterozygotes and homozygotes for the minor allele, respectively). An interaction term, between FPGS rs7033913 heterozygotes and GGH rs11988534 homozygotes for the minor allele, had a p-value <0.0001. CONCLUSIONS: RA subjects taking MTX may have decreased time-to-SigAE with ≥ 1 copy of the minor allele in MTHFR rs1801131. Further investigation is warranted, as these SNPs may indicate susceptibility to MTX toxicity. SN - 0392-856X UR - https://www.unboundmedicine.com/medline/citation/24447348/Folic_acid_pathway_single_nucleotide_polymorphisms_associated_with_methotrexate_significant_adverse_events_in_United_States_veterans_with_rheumatoid_arthritis_ L2 - http://www.clinexprheumatol.org/pubmed/find-pii.asp?pii=24447348 DB - PRIME DP - Unbound Medicine ER -