Abstract
BackgroundMethotrexate (MTX) is currently the anchor drug widely used worldwide in the treatment of rheumatoid arthritis (RA). However, the therapeutic response to MTX has been shown to vary widely among individuals, genders and ethnic groups. The reason for this has been not clarified but it is considered to be partially due to several mechanisms in the cellular pathway of MTX including single-nucleotide polymorphisms (SNPs). The purpose of this study was to investigate the allelic frequencies in different ethnic and/or population groups in the 10 polymorphisms of enzyme proteins and transporters related to the MTX response and pharmacokinetics including MTHFR, TYMS, RFC1, FPGS, GGH, ABCB1, ABCC2 and ABCG2 in unrelated healthy Japanese adults and patients with RA.MethodsTen polymorphisms, methylenetetrahydrofolate reductase (MTHFR) 1298, thymidylate synthase (TYMS) 3'-UTR, reduced folate carrier 1 (RFC1) 80 and−43, folypolyglutamyl synthase (FPGS) 1994, γ-glutamyl hydrolase (GGH) 452 and−401, the ABC transporters (ABCB1 3435, ABCC2 IVS23 + 56, ABCG2 914) of enzyme proteins and transporters related to MTX response and pharmacokinetics in 299 unrelated healthy Japanese adults and 159 Japanese patients with RA were investigated to clarify their contributions to individual variations in response and safety to MTX and establish personalized MTX therapy. SNPs were evaluated using real-time polymerase chain reaction (PCR).ResultsComparison of allelic frequencies in our study with other ethnic/population groups of healthy adults and RA patients showed significant differences in 10 polymorphisms among healthy adults and 7 among RA patients. Allelic frequencies of MTHFR 1298 C, FPGS 1994A and ABCB1 3435 T were lower in Japanese than in Caucasian populations and those of ABCC2 IVS23 + 56 C and ABCG2 914A were higher in Japanese than in Caucasian/European populations in both healthy adults and RA patients. Allelic frequencies of MTHFR 1298 C, GGH−401 T, ABCB1 3435 T, and ABCG2 914A were higher in healthy Japanese adults than in an African population, and those of RFC1 80A, RFC1−43C and ABCC2 IVS23 + 56 C in healthy Japanese adults were lower than in Africans. However, no significant differences were seen in the distribution of allelic frequencies between healthy Japanese adults and RA patients.ConclusionThe variations in allelic frequencies in different ethnic and/or population groups in healthy adults and RA patients may contribute to individual variations in MTX response and toxicity.
Highlights
Methotrexate (MTX) is currently the anchor drug widely used worldwide in the treatment of rheumatoid arthritis (RA)
The variations in allelic frequencies in different ethnic and/or population groups in healthy adults and RA patients may contribute to individual variations in MTX response and toxicity
Allelic frequencies in healthy adult populations and RA patients Among the 298 studies retrieved from the electronic databases and those retrieved from their references by manual search, a total of 14,000 healthy adults from 16 studies [4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19] and 4284 RA patients from 25 studies [5, 6, 9, 14, 20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40], involving HapMap Projects [4] that described Japanese, Asian, European and African groups, were included in the comparative analysis (Tables 1 and 2)
Summary
Methotrexate (MTX) is currently the anchor drug widely used worldwide in the treatment of rheumatoid arthritis (RA). The therapeutic response to MTX has been shown to vary widely among individuals, genders and ethnic groups The reason for this has been not clarified but it is considered to be partially due to several mechanisms in the cellular pathway of MTX including single-nucleotide polymorphisms (SNPs). The therapeutic response to MTX has been shown to vary widely among individuals, genders and ethnic groups [2, 3] The reason for this has been not clarified but it is considered to be partially due to several mechanisms in the cellular pathway of MTX including single-nucleotide polymorphisms (SNPs) in transporters, glutamation, the folate pathway and adenosine pathway [2] such as reduced folate carrier 1 (RFC1), folypolyglutamyl synthase (FPGS), γ-glutamyl hydrolase (GGH), the ABC transporters ABCB1, ABCC2 and ABCG2, methylenetetrahydrofolate reductase (MTHFR), and thymidylate synthase (TYMS). We previously reported that the distribution of MTHFR C677T between black and Japanese populations, of TYMS 5'-UTR alleles between Caucasian or black and Japanese populations, and of TYMS 3'-UTR alleles between Caucasian and Japanese populations showed significant differences, as well as gender differences in TYMS 3'-UTR allelic frequency in Japanese [3]
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