Genetic polymorphisms of enzyme proteins and transporters related to methotrexate response and pharmacokinetics in a Japanese population

Masayuki Hashiguchi; Mikiko Shimizu; Jun Hakamata; Tomomi Tsuru; Takanori Tanaka; Midori Suzaki; Kumika Miyawaki; Takeshi Chiyoda; Osamu Takeuchi; Jiro Hiratsuka; Shin Irie; Junya Maruyama; Mayumi Mochizuki

doi:10.1186/s40780-016-0069-0

Genetic polymorphisms of enzyme proteins and transporters related to methotrexate response and pharmacokinetics in a Japanese population

J Pharm Health Care Sci. 2016 Dec 9:2:35. doi: 10.1186/s40780-016-0069-0. eCollection 2016.

Authors

Affiliations

¹ Division for Evaluation and Analysis of Drug Information, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512 Japan.
² Department of Hygienic Chemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512 Japan.
³ PS Clinic, LTA Clinical Pharmacology Center, 6-18 Tenyacho, Hakata-ku, Fukuoka, 812-0025 Japan.
⁴ Sumida Hospital, LTA Clinical Pharmacology Center, 1-29-1 Honjo, Sumida-ku, Tokyo, 130-0004 Japan.
⁵ Division of Research, BioMedical Laboratory, Kitasato University Kitasato Institute Hospital, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8642 Japan.
⁶ Kyushu Clinical Pharmacology Research Clinic, LTA Clinical Pharmacology Center, 6-18 Tenyacho, Hakata-ku, Fukuoka, 812-0025 Japan.

Abstract

Background: Methotrexate (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.

Methods: Ten 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).

Results: Comparison 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.

Conclusion: 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.

Keywords: Genetic polymorphism; Healthy Japanese population; Methotrexate; Rheumatoid arthritis; SNPs.