title: Sex Differences in mRNA Expression of Reduced Folate Carrier-1, Folypolyformyl Glutamate Synthase, and γ-Glutamyl Hydrolase in a Healthy Japanese Population.
abstract: Sex differences in the prevalence of autoimmune diseases such as rheumatoid arthritis (RA) are well known, but little is known about those differences in relation to therapeutic response. Reduced folate carrier-1 (RFC-1), folypolyformyl glutamate synthase (FPGS), and γ-glutamyl hydrolase (GGH) are important transporters and enzymes that convert methotrexate (MTX) in the body. This study investigated the sex differences in mRNA expression of RFC-1, FPGS, and GGH in 190 unrelated healthy Japanese people. The genotypes and mRNA expression were determined using the real-time PCR method. Significant differences between men and women were observed in RFC-1, FPGS, and GGH mRNA expression. The mRNA expression of FPGS and GGH was greater in women than that in men, but the expression of RFC-1 was less in the former than the latter. In stratified analysis by genotype, significant differences in sex-specific mRNA expression were observed in G/G of FPGS, C/C of GGH 452, and C/C of GGH -401. All showed greater mRNA expression in women than in men. In the 5 single-nucleotide polymorphisms RFC-1 80G>A, RFC-1 -43T>C, FPGS 1994G>A, GGH 452C>T, and GGH -401C>T examined, the FPGS 1994 G/G (1.46-fold), GGH 452 C/C (2.16-fold), and GGH -401 C/C (2.68-fold) genotypes showed significantly higher mRNA expression in women than in men. Healthy Japanese adults in this study showed sex-specific differences in mRNA expression that differed among RFC-1, FPGS, and GGH. Therefore, the relationship between genetic polymorphisms and mRNA expression including sex differences might contribute to the variation in the efficacy/toxicity of MTX in patients with RA.
authors.affiliation: Division for Evaluation and Analysis of Drug Information, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Hashiguchi
authors.affiliation: Sumida Hospital, LTA Clinical Pharmacology Center, Sumida-ku, Tokyo, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Hygienic Chemistry, Faculty of Pharmacy, Keio University, Tokyo, Japan.
authors.forename: Mikiko
authors.initials: M
authors.lastname: Shimizu
authors.affiliation: PS Clinic, LTA Clinical Pharmacology Center, Hakata-ku, Fukuoka, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Tsuru
authors.affiliation: Sumida Hospital, LTA Clinical Pharmacology Center, Sumida-ku, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Chiyoda
authors.affiliation: Division for Evaluation and Analysis of Drug Information, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan.
authors.forename: Kumika
authors.initials: K
authors.lastname: Miyawaki
authors.affiliation: Kyushu Clinical Pharmacology Research Clinic, LTA Clinical Pharmacology Center, Hakata-ku, Fukuoka, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Irie
authors.affiliation: Division of Research, BioMedical Laboratory, Kitasato University Kitasato Institute Hospital, Minato-ku, Tokyo, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Takeuchi
authors.affiliation: Division for Evaluation and Analysis of Drug Information, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Hakamata
authors.affiliation: Division for Evaluation and Analysis of Drug Information, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Mochizuki
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000096:biosynthesis* / Q000235:genetics; D010453:Peptide Synthases / Q000096:biosynthesis* / Q000235:genetics; D011159:Population Surveillance; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D012727:Sex Characteristics; D055815:Young Adult; D011623:gamma-Glutamyl Hydrolase / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D026901:Membrane Transport Proteins; D012333:RNA, Messenger; C120043:SLC19A2 protein, human; D011623:gamma-Glutamyl Hydrolase; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase
keywords: folypolyformyl glutamate synthase; genetic polymorphism; healthy Japanese population; mRNA expression; methotrexate; reduced folate carrier-1; γ-glutamyl hydrolase