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.

Metabolic Phenotype of Wild-Type and As3mt -Knockout C57BL/6J Mice Exposed to Inorganic Arsenic: The Role of Dietary Fat and Folate Intake

“…Precise mechanisms underlying these differences are not understood at present. However, the previously reported sex-specific expression patterns of genes involved in folate transport or metabolism (Hashiguchi et al. 2016) may be, at least in part, responsible for the overall differences in the response to dietary folate intake between males and females.…”

Effects of single nucleotide polymorphisms of the folylpolyglutamate synthase gene on pemetrexed administration‐induced nephropathy

“…5,10,14 rs1544105-C may increase FPGS expression. We also focused on rs10106, which is located at the 3 0 -untranslated region (3 0 -UTR) of FPGS 15,16 and may affect the binding of miRNAs to FPGS mRNA since miRNAs are post-transcriptional regulators that bind to the 3 0 -UTR region of the target mRNA. Although there are no reports of miRNAs binding to FPGS mRNA, we investigated miRNAs that are partially complementary to the 3 0 -UTR of FPGS mRNA and determined their binding energies.…”