Genetic variation in folylpolyglutamate synthase and gamma-glutamyl hydrolase and plasma homocysteine levels in the Singapore Chinese Health Study

Abstract

The enzymes folylpolyglutamate synthase (FPGS) and gamma-glutamyl hydrolase (GGH) are essential for determining intracellular folate availability for one-carbon metabolism (OCM) pathways. FPGS adds glutamyl groups to the folate molecule, thereby converting folate into the preferred substrate for several enzymes in OCM pathways. GGH removes glutamyl groups, allowing folate metabolites to leave the cell. The purpose of this study was to evaluate whether single nucleotide polymorphisms (SNPs) in the FPGS and GGH genes influence measured plasma homocysteine levels. Study participants were a sub-cohort (n=482) from the Singapore Chinese Health Study. SNPs were selected using HapMap tagSNPs and SNPs previously reported in the scientific literature. Multiple linear regression was used to evaluate the association between individual SNPs and plasma homocysteine levels. Two FPGS (rs10106, rs1098774) and 9 GGH (rs719235, rs1031552, rs1800909, rs3758149, rs3780126, rs3824333, rs4617146, rs11545076, rs11545078) SNPs were included in the final analysis. Neither of the FPGS SNPs, but three GGH SNPs were associated with plasma homocysteine levels: rs11545076 (p=0.001), rs1800909 (p=0.02), and rs3758149 (p=0.006). Only one (rs11545076) remained statistically significant after adjusting for multiple comparisons. This study suggests that GGH SNPs, rs11545076, rs1800909, and rs3758149, may have functional relevance and result in alterations in plasma homocysteine levels. Since this is one of the first studies to assess FPGS and GGH genetic variants in relation to plasma homocysteine, further research is needed to confirm these findings and characterize the functional effects of these variants.

Figure 1. Folate Absorption, Cellar Uptake and Retention

Folate hydrolase 1 (FOLH1), proton-coupled folate transporter (PFCT), folate receptor 1 (FOLR1), reduced folate carrier 1 (RFC1), methionine synthase (MTR), Folylpolyglutamate synthase (FPGS), gamma glutamyl hydrolase (GGH).