Impact of FPGS and GGH SNPs on plasma folate and homocysteine levels in the Singapore Chinese health study.

Abstract

Background: Folate has widespread importance to health due to its role in one-carbon metabolism. Folate status and genetic variants in the folate uptake and metabolism pathways have been assessed in relation to numerous disease processes, especially colon cancer and cardiovascular disease. The enzymes folylpolyglutamate synthase (FPGS) and gamma-glutamyl hydrolase (GGH) are essential for maintaining intracellular folate homeostasis. FPGS adds glutamyl groups to the folate molecule, which is essential for cellular retention of folate. The polyglutamted form of folate metabolites is the preferred substrate for many one-carbon metabolism enzymes. GGH removes glutamyl groups, which allows folate to leave the cell. Objective: The purpose of this study was to evaluate whether single nucleotide polymorphisms (SNPs) in the FPGS and GGH genes influence plasma folate and homocysteine levels. Methods: Study participants were a sub-cohort (n = 484) from the Singapore Chinese Health Study. SNPs were selected using a literature review, HapMap, and SNPPer. Multiple linear regression was used to evaluate the association between the SNPs and plasma folate and homocysteine levels. Results: Two FPGS (rs10106, rs1098774) and 9 GGH (rs1031552, rs11545076, rs1800909, rs3758149, rs3780126, rs3824333, rs4617146, rs11545078, rs719235) SNPs were included in the final analysis. None of the FPGS or GGH SNPs were associated with plasma folate levels. Similarly, none of the FPGS SNPs were associated with plasma homocysteine, but three GGH SNPs were associated with plasma homocysteine levels: rs11545076 (p = 0.02), rs1800909 (p = 0.03), and rs3758149 (p = 0.04). In all three, the homozygous variant alleles were associated with lower plasma homocysteine values. Conclusions: It appears that genetic variation in GGH may be influential in determining circulating homocysteine levels, and thus, may influence intracellular folate homeostasis rather than circulating folate levels. Since this is one of the first studies to assess these genetic variants in relation to plasma folate and homocysteine, further research is needed to explore these variants and to better characterize the role of genetic variation in intracellular folate homeostasis.