Genetic Variants Involved in One-Carbon Metabolism: Polymorphism Frequencies and Differences in Homocysteine Concentrations in the Folic Acid Fortification Era

Abstract

Folate and other B vitamins are essential co-factors of one-carbon metabolism, and genetic variants, such as polymorphisms, can alter the metabolism. Furthermore, the adoption of food fortification with folic acid showed a decrease of homocysteine concentration. The aim of this study was to investigate the frequencies of the polymorphisms of enzymes and carrier proteins involved in one-carbon metabolism, and to evaluate homocysteine concentrations in the presence of these genetic variants in a population exposed to mandatory food fortification with folic acid. Using data from a population-based cross-sectional study in São Paulo, Brazil, the study population comprised 750 participants above 12 years of age of both genders. A linear regression model was used to evaluate the homocysteine concentrations according to genetic variants and folate level. The results showed that the minor allelic frequencies were 0.33 for MTHFR (rs1801133), 0.24 for MTHFR (rs1801131), 0.19 for MTR (rs1805087), 0.42 for MTRR (rs1801394), 0.46 for RFC1 (rs1051266), and 0.47 for DHFR (19-bp deletion). The genetic variants of MTHFR 677C>T, MTRR 66A>G and RFC-1 80G>A were different according to race. The homocysteine concentrations increased in the CT and TT compared to CC genotypes of polymorphism MTHFR 677C>T in all populations, and differences between the homocysteine concentrations according to the genotypes of MTHFR 677C>T were observed regardless of folate level.

Keywords: folic acid fortification; genetic variants; homocysteine; one-carbon metabolism; polymorphisms.

Figure 1

Overview of one-carbon metabolism considering metabolites, enzymes, coenzymes, and genetic variants. Abbreviations: methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), reduced folate carrier (RFC), dihydrofolate reductase (DHFR), tetrahydrofolate (THF), cystathionine β-synthase (CBS), dihydrofolate (DHF), human folate receptor (hFR), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), thymidylate synthase (TS), deoxyuridine monophosphate (dUMP), deoxythymidine monophosphate (dTMP), Betaine--Homocysteine S-Methyltransferase (BHMT), dimethyglycine (DMG), glycinamide ribonucleotide (GAR), 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), glycinamide ribonucleotide transformylase (GART), 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase (AICARFT).