MTHFR gene polymorphisms are associated with circulating folate and folate sub‐species concentrations

We studied the association between four polymorphic MTHFR loci [rs1476413, rs1801131 (A1298C), rs1801133 (C677T) and rs4846052] with total serum folate and folate sub‐species concentrations, 5‐methyltetrahydrofolic acid (5MTHF), 5‐formyltetrahydrofolic acid (FOTS), pteroylglutamic acid (PGAS) and tetrahydrofolic acid (THFS). Participants were post‐menopausal women diagnosed with breast cancer (n = 479) between 1994 – 1995. Genotyping was conducted via the Illumina BeadLab 1000 SNP genotyping system. Total serum folate and sub‐species were measured by radio protein binding assay, and by isotope‐dilution LC/MS/MS, respectively. Analysis of variance showed that loci rs1801133 (C677T) was significantly (p < 0.0001) associated with lower total folate levels (9.67 ± 6.97) at the TT homozygous state compared with the heterozygous (mean ± SD, 14.03 ± 10.29) and common (14.91 ± 10.91) allele. The TT state was also significantly associated with lower THFS (1.06 ± 0.70) compared with the other two alleles (2.07 ± 1.47, 2.44 ± 1.58). Further, the rs4846052 loci was significantly (p = 0.02) associated with lower FOTS levels (0.91 ± 0.57) at the recessive allele (TT) compared with the other two alleles (1.26 ± 1.69, 1.08 ± 0.96, respectively). The rs4846052 common allele was also significantly (p = 0.03) associated with lower THFS levels. These results suggest that MTHFR TT677 loci is associated with lower total serum folate and THFS levels, the bioactive form of folate, while the rs4846052 at the dominant allele is associated with lower THFS, suggesting that multiple MTHFR variants may influence folate sub‐species levels and could have implications for folate and cancer outcomes.