Changes in global DNA methylation in response to chronic consumption and withdrawal of folic acid is dependent on the MTHFR 677C T polymorphism

Abstract

We evaluated the effect of the MTHFR C→T polymorphism on global DNA methylation from a double‐blind randomized controlled trial in which Chinese women of reproductive age took supplements of folic acid (100, 400, 4000 μg/d). DNA methylation was expressed as the % of methyl‐C/C (measured by a novel LC‐MS/MS assay) at 0, 1, 3, 6 months of supplementation, and 3 months after withdraw, stratified by MTHFR genotype (CC, CT, TT) (n=135; 15 subjects/genotype x 3 treatment groups). Baseline methylation levels (4.4 +/− 0.12) were identical (p>0.05) across the MTFHR genotypes. Folic acid supplementation resulted in a 13% (p< 0.0001) decrease in global methylation after 1 month of exposure, independently of genotype and dose. After 6 months of supplementation, DNA methylation had returned to baseline in the CT‐ and TT‐subjects taking 100 or 400 μg/d folic acid, but not in CC‐subjects, or in any subject receiving 4 mg/d. During the 3 month washout, DNA methylation decreased further in CC‐ and CT‐, but not in the TT‐subjects. This post‐supplementation decrease in methylation was both genotype and dose dependent, being greatest (compared to baseline) in CC‐subjects taking the 100 μg/d dose (42%, p=0.0001). In conclusion, global DNA methylation response to folic acid supplementation and withdrawal varied by MTHFR genotype with a complex genotype‐dose interaction. Support: Collaborative CDC agreement and GCRC Grant # MO1‐RR00082.