Vitamin D and folate: A reciprocal environmental association based on seasonality and genetic disposition

Objectives: The purpose of this study was (1) to elucidate any reciprocal seasonal relationship that might exist between red cell folate (RCF) and serum vitamin D3 Levels; (2) to explore whether folate-related gene variants that influence/alter DNA-thymidylate and methyl group biosynthesis modify any associations detected in objective 1; and (3) to consider whether these processes might influence reproductive success consistent with the “folate-vitamin D-UV hypothesis of skin pigmentation” evolutionary model. Methods: A large (n = 649) Australian cross-sectional study population was examined. Polymerase chain reaction (PCR)/Restriction fragment length polymorphism (RFLP) analysis was used to genotype C677T-MTHFR, C1420T-SHMT, T401C-MTHFD and 2R > 3R-TS. RCF was measured by chemiluminescent immunoassay and vitamin D2 and D3 by HPLC. Results: RCF and photosynthesized vitamin D3, but not RCF and dietary vitamin D2, exhibit a significant reciprocal association in spring and summer. Three folate genes (C677T-MTHFR, C1420T-SHMT, and 2R > 3R-TS) strengthen this effect in spring, and another (T401C-MTHFD) in summer. Effects are seasonal, and do not occur over the whole year. Conclusions: Findings are consistent with what might be required for the “folate-vitamin D-UV hypothesis of skin pigmentation” model. It suggests genetic influence in provision of one-carbon units by 5,10-methylene-H4folate, may be an important factor in what appears to be a clear seasonal relationship between vitamin D3 and folate status.