Converging evolutionary, environmental and clinical ideas on folate metabolism

Background & objectives: Folate is a UV-labile vitamin, critical to maintenance of DNA synthesis and repair mechanisms. Evidence supports a number of folate-dependent enzymes as being UV-responsive, suggesting that the activity of pathways operating through such enzymes may differ between geographic areas of varied UV exposure. Therefore, we explored the possible association of global UV levels with the prevalence of common polymorphisms in folate-metabolism enzymes. Methods: Data from the PubMed electronic database was collated for the polymorphisms MTHFR-C677T, MTHFR-A1298C, cSHMT-C1420T TYMS 28bp 2R>3R, TYMS 3'UTR ins/del and DHFR 19bp deletion. Data extracted were analysed by the latitude of the study locations, as a surrogate measure of population UV exposure. Results: Frequency of the MTHFR-C677T and MTHFR-A1298C polymorphisms was positively associated with latitude, while a negative association was observed between latitude and frequency of the cSHMT-C1420T and TYMS 28bp 2R>3R variants. Conclusions: These findings provide novel evidence suggestive of folate genotypes being selected to maintain homeostasis between folate-dependent de novo thymidylate synthesis and methylation pathways in environments of differing UV levels. To the authors' knowledge, this is the first study to report significant associations between latitude and the occurrence of MTHFR-A1298C, TYMS 28bp 2R>3R and cSHMT-C1420T polymorphisms. On-going studies are required to further explore the biological significance of these findings.