The Pharmacogenomics Journal (2009) 9, 291–305; doi:10.1038/tpj.2009.29; published online 7 July 2009

Investigation of inter-individual variability of the one-carbon folate pathway: a bioinformatic and genetic review

D F Carr1, G Whiteley1, A Alfirevic1 and M Pirmohamed1 on behalf of the FolATED study team

1Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, Merseyside, UK

Correspondence: Prof. M Pirmohamed, Department of Pharmacology and Therapeutics, Sherrington Building, Ashton Street, Liverpool, Merseyside L69 3GE, UK. E-mail:

Received 27 March 2009; Revised 8 May 2009; Accepted 26 May 2009; Published online 7 July 2009.



Genetic polymorphisms in the one-carbon folate pathway have been widely studied in association with a number of conditions. Most of the research has focused on the 677C>T polymorphism in the coding region of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene. However, there are a total of 25 genes in this pathway coding for enzymes, transporters and receptors, which can be investigated using 267 tagging single nucleotide polymorphisms (SNPs); using SNP database (dbSNP), 38 non-synonymous SNPs with a minor allele frequency of >5% are present in these genes. Most of these variants have not been investigated in relation to disease or drug response phenotypes. In addition, their functional consequences are largely unknown. Prediction of the functional effect using six publicly available programs (PolyPhen, SIFT BLink, PMut, SNPs3D, I-Mutant2.0 and LS-SNP) was limited to functionally well-characterized SNPs such as MTHFR c.677C>T and c.1298A>C ranking low. Epigenetic modifications may also be important with some of these genes. In summary, to date, investigation of the one-carbon folate pathway genes has been limited. Future studies should aim for a more comprehensive assessment of this pathway, while further research is also required in determining the functional effects of these genetic variants.


one-carbon folate, genetics, bioinformatics, MTHFR, dihydrofolate reductase, thymidylate synthase