Figure 1.
Overview of the folate metabolic pathway, adapted from [18].
Folates require several transport systems to enter the cells, the best characterized being the reduced folate carrier (RFC1). Methylenetetrahydrofolate reductase (MTHFR) reduces 5,10-methylenetetrahydrofolate (5,10-MTHF) to 5-methyltetrahydrofolate (5-MTHF). Subsequently, methionine synthase (MTR) transfers a methyl group from 5-MTHF to homocysteine (Hcy) forming methionine (Met) and tetrahydrofolate (THF). Methionine is then converted to S-adenosylmethionine (SAM) in a reaction catalyzed by methionine adenosyltransferase (MAT). Most of the SAM generated is used in transmethylation reactions, whereby SAM is converted to S-adenosylhomocysteine (SAH) by DNA methyltransferases (DNMTs) that transfer the methyl group to the DNA. Vitamin B12 is a cofactor of MTR, and methionine synthase reductase (MTRR) is required for the maintenance of MTR in its active state. If not converted into methionine, Hcy can be used for the synthesis of glutathione (GSH) in a reaction catalyzed by cystathionine b-synthase (CBS) and other enzymes. Another important function of folate derivatives (THF and dihydrofolate: DHF) is in the de novo synthesis of DNA and RNA precursors (dUMP, dTMP, etc). This pathway is mediated by thymidylate synthase (TYMS), methylenetetrahydrofolate dehydrogenase (MTHFD), and phosphoribosylglycinamide transformylase (GART) enzymes.
Figure 2.
Method of coding the polymorphisms in the database.
The code assigned to the polymorphisms transformed each polymorphism in three genotype classes: wild type (major homozygous), heterozygous and mutants (minor homozygous). For each class a binary coding was applied: 0 if variable absent; 1 if variable present. So for example considering the polymorphism MTRR 66A>G which can exist in three variants: AA (major homozygous), AG (heterozygous) and GG (minor homozygous). Supposing that three records are AA, GG and AG, the coding has been applied as shown in the figure.
Figure 3.
Semantic connectivity map obtained with Auto-Cm System.
The figures on the arches of the graph refer to the strength of the association between two adjacent nodes. The range of this value is from 0 to 1.