Single nucleotide polymorphisms (SNPs) and folate-pathway gene variants, ‘The Judas alleles’

Folate pathway enzymes promote also the conversion of dietary vitamins to intracellular active co-enzymes. These complex processes require many physiological and biochemical steps. A defect in the activity of such enzymes can result in anomalous or disturbed conversion or binding reactions necessary for the normal progression of cellular biosynthetic pathways. Although many mutations have been described in the genes of enzymes of one-carbon metabolism, most of them are rare or private mutations often leading to a severe condition named homocystinuria. However, the less severe but more common genetic polymorphisms (usually single nucleotide polymorphisms, SNPs) affecting folate pathway, merit wider attention. Epidemiologic and mechanistic evidences suggest that common folate gene variants are involved in a number of pathologic conditions including neural tube defects, cardiovascular disease and solid or haematological cancers. The first common gene variants associated to pathologic conditions were in the gene of methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), mainly investigated in cardiovascular disease and neoplasia. Here, SNPs are associated to a reduced enzyme activity leading, in the case of 677TT-homozygous condition, to a reduction of about 65% of the MTHFR enzyme activity. Other common and functional variants are in the gene of methionine synthase (MS, A2756G), methionine synthase reductase (MTRR, A66G), thymidylate synthase (TS, 2R3R repeat element), cystathionine-β-synthase (CBS, 844_845ins68), reduced folate carriers-1 (RFC1, G80A), methylenetetrahydrofolate dehydrogenase-1 (MTHFD1, G1958A), and, serine hydroxymethyltransferase-1 (SHMT1, C1420T). Several among such variations have shown to reduced cancer susceptibility though recently, increased negative side effects, drug toxicity and low survival rates have been ascribed to the same gene variations in cancer. This dual-faced behaviour has been defined as the Judas-allele characteristic. For other recently discovered polymorphisms, functional and epidemiological data are limited and/or inconsistent. A fact common to all gene polymorphisms is that allele frequencies may show marked ethnic and geographic variations, basically with effects on disease susceptibility. This chapter will discuss on the commonest gene polymorphisms in folate pathways and their effects on enzyme properties