This review article by Nazki et al (2014) examined the evidence currently available on folate, methylation and genetic polymorphisms. It lists the main functional polymorphisms of the MTHFR gene to be C677T, A1298C, with other reported polymorphisms known for genes T1059C, T1317C and G1793A. In regards to the C677T mutation, the heterozygous C677T mutation functions at 65% activity, with homozygous 677TT just 35% activity when compared with the normal homozygous variant (C677C). The review also examines folate gene polymorphisms in relation to disease states, with cancer a predominant focus.
Breast cancer has been extensively studied in regards to MTHFR polymorphisms, with results still inconsistent. Many studies did report the interactive effect between folate intake and the methylation related genes on breast cancer, with it shown to be a factor for breast cancer risk. Individuals with the 677TT polymorphism showing adequate levels of methylation via high folate intake actually showed modest reductions in colorectal cancer risk when compared to those with the wild type C677C genotype. However, this risk was increased if methylation (and hence folate) levels were low. Other research suggests both 677CT and 677TT polymorphisms both modestly increased colorectal cancer risk. Studies examining the relationship between MTHFR C677T, T677T + Acute Lymphoblastic Leukemia are plentiful but contradictory, with results mainly showing either no significant relationship found, or a decreased susceptibility to ALL with either polymorphisms. The majority of studies completed on Chinese, Italian and Mexican populations found the MTHFR 677TT mutation to be a strong risk factor for gastric cancer.
In relation to other pathologies, numerous studies show the relationship between high maternal homocysteine and the increased risk of Neural Tube Defect development in their offspring, with two Brazilian studies presenting conflicting results. Furthering childhood disabilities, studies have shown links between the C677T mutation and an increased risk of Downs Syndrome in offspring. A Brazilian study linked increase maternal levels of homocystiene with increased risk of DS presentation in offspring. Overall, only the C677T allele was found to be associated with hyperhomocysteinemia. Links between folate/ B12 intake +MTHFR C677T mutations and depression have also been made, with one study conducted on 732 Korean subject finding depression was predicted by lower folate, B12 and high homocysteine.
Nazki et al (2014) concluded by stating the importance of folate for DNA synthesis and methylation, and the broad reaching effects this has in body. In accordance with the viewpoint that genes are influenced by our diet + environment, many studies are able to link a correlation with MTHFR or folate with a disease process or disability, but find it hard to pinpoint them as sole risk factors for a disease.