Clinical Implications of MTHFR Gene Polymorphism in Various Diseases

What prompted me to write this editorial was due to the fact that emerging bodies of in vitro and clinical evidence suggests that MTHFR SNPs may be important as pharmacogenetic determinants in predicting the response to toxicity of methotrexate and 5-fluorouracilbased cancer and anti-inflammatory treatments because of their well-defined and highly relevant biochemical effects on intracellular folate composition and one-carbon transfer reactions. MTHFR gene mutation has been related to many diseases including colon cancer, leukemia, vascular disease, depression, schizophrenia, migraine with aura, glaucoma, Down syndrome, and neural tube defects to name a few. Earlier Research performed during the past decade has clarified our understanding of MTHFR deficiencies that cause hyperhomocysteinemia with homocystinuria, or mild hyperhomocysteinemia. The involvement of MTHFR in disease was first published by Mudd et al. [1] who identified a patient with homocystinuria due to a severe deficiency of the enzyme. Recently, Tongboonchoo et al. [2] reported the association between MTHFR C677T polymorphism with osteoporosis in postmenopausal women. Osteoporosis and osteopenia is rising with the increase in numbers of postmenopausal women, and MTHFR, a homocysteine catabolizing enzyme, was found to be involved in the regulation of bone mineral density (BMD). Further, Zidan et al. [3] Demonstrated an association of MTHFR A1298C polymorphisms with congenital heart diseases (CHD) in Egyptian children and their mothers, while, MTHFR C677T polymorphisms were significantly associated with the risk of CHD in the children only, and an association between combined MTHFR A1298C and C677T polymorphisms and CHD was recorded in the children and their mothers. Also, homocysteine levels were significantly increased with both MTHFR 677TT and 1298CC genotypes in Egyptian children with CHD. The functional point mutation C677T in the MTHFR gene has been reported to contribute to hyperhomocysteinaemia which is a risk factor for atherothrombotic ischaemic strokes. TT genotypes of the MTHFR- C677T polymorphic gene was an important determinant for homocysteine levels in Malaysian ischaemic stroke patients [4]. A Russian study [5] observed that the MTHFR gene polymorphism correlated with an increased risk of migraine, particularly migraine with aura. The substitution of cytosine for thymine at the position 677 of the MTHFR gene leads to formation of the thermolabile form of the protein and development of hyperhomocysteinemia, which increases the probability of migraine. Yigit et al. [6] observed a high association between the MTHFR gene C677T mutation and diabetic neuropathy in the Turkish Population. In addition, they also reported that the history of retinopathy was associated with the MTHFR C677T mutation in patients with diabetic neuropathy. In this brief note I have attempted to highlight the complex role of the MTHFR gene mutations and its association with many diseases, summarizing the current state of knowledge on mutations/polymorphisms in MTHFR and discussed some of our own findings in leukemia and breast cancer. MTHFR is highly polymorphic in the general population [7]. More precisely, the MTHFR gene is located from base pair 11,845,786 to base pair 11,866,159 (Cytogenetic Location: 1p36.3) on chromosome 1. It is expressed in various tissues including the brain, muscle, liver, and stomach [8]. MTHFR gene mutation can cause methylenetetrahydrofolate reductase deficiency. Two common mutations in the MTHFR gene interfere in the production of an enzyme that doesn't work as well as in normal. These "variants" are C677T and A1298C, the nucleotide 677 polymorphism results in an alanine to valine (C → T) substitution. The second common MTHFR polymorphism, a glutamate to alanine (A → C) change at position 1298, also influences the specific activity of the enzyme, homocysteine levels, and plasma folate concentration but to a lesser extent than the C677T polymorphism. Generally, it is believed that MTHFR SNPs are ideal candidates for investigating the role of SNPs in cancer risk modification and treatment. In fact, a huge expanse of molecular epidemiologic evidence indicates that the MTHFR 677 variant T allele is connected with the risk of developing cancer, in a site-specific manner [9]. Furthermore, changes in intracellular folate cofactors resulting from the MTHFR 677T variant may explain cancer risk modification associated with this variant. Because the MTHFR SNPs are prevalent, the pharmacogenetic role of the MTHFR SNPs has significant clinical implications since Methotrexate (MTX) [10] and 5-FluoroUracil (5FU) are widely used for the treatment of common cancers and inflammatory conditions [9]. It is certain that patients with MTHFR SNPs receiving chemo-regimen of these common drugs suffer severe adverse drug reactions. Our studies on SNPs in breast cancer and leukemia [11, 12] are good examples to relook at the role of these SNPs as biomarkers of disease susceptibility and their role in drug-gene interactions [13]. It is hypothesized that there may be a correlation between functional polymorphisms in the gene for the folate metabolizing enzyme, 5,10- methylenetetrahydrofolate reductase and leukemogenesis because of the association between folate status and susceptibility to genetic damage in dividing cells. MTHFR catalyses the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the major circulatory form of folate and carbon donor for the remethylation of homocysteine to methionine. A decrease in the activity of the MTHFR enzyme augments the pool of methylenetetrahydrofolate at the expense of the pool of methyltetrahydrofolate. This increase in availability of methyltetrahydrofolate in the DNA synthesis pathway lessens the misincorporation of uracil into DNA, which may otherwise lead to double-strand breaks during uracil excision repair. Some studies have shown that individuals with adequate folate status, who are homozygous for the MTHFR 677TT mutation, have a reduced incidence of colorectal cancer and leukemia. In our study, we examined the effect of MTHFR C677T and A1298C polymorphisms in Acute Lymphoblastic Leukemia (ALL).. Specifically, we found that individuals with at least one MTHFR mutation at 677CT or 1298AC were less likely