Introduction
Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in the folate metabolism pathway, which plays a vital role in DNA methylation, DNA synthesis, and repair. The MTHFR gene encodes for the enzyme that converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate (5-MTHF) in the presence of the cofactor vitamin B12. The 5-MTHF is then converted to tetrahydrofolate (THF). THF is a necessary precursor for synthesizing purines and pyrimidines, essential building blocks for DNA. Numerous studies have shown that MTHFR gene polymorphisms are associated with various health outcomes, including cardiovascular disease, neural tube defects, and cancer. This article will review the current understanding of MTHFR gene polymorphisms and their effects on health.
MTHFR Gene Polymorphisms
MTHFR gene polymorphisms can be classified into two main types: C677T and A1298C (1). The C677T polymorphism results in a substitution of cytosine (C) for thymine (T) at nucleotide 677, which leads to a change in the amino acid sequence of the MTHFR enzyme. This substitution results in a thermolabile enzyme that has reduced activity (2). The A1298C polymorphism results in a substitution of adenine (A) for cytosine (C) at nucleotide 1298, which also leads to a change in the amino acid sequence of the MTHFR enzyme. This substitution does not result in a thermolabile enzyme, but it does result in reduced activity (3).
Cardiovascular Disease
Numerous studies have investigated the association between MTHFR gene polymorphisms and cardiovascular disease. One meta-analysis of 56 studies found that the C677T polymorphism was significantly associated with an increased risk of coronary artery disease (4). Another meta-analysis of 24 studies found that the A1298C polymorphism was not significantly associated with cardiovascular disease (5).
Neural Tube Defects
Neural tube defects (NTDs) are a group of congenital disabilities that occur when the neural tube fails to close properly during fetal development. Numerous studies have investigated the association between MTHFR gene polymorphisms and NTDs. One meta-analysis of 34 studies found that the C677T polymorphism was significantly associated with an increased risk of NTDs (6). Another meta-analysis of 14 studies found that the A1298C polymorphism was not significantly associated with NTDs (7).
Cancer
Numerous studies have investigated the association between MTHFR gene polymorphisms and cancer. One meta-analysis of 50 studies found that the C677T polymorphism was significantly associated with an increased risk of colorectal cancer (8). Another meta-analysis of 27 studies found that the A1298C polymorphism was not significantly associated with cancer (9).
Conclusion
MTHFR gene polymorphisms have been associated with a range of health outcomes, including cardiovascular disease, neural tube defects, and cancer. The C677T polymorphism is associated with an increased risk of coronary artery disease and neural tube defects, while the A1298C polymorphism is not significantly associated with these outcomes. The C677T polymorphism is also associated with an increased risk of colorectal cancer.
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