Abstract
The 5-10-methylenetetrahydrofolate reductase (MTHFR) enzyme is vital for cellular homeostasis due to its key functions in the one-carbon cycle, which include methionine and folate metabolism and protein, DNA, and RNA synthesis. The enzyme is responsible for maintaining methionine and homocysteine (Hcy) balance to prevent cellular dysfunction. Polymorphisms in the MTHFR gene, especially C677T, have been associated with various diseases, including cardiovascular diseases (CVDs), cancer, inflammatory conditions, diabetes, and vascular disorders. The C677T MTHFR polymorphism is thought to be the most common cause of elevated Hcy levels, which is considered an independent risk factor for CVD. This polymorphism results in an amino acid change from alanine to valine, which prevents optimal functioning of the enzyme at temperatures above 37 °C. Many studies have been conducted to determine whether there is an association between the C677T polymorphism and increased risk for CVD. There is much evidence in favour of this association, while several studies have concluded that the polymorphism cannot be used to predict CVD development or progression. This review discusses current research regarding the C677T polymorphism and its relationship with CVD, inflammation, diabetes, and epigenetic regulation and compares the evidence provided for and against the association with CVD.
Highlights
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Researchers investigating the ethnic and geographical distribution of the C677T Methylenetetrahydrofolate reductase (MTHFR) gene polymorphism in new-borns across 16 regions of Europe, Asia, Australia, the Middle East, and the Americas reported that the the homozygous mutant genotype (TT) genotype was more frequently observed in China, Mexico, and Southern Italy, with a low frequency observed in new-borns of African ancestry [13]
MTHFR-deficient mice fed a high-fat diet exhibited exacerbated effects in inflammatory and lipid pathways, with increased inflammation and lipid accumulation. These results suggest that MTHFR deficiency coupled with a low-quality high-fat diet may increase the risk of developing non-alcoholic fatty liver disease (NAFLD) due to disrupted methylation capacity, lipid metabolism, and inflammatory responses [24]
Summary
5-10-Methylenetetrahydrofolate reductase (MTHFR) is an essential enzyme in folate and homocysteine (Hcy) metabolism. The most common cause of elevated Hcy levels is thought to be the C677T MTHFR polymorphism (rs 1801133) This polymorphism involves the substitution of cytosine with thymine at position 677, resulting in an amino acid change from alanine to valine in the enzyme [1,7,8]. This common MTHFR gene mutation affects Hcy levels and is thought to contribute to hyperhomocysteinemia, reduced folate levels, and several CVD-associated diseases [9].
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