Methylenetetrahydrofolate (MTHFR), the One-Carbon Cycle, and Cardiovascular Risks

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.

Folic acid restricts SARS-CoV-2 invasion by methylating ACE2

“…Accelerating folate circulation can increase the activity of MTHFR or directly enrich folic acid, suggesting that folic acid supplementation may regulate ACE2 expression. Lack of MTHFR expression causes elevated homocysteine levels, which in turn leads to an increased risk of thrombosis and is associated with a higher risk of cardiovascular disease ( Raghubeer and Matsha, 2021 ). This may explain why people with underlying cardiovascular disease tend to become sicker after contracting a respiratory virus.…”

Association of methylenetetrahydrofolate reductase gene polymorphisms and maternal folic acid use with the risk of congenital heart disease

“…The MTHFR gene, in which inherited mutations can influence an optically active enzyme and, accordingly, elevated homocysteine levels ( 18 ), functions in the folate-homocysteine metabolic pathway and has an impact on protein, DNA, and RNA synthesis. The enzyme, therefore, is in charge of maintaining the balance of folic and homocysteine to prevent dysfunction in cells ( 11 ). Population-based studies have demonstrated a sound association of MTHFR genetic variants with the risk of CHD ( 19 , 20 ); however, results of previous studies on this topic have been dissident, with the majority restricted to a minor number of functional non-synonymous polymorphisms ( 21 – 23 ).…”

“…For instance, the genetic polymorphisms rs1801133 (C667T) and rs1801131 (A1298C) of the MTHFR gene piqued interest. The rs1801133 MTHFR polymorphism affected the optimal activity of the enzyme ( 11 ) and increased the level of homocysteine ( 8 ) and the other variation ( MTHFR A1298C) within the presumed regulatory domine also inhibited the enzyme activity ( 12 ). It is worth noting that findings from previous studies involved in the association of the two genetic mutations with the risk of CHD were conflicting ( 13 , 14 ).…”

B vitamin supply in plants and humans: the importance of vitamer homeostasis

“…With insufficient absorption and impaired transport, consequences could be manifold, including immunologic and neurologic dysfunctions (Kronn & Goldman, 2008). Methylene tetrahydrofolate reductase (MTHFR), which converts 5,10‐methylene‐THF to 5‐methyl‐THF (Figure 3b), contributes to Met generation from Hcy and thus plays a crucial role in maintaining cellular folate homeostasis and the 1C pool (Raghubeer & Matsha, 2021). Gene variants of MTHFR, particularly the C677T polymorphism, are quite common among human populations and are thought to be related to certain diseases, such as cardiovascular diseases (CVDs), and pose a higher risk of neural tube defects (NTDs) (Tsang et al., 2015).…”