The MTHFR gene produces a key metabolic enzyme, known as methylene-tetra-hydro-folate reductase (MTHFR), which is responsible for processing amino acids, specifically homocysteine.
Homocysteine is a chemical in the blood that’s naturally metabolized and recycled to build other proteins; but it requires vitamins like B12 and B6 and folic acid.
The MTHFR protein works efficiently by helping this recycling process to ensure homocysteine does not accumulate in the blood. However, genetic variants within this gene can alter the proper functionality of the MTHFR protein, which can be detrimental to the homocysteine recycling process; therefore, causing elevated levels.
There have been numerous studies analyzing the relation of MTHFR variants and elevated homocysteine levels and whether it can be a risk factor for several health conditions such as cardiovascular disease.
Such mutations are very common and over the past 20 years, there have been a great deal of research examining the relationship between homocysteine elevations and MTHFR mutations along with their associations with heart disease.
Homocysteinemia —a condition with mild to moderately elevated homocysteine levels—affects approximately 5-7% of the population. However, extremely high homocysteine elevations are rare; therefore, you’ll never become aware of your MTHFR mutation status without testing.
Some individuals develop elevated homocysteine levels due to a genetic predisposition specifically from the MTHFR gene.
Everyone has two MTHFR genes, where one is inherited from each parent. Individuals with a mutation in one MTHFR gene are said to be heterozygous while those with mutations in both genes are considered homozygous.
There are two known MTHFR gene variants that have been the active area of study for the MTHFR gene, which are C677T and A1298C . The risks associated with having one C677T and one A1298C are approximately the same but are lower than having two copies of either variant .
Between these two, the MTHFR-C677T mutation is significantly more common, especially in certain ethnic and geographic populations. In the U.S., approximately 20-40% of Caucasian and Hispanic individuals have two copies (i.e., homozygous) of the MTHFR-C677T. However, this mutation is also less common in individuals with an African American background at 1-2% .
Inherited mutations in the MTHFR gene alter the MTHFR enzyme by reducing its activity; therefore, making it perform less optimally and leading to elevated levels of homocysteine. According to previous studies, genetic variants of this gene are associated with 50% reduced MTHFR enzyme activity and an increased homocysteine concentration in the blood .
There have been studies indicating that high levels of homocysteine in an individual’s blood can lead to severe cardiovascular diseases by affecting the heart and blood vessels .
More specifically, elevated homocysteine levels are associated with an increased risk for blood blots in the veins and arteries within the heart and can even lead to atherosclerosis (i.e., hardening of the arteries) . However, high levels can also cause clots to occur in other regions of the body, such as the legs, which is referred to as deep vein thrombosis (DVT) . They can also occur in the lung, which is defined as pulmonary embolism (PE) .
Additional risks associated with elevated homocysteine levels can be seen in Table 1 below. Some studies indicate that the higher the homocysteine level in an individual’s blood, the higher the risk of heart disease. Due to these correlations, high levels of homocysteine due to MTHFR gene variants have been considered as a possible risk factor for cardiovascular disease.
o Coronary artery disease (atherosclerosis)
o Heart Attack
o Peripheral arterial disease
o Venous thrombosis (Deep vein thrombosis (DVT), pulmonary embolisms (PE)
o Pregnancy complications
When considering potential risk factor for health conditions like cardiovascular disease, it is important to not only think if the variants put an individual at risk, but if so, how much risk. Despite the numerous studies on MTHFR and health risks, evidence is still lacking regarding an association .
Although reduced enzyme function of MTHFR can lead to higher levels of homocysteine, it does not necessarily cause cardiovascular disease. More specifically, some researchers state that MTHFR mutations by themselves, in the absence of elevated levels, are not a risk factor for cardiovascular diseases and cannot be considered as a clotting disorder as some data shows that the risk is only mildly increased .
In 2010, the American Heart Association issued a statement expressing they do not consider high homocysteine levels from MTHFR variants to be a major risk factor for cardiovascular disease . Additionally, they stated that the overall risk of DVT and PE is only slightly increased and although homocysteine is a risk factor for a first episode of DVT or PE, it does not predict a higher risk of a recurrent clot .
It is not clear whether elevated homocysteine causes the blood to clot more easily or whether it’s just a marker of an increased clotting risk as homocysteine levels can also be effectively lowered by other factors such as vitamin B6 and B12, and folic acid consumption.
According to the American Heart Association, the causal link between homocysteine levels and conditions such as atherosclerosis and clotting issues, have not been yet established . Homocysteine has also been investigated as a risk factor for several other diseases, including autism, cognitive impairment or dementia, and depression . However, in a similar fashion to heart diseases, testing homocysteine in these contexts is considered investigational as more evidence is needed.
Elevated homocysteine levels rarely result from MTHFR mutations alone as people with very high levels should also carefully evaluate other factors that are known to affect homocysteine. More specifically, this can bring attention to dietary deficiencies and lifestyle factors (physical inactivity, smoking, obesity) that can also impact homocysteine levels.
If high levels of homocysteine cannot be explained by these factors, then it may be possible that an MTHFR variant is the root cause for this issue. It’s important to note that the overall risk associated with MTHFR variants is minimal, which is why genetic testing may not always be recommended unless there’s an abnormal elevated level of homocysteine.
Aside from the major causes of increased homocysteine levels, there are ways for individuals to lower these levels and reduce their possible risk with the previously mentioned health risks. For instance, folic acid, vitamin B6, and vitamin B12 can decrease homocysteine in the blood since they are required to recycle it.
A known good source of these components are fruits and vegetables while a daily intake of pills containing them or a combination of all three can be beneficial in lowering levels. Additionally, changes in lifestyle behaviors such as minimizing your alcohol intake and smoking, or managing stress levels can even help balance your homocysteine levels.
MTHFR gene is necessary for processing homocysteine and Vitamin B6, B9, and folic acid. A number of health conditions that may be associated with MTHFR include cardiovascular and thromboembolic diseases (specifically blood clots, stroke, embolism, and heart attacks). However, genomic studies of MTHFR gene variations in individuals have had mixed results, with associations found in some studies but not in others.
Therefore, the variation in the MTHFR gene and its effects in certain heart conditions remains unclear since it’s likely that there are additional factors that influence the processing of homocysteine. A healthy lifestyle may help in lowering the risk for those carrying the high risk mutations of C677T and A1298C.
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 Stephan Moll and MD Elizabeth A. Varga (From Hemophilia and Thrombosis Center and Clot Connect Program), Homocysteine and MTHFR Mutations, Circulation 2015;132:e6–e9.
 CDC: MTHFR Gene, Folic Acid, and Preventing Neural Tube Defects. Last reviewed Jul 6, 2020.
 Xuan, C., Li, H., Zhao, J., Wang, H., Wang, Y., Ning, C., Liu, Z., Zhang, B., He, G., Lun, L.. Association between MTHFR polymorphisms and congenital heart disease: A meta-analysis based on 9,329 cases And 15,076 controls, Nature Scientific Reports 2014, 4: 7311.
 NIH Genetic and Rare Diseases Information Center: MTHFR Gene Variants. Last reviewed Feb 5, 2021.
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