Slow Aging | Healthy living, healthy aging

MTHFR protein, genetics and homocysteine levels

As the body can’t produce folic acid, it needs to be supplied through the diet, and dietary folic acid is biologically processed with the help of the MTHFR protein. Here we go into depth about what this protein is, and much more.

What are homocysteine and folic acid?

It is possible that as we age the amount of vitamin and mineral dietary requirements increase. We may need to increase our intake of specific nutrients to accommodate changes in our cellular chemistry when we are older. One of these nutrients is vitamin B9, also known as folic acid, given its emerging effects on the amount of the amino acid homocysteine circulating in blood plasma.

Link between increased homocysteine levels and chronic disorders

Homocysteine is an intermediate molecule produced during normal biological processes, and it is required for healthy human cells.

The amount of total homocysteine (tHcy) in circulating blood levels, however, increases with advancing age in both men and women. If our circulating blood levels of tHcy are higher than 8-15 μmol/L, our risk for a variety of diseases such as cardiovascular disease, blood clots, cognitive problems, and specific cancers increases.

A large community-based study of 18,000 individuals living in Norway over an extended amount of time confirmed that a strong relationship exists between increased homocysteine levels and serious chronic disorders.

Role of folic acid in processing homocysteine, and the MTHFR protein

One of the biological pathways that human cells use to process homocysteine requires folic acid.

The human body cannot produce folic acid so it must be supplied through the diet. Dietary folic acid is biologically processed through multiple steps requiring the MTHFR protein (methylenetetrahydrofolate reductase (NAD(P)H).

MTHFR is an enzymatic protein, meaning it can facilitate the conversion of one biological compound into a different biological compound at a rapid speed. Any changes to the MTHFR protein structure can alter its ability to efficiently perform this function.

The MTHFR protein is produced from the MTHFR gene (i.e. a specific piece of DNA), which consists of two distinct regions responsible for making MTHFR proteins. A specific mutation in either gene region that produces the MTHFR protein – denoted C677T – has been demonstrated to inhibit MTHFR from effectively utilizing the biological products produced from dietary folic acid.

Given that the intermediate product homocysteine is not efficiently processed without conversion of folic acid into other compounds, this specific mutation in MTHFR is correlated with increased total homocysteine blood plasma levels.

If we have no mutation in the MTHFR gene, we have a genotype of MTHFR 677CC (the two Cs denoting the genotype for each of the gene regions).

If we have mutations in both gene regions coding for the MTHFR protein, we have the genotype MTHFR 677TT.  People with MTHFR 677TT have a small increased risk for heart disease and venous thrombosis. They also have a larger increased risk for depression. This data is consistent with the published association of moderately raised homocysteine levels with dementia and cognitive impairment in elderly people.

Current studies suggest that approximately 7% of the general population has the genotype MTHFR 677TT, and of those people about 73% will definitely exhibit increased blood levels of homocysteine.

Therefore, a loss in the enzymatic function of the MTHFR protein is associated with elevated homocysteine. With advanced aging, if we have MTHFR 677TT then we may need to increase our dietary intake of folic acid more than those of us with other genotypes.

Who should be tested for genetic mutations in the MTHFR gene?

Though there is a strong and consistent association between the MTHFR 677TT mutation and elevated homocysteine levels, this mutation has not yet been demonstrated to be the defining cause for a specific disease; thus, genetic testing for this mutation is considered controversial.

Some studies suggest that people with a mutation in the MTHFR gene in combination with other gene mutations may be required for disease development. Nevertheless, the US National Institute of Health’s GARD Information Center suggests that if we have a personal or family history of heart disease or blood clots, then we should consider being tested for the common MTHFR gene mutations.

Likewise, the Mayo Clinic, a premier health and research institute in the USA, suggests that we should be tested for the MTHFR C677T mutation if we have either an increased basal homocysteine level or an abnormal methionine-load test and also have, or have had, one of the following conditions:

High levels of total homocysteine in blood plasma (hyperhomocysteinemia) are an independent and strong risk factor for all of the diseases mentioned above.

Though the MTHFR gene is known to be prone to multiple mutations, current data only demonstrates strong health-related risks for individuals with the genotype MTHFR 677TT.

The Federal Drug Administration (FDA) in the USA has approved several tests available for analyzing the MTHFR C677T mutation. As with all genetic testing, it’s best if you consult your general practitioner to ensure the test is appropriate and understood.

Taking action if you have the MTHFR 677TT genotype associated with increased disease risk

Though aging causes our homocysteine levels to increase, other factors such as genetics, physical inactivity, smoking, high blood pressure, high cholesterol, high levels of coffee consumption, and low blood levels of folic acid and vitamin B12 were all observed in individuals with elevated levels of total homocysteine.

From all of these risk factors, age, folic acid intake, smoking, and coffee consumption had the strongest correlation with high levels of homocysteine.

Changing our lifestyle factors, when possible, especially for individuals who are MTHFR 677TT, may provide a way to naturally lower homocysteine levels in the blood.

Physical activity, moderate alcohol consumption, and a good folic acid or vitamin B12 status are associated with lower total homocysteine levels in individuals. In fact, a single clinical trial demonstrated that taking at least 0.2 mg of folic acid per day could efficiently lower total homocysteine levels.

Many countries, such as the USA and Australia, have a mandatory folic acid fortification program requiring that certain foods, mainly grains, contain specific amounts of folic acid. Ensuring we have an adequate intake of these fortified foods is also a method for increasing dietary levels of folic acid.

How can genetic testing affect your total health?

Your ability to manage homocysteine blood levels may decrease your risk for specific age-related diseases.

Knowing your MTHFR genetic status is one important factor that can aid you in determining how aggressive to be in monitoring total homocysteine levels.

A complete picture of your health may benefit from knowledge of genotype specific mutations, especially if you are already prone to or display specific disease symptoms. You have the ability to decrease your risk for these disease symptoms through learning more about your personal genetic profile.

Websites you can visit for additional information:

More information on the MTHFR gene and its functions

http://ghr.nlm.nih.gov/gene/MTHFR

Explanation of MTHFR and its biological processing pathways

http://doccarnahan.blogspot.com/2013/05/mthfr-gene-mutation-whats-big-deal.html

Mayo Clinic’s MTHFR testing

http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/81648

References

Bousman CA, Potiriadis M, Everall IP, Gunn JM. Methylenetetrahydrofolate reductase (MTHFR) genetic variation and major depressive disorder prognosis: A five-year prospective cohort study of primary care attendees. Am J Med Genet B Neuropsychiatr Genet. 2014;165:68-76.

Gellekink H, den Heijer M, Heil SG, Blom HJ. Genetic determinants of plasma total homocysteine. Semin Vasc Med. 2005;5:98–109.

Li P and Qin C. Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and susceptibility to ischemic stroke: A meta-analysis. Gene. 2014;535:359-64.

Ravaglia G, Forti P, Maioli F, Martelli M, Servadei L, Brunetti N, PorcelliniE, Licastro F. Homocysteine and folate as risk factors for dementia and Alzheimer disease. Am J Clin Nutr. 2005;82:636–43.

Refsum H, Nurk E, Smith AD, Ueland PM, Gjesdal CG, Bjelland I, Tverdal A, Tell GS, Nygård O, Vollset SE. The Hordaland Homocysteine Study: A Community-Based Study of Homocysteine, Its Determinants, and Associations with Disease. J Nutr. 2006; 136:1731S-40S.

Smith AD. Homocysteine, B vitamins, and cognitive deficit in the elderly.Am J Clin Nutr. 2002;75:785–6.

Yan S, Xu D, Wang P, Wang P, Liu C, Hua C, Jiang T, Zhang B, Li Z, Lu L, Liu X, Wang B, Zhang D, Zhang R, He S, Sun B, Wang X. MTHFR C677T polymorphism contributes to the risk for gastric cancer. Tumour Biol. 2013; Advance online publication. 10.1007/s13277-013-1282-1.

 

Last Reviewed 10/Feb/2017

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