MTHFR

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Also known as: MTHFR DNA testing
Formal name: Methylenetetrahydrofolate Reductase Mutations, C677T and A1298C
Related tests: Homocysteine, Factor V Leiden Mutation and PT 20210 Mutation, Vitamin B12 & Folate, Cardiac Risk Assessment, Methotrexate

At a Glance

Why Get Tested?

To evaluate the cause of elevated homocysteine levels; sometimes to help determine your risk of thrombosis or premature cardiovascular disease (CVD)

When to Get Tested?

When you have elevated homocysteine levels; sometimes when a close relative has MTHFR gene mutations or has developed CVD or thrombosis at an early age

Sample Required?

A blood sample drawn from a vein in your arm

Test Preparation Needed?

None

The Test Sample

What is being tested?

The methylenetetrahydrofolate reductase (MTHFR) gene oversees the production of the MTHFR enzyme. This enzyme changes one form of folate into another and is part of the process that converts homocysteine into methionine, an important building block for many proteins.

MTHFR testing detects two relatively common DNA sequence variants (single nucleotide polymorphisms, SNPs) in the MTHFR gene, C677T and A1298C. These SNPs result in changes in the DNA (or mutations) and are associated with increased homocysteine levels in the blood, which may increase the risk of premature cardiovascular disease (CVD), thrombosis, and stroke. Approximately 10-12% of the North American population is homozygous for C677T. There is some ethnic variability in the frequency, with the highest being in those of Mediterranean ancestry and the lowest in those of African ancestry.

The C677T variant results in a less active form of the MTHFR enzyme. When a person has two copies of the MTHFR C677T gene mutation (homozygous) or one copy of MTHFR C677T and one copy of A1298C (compound heterozygous), decreased MTHFR enzyme activity slows down the homocysteine-to-methionine conversion process and can lead to a buildup of homocysteine in the blood.

The increase in homocysteine is often mild to moderate but will vary from person to person depending upon the amount MTHFR enzyme activity. Homocysteine buildup is worsened when the affected person is folate-deficient.

Results of some studies suggest that high levels of homocysteine in the blood may contribute to risk of CVD by damaging blood vessel walls and promoting formation of plaque (atherosclerosis) and inappropriate blood clots (thrombosis). However, a direct link between homocysteine levels and CVD or thrombotic risk has not been proven. For more on this, see the article on Homocysteine.

How is the sample collected for testing?

A blood sample is obtained by inserting a needle into a vein in the arm.

NOTE: If undergoing medical tests makes you or someone you care for anxious, embarrassed, or even difficult to manage, you might consider reading one or more of the following articles: Coping with Test Pain, Discomfort, and Anxiety, Tips on Blood Testing, Tips to Help Children through Their Medical Tests, and Tips to Help the Elderly through Their Medical Tests.

Another article, Follow That Sample, provides a glimpse at the collection and processing of a blood sample and throat culture.

Is any test preparation needed to ensure the quality of the sample?

No test preparation is needed.

The Test

How is it used?

The methylenetetrahydrofolate reductase (MTHFR) mutation test is used to detect two relatively common mutations in the MTHFR gene that are associated with elevated levels of homocysteine in the blood. It is not routinely ordered.

This test is sometimes ordered as a followup to an elevated homocysteine test and may be occasionally ordered along with other cardiac risk tests if a person has a personal or family history of premature cardiovascular disease (CVD) or thrombosis. It may be ordered if a person has a close relative with known MTHFR genetic mutations. MTHFR C677T and A1298C gene mutations are the most common and the ones that are typically tested. If someone has a different mutation in their family, then that specific mutation should be tested.

An MTHFR test may sometimes be ordered along with other inherited clotting risk tests, such as Factor V Leiden or Prothrombin 20210 mutation tests to help evaluate a person's overall risk of developing inappropriate blood clots.

Though the MTHFR test may be used to help determine the cause of elevated homocysteine, the value of measuring homocysteine levels is not clear. While evidence from some studies suggests that elevated homocysteine levels contribute to the risk of CVD and/or thrombosis, a direct link has not been established. Routine testing for homocysteine levels as a cardiac risk marker is not yet recommended. Furthermore, use of homocysteine levels for the purpose of determining risk of CVD, peripheral vascular disease, and stroke is in doubt at this time given that several studies showed no benefit or lowering of risk in people who were treated with folic acid and vitamin B supplements that lowered their homocysteine level.

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When is it ordered?

The MTHFR test may sometimes be ordered when a person has elevated homocysteine levels, especially when they have a personal or family history of premature CVD or thrombosis. It may sometimes be ordered when a close relative has MTHFR gene mutations.

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What does the test result mean?

Only a small percentage of cases of elevated homocysteine are due to an inherited cause. Of these, MTHFR C677T and A1298C mutations are among the most common.

If a person has two copies (homozygous) of MTHFR C677T, or has one copy of C677T and one of A1298C, then it is likely that elevated homocysteine levels are due to these inherited mutations, or that the mutations are contributing to them.

Two copies of A1298C are not typically associated with increased homocysteine levels.

If the MTHFR test is negative, then the C677T and A1298C mutations were not detected and the tested person's elevated homocysteine level is likely due to another cause. Other, more rare MTHFR genetic mutations will not be detected with typical testing.

Those with MTHFR mutations and other clotting risk factors, such as Factor V Leiden or PT 20210 mutations, may be at an increased risk of thrombosis.

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Is there anything else I should know?

People who have elevated homocysteine levels may be at an increased risk of developing premature CVD and/or thrombosis, but many, including those with MTHFR mutations, will never develop CVD or thrombosis. The role of homocysteine in cardiac risk assessment is still in the process of being determined.

Besides MTHFR mutations, there are other causes of elevated homocysteine levels, including deficiency of vitamins B6, B12, and/or folate; these vitamins are required for homocysteine metabolism.

For MTHFR mutations, the C677T variant results in substitution of the amino acid alanine for valine. The A1298C variant results in an alanine substitution (versus a gultamine). The C677T valine substitution results in a less active form of the MTHFR enzyme.

Some studies have shown links between MTHFR genetic mutations and an increased risk of neural tube defects, pre-eclampsia, and certain cancers, but the test is not used clinically with these conditions.

The MTHFR enzyme is involved in folate metabolism. Because of this, those who have MTHFR mutations and take drugs that affect folate metabolism, such as methotrexate, may be more likely to experience toxicity. An MTHFR test may be performed on a person who is prescribed methotrexate in order to adjust dosages and reduce risk of toxicity.

MTHFR mutations are a rare cause of homocystinuria, a condition caused by a defective enzyme that disrupts methionine metabolism, leads to greatly increased amounts of homocysteine in the blood and urine, and causes a variety of complications. The most common cause of this condition is a deficiency in the cystathionine B-synthase (CBS) enzyme. The MTHFR mutations that cause homocystinuria are typically not detected by this test.

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Common Questions

1.  Who performs MTHFR testing?

It is not offered in every laboratory. In most cases, your blood will be sent to a reference laboratory.

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2.  Can my MTHFR genes change?

No, you inherit a copy of the gene from each of your parents and they will not change over time.

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3.  If I have the same MTHFR gene mutations as a relative, why is my homocysteine level significantly different?

Even when two people have the same MTHFR mutations, the results and their risks are often different. Many things can affect homocysteine levels, including MTHFR enzyme activity, folate levels, and a person's health status.

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Article Sources

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NOTE: This article is based on research that utilizes the sources cited here as well as the collective experience of the Lab Tests Online Editorial Review Board. This article is periodically reviewed by the Editorial Board and may be updated as a result of the review. Any new sources cited will be added to the list and distinguished from the original sources used.

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(© 2006-2010). Methylenetetrahydrofolate Reductase (MTHFR) 2 Mutations: 0055655. ARUP's Laboratory Test Directory [On-line information]. Available online at http://www.aruplab.com/guides/ug/tests/0055655.jsp through http://www.aruplab.com. Accessed October 2010.

Varga, E. et. al. (2005 May 17). Homocysteine and MTHFR Mutations, Relation to Thrombosis and Coronary Artery Disease. Circulation. 2005;111:e289-e293 [On-line information]. Available online at http://circ.ahajournals.org/cgi/content/full/111/19/e289 through http://circ.ahajournals.org. Accessed October 2010.

Curtin, K. et. al. (2004 February). MTHFR C677T and A1298C Polymorphisms. Cancer Epidemiology, Biomarkers & Prevention. February 1, 2004 13; 285 [On-line information]. Available online at http://cebp.aacrjournals.org/content/13/2/285.full through http://cebp.aacrjournals.org. Accessed October 2010.

(2005 June 17). MTHFR Gene Variants and Birth Defects. CDC Birth Defects [On-line information] Available online at http://www.cdc.gov/ncbddd/bd/mthfr.htm through http://www.cdc.gov. Accessed October 2010.

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