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
A blood sample taken from a vein in your arm
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%of the British population is homozygous for C677T. The prevalence is higher in those of Mediterranean and lower in those of African or Indian Asian descent.
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 build-up 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. The rise in homocysteine within the bloodstream 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.
Is any test preparation needed to ensure the quality of the sample?
No test preparation is needed.
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 performed within the UK.
This test is sometimes requested as a follow up to an elevated homocysteine test and may be occasionally requested 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 requested 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 requested 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.
When is it requested?
What does the test result mean?
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, rarer MTHFR genetic mutations will not be detected with typical testing.
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 glutamine). 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.
Who performs MTHFR testing?
Can my MTHFR genes change?
If I have the same MTHFR gene mutations as a relative, why is my homocysteine level significantly different?
On This Site
Tests: Homocysteine, Factor V Leiden Mutation and PT 20210 Mutation,Vitamin B12 & Folate, Cardiac Risk Assessment, Methotrexate
Conditions: Heart Disease, Cardiovascular Disease, Hypercoagulable Disorders, Neural Tube Defects, Stroke
Elsewhere On The Web
Genetics Home Reference: MTHFR
NIH, Genetic and Rare Diseases Information Center: Homocysteinemia due to MTHFR deficiency
American Heart Association: Homocysteine, Folic Acid and Cardiovascular Disease
British Medical Journal article on role of C677T on coronary artery disease (2005)