MTHFR, genetic mutation test

Clinical significance
The cytosine (C) to thymine (T) mutation at position 677 of the MTHFR (methylenetetrahydrofolate reductase) gene reduces the enzyme activity of this protein by 50%. This variant is inherited in an autosomal recessive pattern and raises plasma homocysteine levels, especially after an oral methionine load.
The gene frequency of the mutation in Europe is 3-3.7%, with a prevalence of the homozygous genotype of 8-15% of the population and of the heterozygous genotype of 42-46%.
The vascular damage and risk from hyperhomocysteinaemia (raised plasma homocysteine) are gradual and continuous, so there is no threshold separating risk from no risk. Assuming a linear relationship between homocysteine levels and the risk of thrombosis, it has been calculated that an increase of 5 μmol/l in homocysteine raises the normal risk of peripheral arterial disease 7-fold and the normal risk of venous thrombosis in the limbs 2.6-fold (especially in young people under 40, and in women).
A second change in the MTHFR gene, the replacement of an adenine with a cytosine at position 1298 (A1298C), has also been associated with reduced MTHFR levels. In particular, homozygous carriers retain 60% of enzyme activity.
Compound heterozygotes (carrying both the C677T and A1298C mutations) retain 50-60% of activity.
The relative risk of venous thromboembolism due to reduced MTHFR activity can increase with double heterozygosity, i.e. when the factor V Leiden variant or the G20210A prothrombin variant is also present.
The build-up of homocysteine on the vessel wall as a result of MTHFR mutations is harmful both through a direct action on the endothelium and vessel wall and through an action on clotting factors, lipoproteins and platelets, in the latter case increasing platelet stickiness and aggregation.
However, the C677T and A1298C mutations are a cardiovascular risk factor only in people with low folate status: this underlines the importance, both for prevention and for treatment, of dietary folic acid, whose deficiency is a necessary contributing cause.