The MTHFR gene provides instructions for making an enzyme called methylenetetrahydrofolate reductase. This enzyme plays a role in processing amino acids, the building blocks of proteins. Methylenetetrahydrofolate reductase is important for a chemical reaction involving the vitamin folate (also called vitamin B9).
The MTHFR (methylenetetrahydrofolate reductase) gene produces an enzyme involved in the processing of folate and regulation of homocysteine in the body. Folate is a critical nutrient involved in methylation, DNA synthesis, and amino acid metabolism. Impaired folate metabolism due to MTHFR enzyme inactivity or a low folate level results in elevated plasma homocysteine. Homocysteine is an amino acid synthesized by the body through demethylation of methionine.
In the presence of adequate B-vitamins, homocysteine is either irreversibly degraded to cysteine or it is remethylated back to methionine, an essential amino acid. An elevated homocysteine level is known to be an independent risk factor for ischemic stroke, thrombotic and cardiovascular diseases. Folate, vitamin B6 and vitamin B12 are all necessary molecules for the proper conversion of homocysteine into methionine. A deficiency in any one of these molecules can cause homocysteine levels to rise.
Genetic Markers Included
The two single nucleotide variants known to affect MTHFR function are the C677T (a change from cytosine to thymine at position 677 within the gene) and A1298C (a change from adenine to cytosine at position 1298 within the gene) mutations. It is not uncommon for some individuals to have both MTHFR variants.
Clinical relevance is associated with homozygosity for either C677T or A1298C, and the compound heterozygous state (presence of both heterozygous alleles C677T/ A1298C). In general, these variants produce an MTHFR enzyme with reduced function and activity.
Reduced functionality of MTHFR can cause homocysteine levels to escalate, and this issue is intensified with low levels of folate. Genotyping of the MTHFR gene can inform physicians of a patient’s predispositions for elevated homocysteine. Elevated homocysteine is associated with atherosclerosis and blood clots. With this knowledge, physicians can recommend a proper diet and make medical recommendations to help decrease elevated plasma homocysteine.
- Van der Put NM et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet. 1998; 62(5):1044–51.
- Wagner C. Biochemical role of folate in cellular metabolism. In: Bailey LB, editor. Folate in health and disease. New York, NY: Marcel Dekker Inc.; 1995. p. 23–42.
- Bailey LB and JF Gregory III. Polymorphisms of Methylenetetrahydrofolate Reductase and Other Enzymes: Metabolic Significance, Risks and Impact on Folate Requirement. J Nutr. 1999; 129(5):919-22.
- Stover PJ. Polymorphisms in 1-Carbon Metabolism, Epigenetics and Folate-Related Pathologies. J. Nutrigenet Nutrigenomics. 2012; 4(5):293-305.
- Refsum H et al. The Hordaland Homocysteine Study: A Community-Based Study of Homocysteine, Its Determinants, and Associations with Disease. J Nutr. 2006; 136:1731S-1740S.
- Frosst P et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995; 10:111–113.
- Weisberg I et al. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab. 1998; 64:169–72.
- Teng Z. The 677C>T (rs1801133) polymorphism in the MTHFR gene contributes to colorectal cancer risk: a meta-analysis based on 71 research studies. PLoS One. 2013; 8(2):e55332.
- Yang L, et al. Impact of methylenetetrahydrofolate reductase (MTHFR) polymorphisms on methotrexate-induced toxicities in acute lymphoblastic leukemia: a meta-analysis. Tumor Biol. 2012; 33(5):1445–54.
- Bjelland I et al. Folate, Vitamin B12, Homocysteine, and the MTHFR 677CT Polymorphism in Anxiety and Depression: The Hordaland Homocysteine Study. Arch Gen Psychiatry. 2003; 60(6):618-626.
- Beydoun MA et al. Serum folate, vitamin B-12 and homocysteine and their association with depressive symptoms among US adults. Psychosom Med. 2010; 72(9):862-873.
- Nurk E et al. Plasma Total Homocysteine and Memory in the Elderly: The Hordaland Homocysteine Study. Ann Neurol. 2005; 58:847-857.
- Rajagopalan P et al. Common folate gene variant, MTHFR C677T, is associated with brain structure in two independent cohorts of people with mild cognitive impairment. Neuroimage Clin. 2012; 1(1):179-187. 179-187.
- Cotlarciuc I et al. Effect of genetic variants associated with plasma homocysteine levels on stroke risk. Stroke. 2014; 45(7):1920-4.
- Refsum H et al. The Hordaland Homocysteine Study: A community- based study of homocysteine, its determinants, and associations with disease. The Journal of Nutrition. 2006; 136:1731S-1740S.
- Simpson J et al. Micronutrients and women of reproductive potential: required dietary intake and consequences of dietary deficiency or excess. Part I – Folate, Vitamin B12, Vitamin B6. J Matern Fetal Neonatal Med. 2011; 24(1):1-24.
- NIH: Office of Dietary Supplements. Folate. http://ods.od.nih.gov/factsheets/Folate-HealthProfessional/
- Pietrzrik K. Folic acid and L-5-Methyltetrahydrofolate: Comparison of Clinical Pharmacokinetics and Pharmacodynamics. Cln Pharmacokinet. 2010; 49(8):535-548.
- Jain R et al. Beyond the resistance: how novel neurobiological understandings of depression may lead to advanced treatment strategies. J Clin Psychiatry. 2012; 73(11):e30.
- Soleimani A et al. Comparison of oral folic acid and folinic acid on blood homocysteine level of patients on hemodialysis. Iran J Kidney Dis. 2011: 5(1):45-9.
- Chen Z et al. Purification and Kinetic Mechanism of a Mammalian Methionine Synthase from Pig Liver. J Biol Chem. 1994; 269(44):27193-27197.
- Ho G et al. Methylenetetrahydrofolate Reductase Polymorphisms and Homocysteine-Lowering Effect of Vitamin Therapy in Singaporean Stroke Patients. Stroke. 2006; 37:456-460.
- Chen X et al. Contrasting behaviors of mutant cystathionine beta-synthase enzymes associated with pyridoxine response. Hum Mutat. 2006; 275(5):474-482.
- Dell’Edera D et al. Effect of multivitamins on plasma homocysteine in patients with the 5,10 methylenetetrahydrofolate reductase C677T homozygous state. Molecular Medicine Reports. 2013; 8:609-612.
- Betaine: Drug Information. http://www.uptodate.com/contents/betaine-drug-information?source=search_result&search=betaine&selectedTitle=1~9
- Lawson-Yuen A eta l. The use of betaine in treatment of elevated homocysteine. Mol Genet Metab. 2006; 88(3):201-207.
- Hultberg B et al. Plasma homocysteine and thiol compound fractions after oral administration of N-acetylcysteine. Scand J Clin Lab Invest. 1994; 54:417–422.
There are no reviews yet.