MTHFR Genotyping

The MTHFR genotyping test offered by Spectracell Laboratories plays a crucial role in functional medicine by analyzing variations in the MTHFR gene, which encodes for the enzyme methylenetetrahydrofolate reductase (MTHFR). 

Certain genetic variations, particularly in the C677T and A1298C polymorphisms, can affect the MTHFR enzyme's activity.  This leads to altered folate metabolism which can potentially impact various physiological processes.  

Because methylation occurs in almost every cell in the body, alterations in MTHFR functioning may have profound implications in human health. Understanding an individual's MTHFR genotype is essential for personalized healthcare, as it can inform treatment strategies and interventions tailored to mitigate the associated risks. 

Scientific studies have linked MTHFR polymorphisms to a range of health conditions, including cardiovascular diseases, neural tube defects, psychiatric disorders, and pregnancy complications.  [1., 5., 9., 10.] 

MTHFR genotyping offers valuable insights into an individual's genetic predispositions and enables targeted approaches to optimize health and prevent disease.

Why is Understanding MTHFR Genotyping Important?

MTHFR, or methylenetetrahydrofolate reductase, is an enzyme responsible for catalyzing the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the primary circulatory form of folate which is utilized in homocysteine remethylation to methionine.  

It is an essential part in homocysteine metabolism; elevated homocysteine levels are linked with an increased risk of cardiovascular disease, stroke, and thrombosis, although the mechanism is not yet fully understood.  [8.]

By identifying MTHFR mutations through genotyping, healthcare providers can devise personalized strategies, such as dietary modifications and vitamin supplementation, to address elevated homocysteine levels and mitigate associated health risks.

What Can MTHFR Genotyping Show?

Individuals can have different genotypes for the MTHFR gene, including heterozygous and homozygous statuses. Heterozygous status means that a person carries one copy of a variant allele, while homozygous status means they carry two copies.  

Heterozygosity of the most commonly known variant, C677T, confers about 65% of the enzyme’s normal function, while homozygosity of the C677T variant confers about 30% of the enzyme’s normal function.  [4.]  Another common variant,  A1298C, is also linked to reduced MTHFR enzyme activity and altered folate metabolism, potentially increasing the risk of various health conditions.  

What are the Practical Applications for MTHFR Genotyping?

MTHFR genotyping offers various practical applications in clinical settings. Understanding an individual's MTHFR genotype can help personalize treatment strategies, especially in conditions influenced by folate metabolism, such as cardiovascular diseases, neural tube defects, psychiatric disorders, and pregnancy complications. [1., 5., 9.]  

For example, individuals with specific MTHFR variants may benefit from supplementation with methylfolate rather than folic acid, as methylfolate bypasses the MTHFR enzyme pathway.  Ensuring adequate B12 vitamin status, and appropriate supplementation with methylcobalamin, as well as adequate vitamin B6 status may be appropriate. [7.]  

Individuals who are heterozygous or homozygous for the major MTHFR variants C677T and A1298C should also practice appropriate lifestyle measures to reduce inflammation, promote cardiovascular health, and ensure optimal nutrient status.   

Moreover, MTHFR genotyping can guide medication dosing, particularly for drugs like methotrexate, where MTHFR variants affect drug metabolism and toxicity.  [2.]  Additionally, MTHFR genotyping may inform dietary recommendations, lifestyle modifications, and preventive measures tailored to an individual's genetic profile, promoting personalized and precision medicine approaches.

Who Could Benefit from MTHFR Genotyping?

Individuals with a Family History of Cardiovascular Diseases (CVD): MTHFR polymorphisms have been associated with an increased risk of CVD, including coronary artery disease and venous thrombosis.  [4., 9.]   Genotyping can help identify individuals who may benefit from preventive measures such as lifestyle modifications, dietary changes, and personalized medication strategies.

Pregnant Women: MTHFR variants have been linked to pregnancy complications, including recurrent miscarriages, preeclampsia, and neural tube defects.  [5., 9.] Genotyping can aid in identifying high-risk pregnancies and implementing appropriate interventions, such as supplementation with methylfolate and other prenatal vitamins.  [7.]

Individuals with a History of Depression or Psychiatric Disorders: MTHFR gene polymorphisms have been associated with an increased susceptibility to depression, bipolar disorder, and schizophrenia.  [6., 10.]  Genotyping can help tailor treatment approaches, including the use of methylfolate supplementation as an adjunctive therapy alongside conventional psychiatric medications.

Patients with Chronic Diseases Requiring Methotrexate Therapy: Methotrexate is commonly used to treat conditions such as rheumatoid arthritis, psoriasis, and certain cancers. MTHFR variants influence methotrexate metabolism and may affect treatment response and toxicity.  [2.] Genotyping can guide medication dosing and reduce the risk of adverse effects.

Couples Planning to Conceive: MTHFR polymorphisms can impact fertility and increase the risk of recurrent miscarriages and fetal abnormalities.  [1., 7.]  Genotyping both partners can identify potential genetic risks and inform preconception counseling, allowing for proactive measures to optimize pregnancy outcomes.

Individuals Wanting to Optimize their Health and Wellness: MTHFR genotyping offers valuable insights for individuals seeking to optimize their health and wellness by providing information on genetic variations that impact folate metabolism. Understanding one's MTHFR status can guide personalized strategies such as tailored supplementation with methylfolate and other nutrients, optimizing methylation processes, and potentially reducing the risk of associated health conditions.

References:

[1] Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995 May;10(1):111-3. doi: 10.1038/ng0595-111. PMID: 7647779.

[2.] Kurzawski M, Pawlik A, Safranow K, Herczynska M, Drozdzik M. 677C>T and 1298A>C MTHFR polymorphisms affect methotrexate treatment outcome in rheumatoid arthritis. Pharmacogenomics. 2007;8(11):1551-1559. doi:https://doi.org/10.2217/14622416.8.11.1551

[3.] Leclerc D, Sibani S, Rozen R. Molecular Biology of Methylenetetrahydrofolate Reductase (MTHFR) and Overview of Mutations/Polymorphisms. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013. Available from: https://www.ncbi.nlm.nih.gov/books/NBK6561/

[4.] Moll S, Varga EA. Homocysteine and MTHFR Mutations. Circulation. 2015;132(1). doi:https://doi.org/10.1161/circulationaha.114.013311 

[5.] Nazki FH, Sameer AS, Ganaie BA. Folate: metabolism, genes, polymorphisms and the associated diseases. Gene. 2014 Jan 1;533(1):11-20. doi: 10.1016/j.gene.2013.09.063. Epub 2013 Oct 1. PMID: 24091066.

[6.] Peerbooms OL, van Os J, Drukker M, Kenis G, Hoogveld L; MTHFR in Psychiatry Group; de Hert M, Delespaul P, van Winkel R, Rutten BP. Meta-analysis of MTHFR gene variants in schizophrenia, bipolar disorder and unipolar depressive disorder: evidence for a common genetic vulnerability? Brain Behav Immun. 2011 Nov;25(8):1530-43. doi: 10.1016/j.bbi.2010.12.006. Epub 2010 Dec 24. PMID: 21185933.

[7.] Serapinas D, Boreikaite E, Bartkeviciute A, Bandzeviciene R, Silkunas M, Bartkeviciene D. The importance of folate, vitamins B6 and B12 for the lowering of homocysteine concentrations for patients with recurrent pregnancy loss and MTHFR mutations. Reprod Toxicol. 2017 Sep;72:159-163. doi: 10.1016/j.reprotox.2017.07.001. Epub 2017 Jul 6. PMID: 28689805.

[8.] Son P, Lewis L. Hyperhomocysteinemia. [Updated 2022 May 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554408/

[9.] van der Put NM, Gabreëls F, Stevens EM, Smeitink JA, Trijbels FJ, Eskes TK, van den Heuvel LP, Blom HJ. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet. 1998 May;62(5):1044-51. doi: 10.1086/301825. PMID: 9545395; PMCID: PMC1377082.

[10.] Zhang YX, Yang LP, Gai C, Cheng CC, Guo ZY, Sun HM, Hu D. Association between variants of MTHFR genes and psychiatric disorders: A meta-analysis. Front Psychiatry. 2022 Aug 18;13:976428. doi: 10.3389/fpsyt.2022.976428. PMID: 36061291; PMCID: PMC9433753.