By Kathy O’Brien, MS, CGC and Michelle Hoard, MS, CGC

Better Health

M-T-H-F-R, 5 letters that often cause confusion among many healthcare professionals that stems from a large amount of conflicting information in the literature, as well as misinformation from the internet.

Patients requesting MTHFR testing often do so after hearing that a family member tested “positive,” or after reading internet claims. MTHFR has been blamed for a laundry list of ailments including cardiovascular disease, thrombosis, pregnancy loss, open neural tube defects, depression, and other psychiatric illnesses, cognitive problems, migraines, cancer, and hundreds of other things. But do any of these associations have merit? What do you do when your patient comes into your office requesting this test?  What if your patient has already had testing elsewhere and is coming to you for next steps?

Let’s start by taking a closer look at MTHFR, which is the gene that codes for the enzyme methylenetetrahydrofolate reductase. This enzyme plays a role in folate metabolism and reduced enzyme activity of MTHFR is a genetic risk factor for hyperhomocysteinemia. Two common variants in the MTHFR gene are C677T, also known as the “thermolabile” variant, and the other is A1286C. Both variants are missense changes and lead to reduced enzyme activity.

Both variants occur frequently in the general population. In fact, estimates show that 60%-70% of the population have at least one MTHFR variant. It is important to note that about 25% of people of Hispanic descent, 10%-15% of people of European descent, and 6% of people of African descent are homozygous for the C677T variant (1). People with two copies of C677T may have mild or moderately elevated homocysteine levels and lower serum folate levels, while A1286C may be milder. But what about all of the other “risks” brought up in the literature?

Does MTHFR impact cardiovascular disease/thrombosis?

Reduced MTHFR enzyme and the possible association with thrombosis and cardiovascular disease gained notoriety in the past.  However, numerous well-conducted studies have failed to confirm these initial associations. Thus, testing for MTHFR is not recommended by numerous professional societies including the American College of Medical Genetics (ACMG), the American College of Obstetricians and Gynecologists (ACOG), and the American Heart Association for either of these conditions (2, 3, 4).  If MTHFR genetic testing has already been conducted, and if the patient is found to have two C677T variants, ACMG suggests evaluation of plasma homocysteine.  If the homocysteine is normal, the patient can be reassured there is no increased risk for thrombosis based on their MTHFR result (2). If the homocysteine is elevated, the patient may have a mildly increased risk for venous thrombosis but an increased risk for cardiovascular disease is still not a concern.

What about MTHFR and pregnancy?

An association between MTHFR and an increased risk for recurrent pregnancy loss and stillbirth had previously been suggested, but the best available information from well-controlled studies does not support these associations.  Both ACOG and ACMG do not recommend testing for MTHFR for these indications.  Additionally, in their 2018 Practice bulletin, ACOG concluded that there is no association between MTHFR mutations and fetal growth restriction (3, 2).

Two copies of the C677T variant may increase the risk for open neural tube defects such as spina bifida; however, this risk can be counteracted by folic acid supplementation during pregnancy and the fortification of grain products in the United States. This recommendation applies to all women of childbearing age, regardless of their MTHFR genotype (3). For pregnant women concerned about open neural tube defects there are reliable screening and diagnostic tests including measurement of serum or amniotic fluid AFP and ultrasound.

Does MTHFR impact drug toxicity?

Given that MTHFR is involved in folate metabolism, variants may contribute to toxicity of some drugs like methotrexate.  Several studies have shown that individuals with two C677T variants are at increased risk for methotrexate toxicity, including hepatic and gastrointestinal toxicity, neurotoxicity, and hematologic toxicity (5,6). However other studies which included children taking methotrexate for acute lymphoblastic leukemia did not replicate this association (7).

MTHFR and Wellness

While there is no shortage of reports in the literature suggesting possible links between MTHFR and cognitive issues, mental illness, or even cancer, there is currently no widely accepted conclusive evidence showing MTHFR increases these risks.  Further studies in this area may provide additional insight, however, testing is not currently standard of care (8).

The C667T and A1298C variants in the MTHFR gene have a complicated history regarding their role in disease which is still the subject of study in many clinical areas. One thing that these two variants can be associated with is mild to moderate hyperhomocysteinemia which may present some increased risk for things like thrombosis.  Further studies will hopefully provide further insight surrounding additional concerns. (2)

If you still have questions about how this test may apply to your patients, the genetic counselors at Quest Diagnostics are available to help you navigate this difficult topic.  Visit our website or call Quest Genomics Client Services at 1.866.GENE.INFO (1.866.436.3463) with your questions about testing.

(1) Wilcken B, Bamforth F, Li Z, et al. Geographical and ethnic variation of the 677C>T allele of 5,10 methylenetetrahydrofolate reductase (MTHFR): findings from over 7000 newborns from 16 areas world wide [published correction appears in J Med Genet. 2004 May;41(5):400. Redlund, M [corrected to Renlund, M]]. J Med Genet. 2003;40(8):619-625. doi:10.1136/jmg.40.8.619
(2) Hickey, S., Curry, C. & Toriello, H. ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genet Med 15, 153–156 (2013).
(3) ACOG Practice Bulletin No 197, Inherited Thrombophilias in Pregnancy, Obstetrics & Gynecology, V132, No1, July 2018
(4) Moll, et al, Homocysteine and MTHFR mutations, Circulation, July 2015, 132
(5)Eissa DS, Ahmed TM. C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase gene: effect on methotrexate-related toxicity in adult acute lymphoblastic leukaemia. Blood Coagul Fibrinolysis. 2013 Mar;24(2):181-8. doi: 10.1097/MBC.0b013e32835b249d.
(6) Lin, et al, Impact of methylenetetrahydrofolate reductase (MTHFR) polymorphisms on methotrexate-inducted toxicities in acute lymphoblastic leukemia:  a meta-analysis, Tumour biology:  the journal of the International Society for Oncodevelopmental Biology and Medicine , 2012 Oct; 33(5): 1445-54
(7) Lopez-Lopez E, Martin-Guerrero I, Ballesteros J, Garcia-Orad A. A systematic review and meta-analysis of MTHFR polymorphisms in methotrexate toxicity prediction in pediatric acute lymphoblastic leukemia. Pharmacogenomics J. 2013 Dec;13(6):498-506. doi: 10.1038/tpj.2012.44. Epub 2012 Oct 23. PMID: 23089671.
(8)Levin BL, Varga E. MTHFR: Addressing Genetic Counseling Dilemmas Using Evidence-Based Literature. J Genet Couns. 2016 Oct;25(5):901-11. doi: 10.1007/s10897-016-9956-7. Epub 2016 Apr 30.