Methylenetetrahydrofolate Reductase (MTHFR)

Methylenetetrahydrofolate Reductase (MTHFR)

Methylenetetrahydrofolate Reductase (MTHFR)

Methylenetetrahydrofolate Reductase (MTHFR) polymorphism is the most common genetic cause of elevated levels of homocysteine in the plasma (hyperhomocysteinemia). Hyperhomocysteinemia (too much homocysteine in the blood) is associated with numerous health problems which will be discussed here. The MTHFR enzyme plays an important role in processing amino acids, specifically, the conversion of homocysteine to methionine. Genetic variations in the MTHFR gene can lead to impaired function or inactivation of this enzyme, which results in elevated levels of homocysteine, especially in individuals who are also deficient in the active form of folate and other key nutrients (more about that later).

How common is the MTHFR Polymorphism?

A common genetic variant in the MTHFR gene is a 677C>T polymorphism (NM_005957.4:c.665C>T, rs1801133). This variant encodes a thermolabile enzyme that is less active at higher temperatures. Individuals who carry two copies of this variant (“TT homozygous”) tend to have higher homocysteine levels and lower serum folate levels compared to controls. More than 25% of Hispanics and around 10-15% of North America Caucasians are estimated to be homozygous for the “thermolabile” variant (TT genotype).

The TT genotype is least common in individuals of African descent (6%). Another common MTHFR variant, 1298A>C (NM_005957.4:c.1286A>C, rs1801131), does not cause increased homocysteine levels in heterozygous or homozygous individuals, but combined heterozygosity of 1298A>C and 677C>T results in an outcome similar to TT homozygous individuals. In other words, this MTHFR genetic problem is pretty common.

Diagnosis of the MTHFR Polymorphism

A blood test that measures total homocysteine levels can diagnose hyperhomocysteinemia. This should be the first test undertaken by pretty much everyone, just to screen for potential health problems that may arise as a result of high homocysteine. Genetic testing of the MTHFR gene may be used to confirm the diagnosis of an inherited hyperhomocysteinemia caused by MTHFR deficiency.


Diseases associated with the MTHFR Gene

1.      Brain cancer

A recent Meta-analysis found a significant association of MTHFR A1298C (rs1801131) variant genotypes with increased incidence of meningioma and glioma in this study population (CA vs. AA: OR=1.22, P<0.001; CA+CC vs. AA: OR=1.18, P=0.002). Moreover, they found that MTRR A66G (rs1801394) variant genotypes was associated with increased risk of meningioma and glioma (G vs. A: OR=1.11, P=0.020; GG vs. AA+AG: OR=1.17, P=0.043; GG vs. AA: OR=1.22, P=0.023). In conclusion, the meta-analysis suggests that two folate metabolism genetic variants MTRR A66G (rs1801394) and MTHFR A1298C (rs1801131) contribute to genetic susceptibility to meningioma and glioma in adults. And, while all brain cancers are bad, these two are particularly nasty with high mortality rates respectively.

2.      Recurrent pregnancy loss and MTHFR mutations

In patients with MTHFR mutations and hyperhomocysteinemia, recurrent pregnancy loss is a frequent feature. The aim of one study was to evaluate the impact of methylfolate (the active form of folic acid), vitamins B6 and B12 supplementation for the lowering of total homocysteine concentrations and pregnancy. 16 patients who had had 3 or more miscarriages and MTHFR mutations were used in the study. They received methylfolate (5mg/day), vitamin B6 (50mg/day) and vitamin B12 (1mg/week). Supplementation induced a decrease in homocysteine from 19.4±5.3μmol/L to a healthy 6.9±2.2μmol/L after folate supplementation (p<0.05). During one year 7 women became pregnant and delivered. Two women delivered from the homozygous C677T mutations group (7 patients) and combined heterozygous C677T/A1298C mutations group (5 patients), while 3 deliveries were in A1298C homozygous mutations group (4 patients). In conclusion, methylfolate, vitamins B6 and B12 supplementation in woman with MTHFR mutations has a beneficial effect on pregnancy outcome. This study just outlines the importance of homocysteine levels on all women of child bearing age and gene testing if homocysteine levels are elevated.

3.      Colorectal cancer

A case-control study was used to assess the relationship between the tagging polymorphisms in methylenetetrahydrofolate reductase (MTHFR) gene and the susceptibility to colorectal cancer (CRC) in a Chinese Han population.

The results revealed that MTHFR rs1801133 G>A polymorphism was associated with a decreased risk of overall CRC. While MTHFR rs4845882 G>A polymorphism conferred an increased risk to overall CRC. In a stratified analysis by CRC region, it was found MTHFR rs3753584 T>C and rs9651118 T>C polymorphisms were associated with the increased risk of colon cancer. In addition, a significantly increased risk of rectum cancer associated with MTHFR rs3753584 T>C polymorphism was overt. However, MTHFR rs1801133 G>A polymorphism conferred a decreased risk to colon cancer.

In conclusion, findings of the present study reveal that the tagging polymorphisms in MTHFR gene (rs3753584 T>C, rs9651118 T>C and rs4845882 G>A) are associated with the increased risk of CRC. However, MTHFR rs1801133 G>A polymorphism confers a decreased risk to CRC. Keep in mind, bowel cancer is a hugely common cancer responsible for thousands of deaths each year.


Figure 1. The biochemistry of Homocysteine and MTHFR (in light blue).

4.      Ischemic stroke

Ischemic stroke is a condition characterized by reduced blood supply to part of the brain, initiating the ischemic cascade, leading to dysfunction of the brain tissue in that area. It is one of the leading causes of death and disability and is estimated to cause around 5.7 million deaths worldwide.

MTFHR C677T is a common mutation of MTHFR and those homozygous for the MTFHR C677T produce a thermo-labile form of the protein with drastically reduced catalytic activity resulting in elevated plasma homocystiene levels - a common risk factor for cardiovascular diseases. To evaluate this association, a large meta-analysis was undertaken of existing published studies, which included 72 studies involving 12390 cases and 16274 controls. The forest plot was made to evaluate the overall risk of the mutation in the etiology of Ischemic Stroke.

The overall Odds- ratio of the study revealed a ∼32% increased risk of Ischemic stroke in the presence of MTHFR C667T mutation compared to controls. This is a horrifying statistic as stokes devastate millions of people lives, killing most and causing devastating, long lasting disability in many millions of others.

5.      Subclinical Hypothyroidism

The aim of one recent study was to investigate the link between the MTHFR gene C677T polymorphism and patients with Subclinical Hypothyroidism (SCH). In this study 19 adult patients with subclinical hypothyroidism and 19 healthy controls (mean age 31±5.5 and 33±5.1 years respectively) were recruited. All patients were diagnosed based on serum levels of TSH, FT4, anti-TG and anti-TPO antibodies.

This study indicated that the MTHFR C677T variant may contribute in alteration of epigenetic regulation such as DNA methylation mediated by DNA methyltransferases in patients with subclinical hypothyroidism and also, carriers of the T allele might have an increasing risk of developing SCH.

What this means clinically is that when someone’s thyroid levels are low, it could be due to a number of factors. One factor could be the MTHFR C677T variant yet, this is rarely tested for by the prescribing doctor. Often, the patient is correctly prescribed thyroxine to boost thyroid levels. While this technically the right thing to do, the cause of why the individual has low thyroid levels are rarely investigated. Considering lower thyroid levels are often found in young women, it may be prudent to also screen for homocysteine. If homocysteine is found to be elevated, the treatment may turn out to be not thyroxin but B vitamins.

 6.      Breast cancer risk

The association between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and breast cancer risk has been extensively explored. The precise effects of MTHFR polymorphisms on the risk of breast cancer, a systemic review and most comprehensive meta-analysis of all available studies relating MTHFR rs1801133 gene polymorphism to the risk of breast cancer was conducted.

The results reviewed a total of 83 studies with 35,029 cases and 38,990 controls. Overall, MTHFR rs1801133 gene polymorphism was proved to contribute to the risk of breast cancer under all genetic models (TT vs. CC: Pheterogeneity Basically, the results of this huge meta-analysis found that MTHFR rs1801133 gene polymorphism may associated with breast cancer.

The implications of this are huge. Breast cancer strikes the fear into the hearts of women everywhere.

7.      Alzheimer’s disease

The association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and susceptibility to Alzheimer’s disease (AD) was examined in previous studies. A recent, huge meta-analysis was designed to investigate the association of MTHFR C677T polymorphism with AD. Nine studies were identified by search of PubMed, Google Scholar, Elsevier, Springer Link databases, up to January 2013.

All of these studies combined found that MTHFR C677T polymorphism had a significant association with susceptibility to AD in all genetic models (for T vs C: OR 1.29, 95 % CI 1.15-1.44, p < 0.0001; for TT + CT vs CC: OR 1.38, 95 % CI 1.16-1.364, p = 0.0002; for TT vs CC: OR 1.60, 95 % CI 1.25-2.04, p = 0.0001; for CT vs CC: OR 1.28, 95 % CI 1.1-1.53, p < 0.008; for TT vs CT + CC: OR 1.37, 95 % CI 1.12-1.67, p = 0.002).

Results from this meta-analysis supported that the MTHFR C677T polymorphism was associated with an increased risk of AD.

In one way, this is good news. Sure, this means that you can find out that you are genetically predisposed to one of the most devastating diseases going around however; unlike other genetic diseases, you can relatively easily do something about this problem gene by taking inexpensive supplements.


8.      Heart Failure

Hyperhomocysteinemia was found to be uniformly associated with the development of heart failure (HF) and HF mortality; however, it is uncertain whether this relation is causative or not. We used Mendelian randomization to examine the associations of the methylene tetrahydrofolate gene (MTHFR) and paraoxonase 1 gene (PON1) variants as a proxy for lifelong exposure to high Hcy and Hcy-thiolactone concentrations with the development of HF in men aged ≤60years and the occurrence of adverse effects at one-year follow-up.

A recent study enrolled 172 men with HF: 117 with ischemic etiology (iHF) related to coronary artery disease (CAD) and 55 with non-ischemic etiology (niHF) related to dilated cardiomyopathy (DCM). The reference group of 329 CAD patients without HF and the control group of 384 men were also analyzed.

The study found that Hyperhomocysteinemia (OR=2.0, P<0.05) and the MTHFR 677TT/1298AA, 677CC/1298CC genotypes (OR=1.6, P=0.03) were associated with HF regardless of its etiology, especially among normotensives (OR=4.6, P=0.001 and OR=2.3, P=0.003, respectively).

Usually, heart failure is associated with years of high blood pressure. This study found that high homocysteine is associated with heart failure, even if your blood pressure is normal (normotensives). What this means again is a simple blood test can help to prevent yet another huge killer, even though you have normal blood pressure.

Figure 2. The MTHFR gene and the production of neurotransmitters may indicate this gene is involved in mental health.

Mental Health and MTHFR

9.      Schizophrenia

As discussed, C677T polymorphism of MTHFR gene was reported as risk factor for congenital defects, metabolic and neuropsychiatric disorders. A recent meta-analysis of all available case-control studies was performed on investigating the link between the MTHFR gene and schizophrenia. PubMed, Google Scholar, Springer Link and Elsevier databases were searched for eligible case-control studies. Total 38 studies with 10,069 cases and 13,372 controls were included in the present meta-analysis.

Results of meta-analysis showed significant associated between C677T polymorphism and risk of schizophrenia (ORTvsC=1.18, 95%CI=1.10-1.27, p=<0.001; ORCTvsCC=1.10, 95%CI=1.04-1.17, p=<0.001; ORTTvsCC=1.40, 95%CI=1.20-1.64, p=<0.001; ORTT+CTvsCC=1.19, 95%CI=1.09-1.30, p=<0.001). We also performed subgroup and sensitivity analyses. Subgroup analysis was done according to ethnicity and significant association was found between C677T polymorphism and risk of schizophrenia in all three ethnic populations-African (OR=2.51; 95%CI=1.86-3.40; p=<0.001), Asian (OR=1.21; 95%CI=1.10-1.33; p=<0.001) and Caucasian (OR=1.07; 95%CI=1.01-1.14; p=0.01).

In conclusion, the results of the present meta-analysis suggested that the MTHFR C677T polymorphism is a risk factor for schizophrenia.

This is a scary finding because if this gene was causing schizophrenia, this would vastly alter the treatment for these individuals and of course improve their outcomes.

10.   Autism

Autism is a heterogeneous neurodevelopmental disease that manifests within the first 3 years of life. Numerous articles reported that dysfunctional folate-methionine pathway enzymes may play an important role in the pathophysiology of autism. Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme of this pathway and MTHFR C677T polymorphism reported as risk factor for autism in several case control studies.

A present, recent meta-analysis was designed to investigate the relationship of the MTHFR C677T polymorphism with the risk of autism. Electronic databases were searched for case control studies with following search terms - 'MTHFR', 'C677T', in combination with 'Autism'. Pooled OR with its corresponding 95 % CI was calculated and used as association measure to investigate the association between MTHFR C677T polymorphism and risk of autism.

Total of thirteen studies were found suitable for the inclusion in the present meta-analysis, which comprises 1978 cases and 7257 controls. In total 13 studies, 9 studies were from Caucasian population and 4 studies were from Asian population.

The association between C677T polymorphism and autism was significant in Caucasian (ORTvs.C = 1.43; 95 % CI = 1.1-1.87; p = 0.009) and Asian population (ORTvs.C = 1.68; 95 % CI = 1.02-2.77; p = 0.04) using allele contrast model. In conclusion, present meta-analysis study strongly suggested a significant association of the MTHFR C677T polymorphism with autism.

This is another piece in the Autism puzzle. These kids suffering autism may have this MTHFR problem and testing for it, may reveal one of the underlying problems that drives the disease. Given these results, it would stongly suggest that autistic kids be tested for the MTHFR Polymorphism.

So, what do the Australian medical authorities say about testing for the MTHFR gene?

Disturbingly, Australian authorities down play the importance of the MTHFR testing. In a recent Australian study, the author concluded that based on the available scientific evidence, we propose that there are very limited clinical indications for testing for the 677C>T and the 1298A>C polymorphisms in the MTHFR gene, and that testing is not indicated as a non-specific screening test in the asymptomatic general population.

What should you do if you are interested in checking your genes?

First of all, schedule an appointment with your doctor. Your first point of call is to get a baseline test of your homocysteine level; And while your GP may be reluctant to order an expensive MTHFR test, a homocysteine test if a low-cost routine that is covered by Medicare. While you are at it, consider testing other asking for other routine tests (e.g. hormones, cholesterol etc). Be aware that you need to test for homocysteine while you are fasting.

What if your homocysteine is high?

Firstly, if your homo-cysteine is low, well done. Keep doing what you are doing. However; if your result comes back high (say above 10 micromoles per litre (mcmol/L).) then you need to act. Don’t wait to get one of the before mentioned diseases, then do the test. We are all about prevention here.


The first thing you need to start with is a diet high in fruits, vegetables, salads, fruits, nuts and seeds. Eat other healthy foods like cold water fish and grass feed meet, eggs and chicken. Exercise regularly and achieve a healthy weight. OK, this is standard stuff so let’s get down to what supplements help with high homo-cysteine.


Find a supplement based on whole foods. This is by far the best course of action. If this is impossible, the second best option is to supplement with methylfolate, methylcobalamin, riboflavone and pyridoxyl-5-phosphate. Remember, these supplements are a second best option. Avoid taking methionine and cysteine! These common supplements are found in a lot of supplements and it boosts homocysteine levels. These are the first things that needs to be eliminated.


Figure 3. If you are positive for the MTHFR gene, you folic acid may be doing nothing for you.

Further testing

Assuming your homocysteine is high, ask your doctor to test for the MTHFR polymorphism genes. Remember, this may be met with some resistance from your doctor and if this is the case, you can offer to pay for the test if you are in a position to do so. If not, the treatment is still the same. Taking the supplements, eating right an exercising (i.e. the treatment) would still be the same. After treating yourself this way for a few months, ask for your homocysteine to be rechecked and monitor how you are progressing.

Take home message

I think the science is overwhelming now. High homocysteine/MTHFR levels are a problem. It was once thought as in innocent bystander but the huge amount of data all point to homocysteine and the MTHFR Polymorphism being associated with a number of diseases. And, while association does always mean causation, the evidence that homocysteine is implicated in disease is a real threat.

The great news is that even if your levels are high, supplementing with a whole food supplement or specific activated B vitamins is a relatively simple and cost-effective answer to reduce this potentially very dangerous chemical.



Dean L. Methylenetetrahydrofolate Reductase Deficiency. 2012 Mar 8 . In: Pratt V, McLeod H, Dean L, et al., editors. Medical Genetics Summaries . Bethesda (MD): National Center for Biotechnology Information (US); 2012

Dean L. Methylenetetrahydrofolate Reductase Deficiency. 2012 Mar 8 . In: Pratt V, McLeod H, Dean L, et al., editors. Medical Genetics Summaries . Bethesda (MD): National Center for Biotechnology Information (US); 2012

Dean L. Methylenetetrahydrofolate Reductase Deficiency. 2012 Mar 8 . In: Pratt V, McLeod H, Dean L, et al., editors. Medical Genetics Summaries . Bethesda (MD): National Center for Biotechnology Information (US); 2012

Oncotarget. 2017 Jul 4. Folate metabolism genetic polymorphisms and meningioma and glioma susceptibility in adults. Chen D1, Dong J1, Huang Y2, Gao F1, Yang X1, Gong X1, Lv X3, Chu C4, Wu Y1, Zheng Y5.

Reprod Toxicol. 2017 Jul 6. The importance of folate, vitamins B6 and B12 for the lowering of homocysteine concentrations for patients with recurrent pregnancy loss and MTHFR mutations. Serapinas D1, Boreikaite E2, Bartkeviciute A2, Bandzeviciene R3, Silkunas M2, Bartkeviciene D2.

Oncotarget. 2017 Jun 29. Investigation of methylenetetrahydrofolate reductase tagging polymorphisms with colorectal cancer in Chinese Han population. Zhang S1, Chen S2, Chen Y3,4, Kang M2, Liu C5, Qiu H6, Wang Y7, Tang W2,5.

Bioinformation. 2017 Jun 30;13(6):214-219. Meta-analysis study to evaluate the association of MTHFR C677T polymorphism with risk of ischemic stroke. Abhinand PA1, Manikandan M1, Mahalakshmi R1, Ragunath PK1.

Georgian Med News. 2017 Apr;(265):19-24. MTHFR GENE C677T POLYMORPHISM AND LEVELS OF DNA METHYLTRASFERASES IN SUBCLINICAL HYPOTHYROIDISM. Kvaratskhelia T1, Kvaratskhelia E1, Kankava K1, Abzianidze E1.

Minerva Medica 2017 February;108(1):57-73 Cumulative review and meta-analyses on the association between MTHFR rs1801133 polymorphism and breast cancer risk: a pooled analysis of 83 studies with 74,019 participants. Yun ZHANG 1, Hongjun JIA 2, Shoufeng WANG 1, Dazhi JIANG 3

Indian J Clin Biochem. 2016 Jul;31(3):245-52. Folate Pathway Gene Methylenetetrahydrofolate Reductase C677T Polymorphism and Alzheimer Disease Risk in Asian Population. Rai V.

Int J Cardiol. 2017 Feb 1;228:37-44. Is hyperhomocysteinemia a causal factor for heart failure? The impact of the functional variants of MTHFR and PON1 on ischemic and non-ischemic etiology. Strauss E1, Supinski W2, Radziemski A3, Oszkinis G4, Pawlak AL5, Gluszek J6.

Asian J Psychiatr. 2016 Apr;20:41-51. Role of MTHFR C677T gene polymorphism in the susceptibility of schizophrenia: An updated meta-analysis. Yadav U1, Kumar P1, Gupta S2, Rai V3.

Metab Brain Dis. 2016 Aug;31(4):727-35. Association of methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism with autism: evidence of genetic susceptibility. Rai V1.

Aust Fam Physician. 2016 Apr;45(4):237-40. MTHFR genetic testing: Controversy and clinical implications. Long S, Goldblatt J.