MTHFR C677T: Benefits of this mutation

Much has been written about the MTHFR C677T variant, with websites and facebook groups named after it and proclaiming doom for all who have it.  This was actually one of the first variants that I had heard about and was one of the reasons that I got the 23andMe testing in the first place.

For a genetic variant to be so prevalent in the population, there are usually positive benefits that weigh against the negatives.  So instead of focusing on the negatives here, I’m going to look at some of the positive research study results for those with this variant.  Yep – I probably have an optimistic, glass-half-full gene!

A little background on MTHFR….
MTHFR stands for methylenetetrahydrofolate reductase.  This gene that codes for the MTHFR enzyme that converts 5,10 methylenetetrahydrofolate to 5-methyltetrahydrofolate.  It is a rate-limiting step in the methylation cycle, and basically a step in the breakdown of folate into the products that your body needs for quite a few cellular functions.

The MTHFR C677T variant is one that has been studied extensively. C is the wildtype or normal allele, and T is the variant. Those who are C/T or T/T have less MTHFR enzyme function than those who have the C/C wildtype.

When looking at 23andMe data for this variant, the alleles are given on the opposite strand of the DNA than what you see in studies. So you need to mentally convert T to A and C to G when you are reading through the research.

Check your genetic data for rs1801133 (23andMe v4, v5; AncestryDNA):

  • G/G: normal (wildtype)
  • A/G: one copy of C677T allele (heterozygous), MTHFR efficiency reduced by 40%
  • A/A: two copies of C677T (homozygous), MTHFR efficiency reduced by 70 – 80%

After reading about all of the terrible consequences of this enzyme reduction on different websites, one could assume their fate is doomed by having this variant. But it seems that there are both pros and cons to this variant, and environmental interactions, as well as other genes, play a big role in how important the MTHFR variant is to your health. Additionally, 5-methyltetrahydrofolate is available as a supplement, which some people with the variant find to be very helpful.

Studies finding protective effects of MTHFR C677T variant:

Note that the T allele in studies corresponds to an A in your 23andMe or AncestryDNA data.

  • A meta-analysis found that the TT genotype decreases the risk of colon cancer.[ref]
  • A 2015 meta-analysis (study that looked at several previous studies) found that for Asian men, the T/T variant was protective against prostate cancer.  It also found that across all populations, when comparing men with prostate cancer to a control group with benign prostate enlargement, the T/T genotype was protective against prostate cancer.  [ref]
  • A 2016 Iranian study found that the T allele of MTHFR C677T was protective against susceptibility to retinoblastoma.  [ref]
  • A 2015 Brazilian study found the C/T and T/T genotypes “acted as a protective factor” in oral squamous cell cancer. [ref]
  • A 2014 longevity study in China found that the T allele was more prevalent among their long-lived group (aged 90 and older), especially in females.  [ref]
  • A 2014 Chinese study found that the T/T genotype of MTHFR C677T was protective against gastric cancer. [ref]
  • A small 2013 study found that “possessing T allele of MTHFR C677T mutation indicates a protective association on BMI independently from other risk factors.” [ref]
  • A 2013 Iranian study found that the T allele was protective against gastric cancer. [ref]
  • A 2012 meta-study of Chinese populations found that the T allele may be protective against acute lymphoblastic leukemia in children.  [ref]
  • A 2012 meta-analysis found that in Asian studies on prostate cancer risk, the T/T genotype vs C/C genotype had a significantly reduced prostate cancer risk (OR=0.47).

Mixed results:

  • A 2013 meta-analysis found that while MTHFR 677T/T homozygous was found to have a higher susceptibility to lung cancer in smokers, the T/T “homozygote carriers had a better response to platinum-based chemotherapy in advanced NSCLC in the recessive model.”  [ref]
  • A 2013 meta-analysis found that Caucasian women carrying the T/T allele had a lower risk of cervical cancer, but Asian women with T/T were at a higher risk of cervical cancer.  [ref]
  • A 2013 study of a Tenerife Island population found that while the T allele was more frequent in colorectal cancer patients, those with the T allele had a higher survival rate after chemotherapy.  [ref]
  • A 2014  study showed that while the T allele is associated with a risk of higher homocysteine levels, that higher risk is eliminated through adequate riboflavin (vitamin B2) levels [ref]

Studies showing problems with the variant are also abundant.

  • A 2015 meta-analysis found that type-2 diabetic patients carrying the T allele were more susceptible to diabetic nephropathy. [ref]
  • Many studies have shown that the C/T and T/T genotypes are associated with higher homocysteine levels.  [ref]
  • A 2014 meta-analysis found that the MTHFR T-allele gives a greater risk of gastric cancer.  That same study found that for MTHFR A1298C, the C allele may be protective against gastric cancer in certain populations. [ref]
  • many, many more studies show the effect of this variant on heart disease and homocysteine levels.

Eat your greens:

Some studies have found that risks associated with the MTHFR C677T variant are negated through higher folate levels.

  • A 2012 Mexican study found that for those with the 677T/T genotype, the risk of neural tube defects was 95% lower for those with the highest folate levels vs. the lower folate levels. [ref]
  • A 2014 Chinese study found: “The MTHFR 667 T allele and MTR 2756 G allele were associated with a higher risk of breast cancer in individuals with low folate intake, vitamin B6, and vitamin B12, but the association disappeared among subjects with moderate and high intake of folate, vitamin B6, and vitamin B12.” [ref]
  • A 2014 study found that while carriers of the 677 T allele had an overall increased risk of breast cancer, those with a low folate and B6 intake had an even higher risk of breast cancer [ref]


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7 Comments on “MTHFR C677T: Benefits of this mutation

  1. Pingback: Folic Acid supplementation and your genes | Genetic Lifehacks

  2. Hi Debbie, I’m having a difficult time interpreting what my 23andme raw data is telling me in regard to MTHFR. I wondered if you could help. It was particularly confusing above when you said their data should be mentally converted. For rs1801133, my raw data shows my genotype as A/A. I think I’m reading from your data above: AA: two copies of C677T (homozygous), MTHFR efficiency reduced by 70 – 80%
    My Dad and I do have moderately elevated homocysteine levels and I’m trying to see if this snp has to do with it.
    Would appreciate some guidance. Thank you.

    • Hi Jeff,
      Thanks for reaching out with your question. I’ll try to changing the wording on the page to make it clearer!
      Yes, if you have AA for the MTHFR C677T variant, you carry two copies of the variant with reduced efficiency. This is linked to higher homocysteine levels in some people.
      There are quite a few studies that show a combo of methyl folate, B12, and B6 work to lower homocysteine levels for most people. Here are a couple of the studies: https://www.ncbi.nlm.nih.gov/pubmed/29813097, https://www.ncbi.nlm.nih.gov/pubmed/19303062, https://www.ncbi.nlm.nih.gov/pubmed/27035272
      Just a personal word of caution that you may want to start with lower amounts of the active form of the B vitamins to see if you have any side effects.
      Debbie

  3. I’m feeling confused and hoping you can help. I had genetic testing through another company, not 23andme. My MTHFR results are C677T AG genotype, and A1298C TT genotype. What does this mean? Thank you!

    • Hi Laurel –
      Your test results show that you are heterozygous (one copy) for the MTHFR C677T variant. This reduces your ability to convert folates to methylfolate by about 40%. The TT genotype for A1298C is the normal one. You can read more about it here: https://www.geneticlifehacks.com/mthfr/

  4. My 23andme results came back showing my genotype at AA. Does this increase my risk of Alzheimer’s Disease?

    • Hi Dee –
      Being homozygous for the MTHFR C677T variant does statistically increase your risk of Alzheimer’s a little bit.
      Some studies indicate that this may be due to elevated homocysteine levels, so if you don’t have high homocysteine, the MTHFR variant may not impact your risk of Alzheimer’s.
      https://link.springer.com/article/10.1007/s12035-016-9722-8
      Debbie

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