MTR and MTRR are two genes involved in the conversion of homocysteine to methione, and a couple of fairly common gene variants cause the genes to work differently.
Why is this something to care about?
Well, let’s dig into a bit of science to answer that question. Methionine is an essential amino acid, used in the production of proteins; it plays an integral part in the methylation pathway. S-adenosyl methionine (SAMe) is a derivative of methionine and is involved in many cellular pathways as a methyl donor.

Methionine synthase (MTR) - image from Wikimedia Commons

Methionine synthase (MTR) – image from Wikimedia Commons

MTR (methionine synthase) and MTRR (methionine synthase reductase) code for enzymes work together in the methylation cycle. MTR works in the final step to regenerate homocysteine into methionine using methylcobalamin (methyl-B12), and MTRR regenerates the methylcobalamin for MTR to use. [ref]  Both are a vital part of the methylation cycle.

The Genetics Home Reference sums it up this way: “The MTR gene provides instructions for making an enzyme called methionine synthase. This enzyme plays a role in processing amino acids, the building blocks of proteins. Specifically, methionine synthase carries out a chemical reaction that converts the amino acid homocysteine to another amino acid called methionine. The body uses methionine to make proteins and other important compounds. To function properly, methionine synthase requires methylcobalamin (a form of vitamin B12) and another enzyme called methionine synthase reductase, which is produced from the MTRR gene.”

MTR Genetic Variants:

Check your 23andMe results for rs1805087 (v4, v5):

  • AA: normal (wildtype)
  • AG: increased enzyme activity
  • GG: increased enzyme activity

Studies have linked an MTR variant to several folate pathway problems including higher homocysteine levels.  The rs1805087 variant is also known as A2756G, with G being the minor allele. The G allele causes an increase in methylation, thus possibly causing a decrease in methyl groups available for other pathways to use and also using up methylB12 more quickly than normal. [ref]

MTR uses methylcobalamin (methyl-B12) and zinc in the reaction of converting homocysteine to methionine.  Thus, an increase in enzyme activity can keep homocysteine levels lower (generally a good thing) but only if there is plentiful methylcobalamin. So people with this variant might want to ensure that they are getting  methylB12 and zinc, either through diet or supplements.

Other studies on this variant:

  • A 2015 study showed that rs1805087 is a risk factor for mild cognitive impairment (Chinese study).  The study notes that high homocysteine levels are a risk factor for the decline in cognitive function in the elderly. [ref]
  • A 2015 study found that adhering to the Mediterranean diet reduced the risk of breast cancer for those with the MTR polymorphism.  [ref]
  • Quite a few recent studies found no association between the MTR polymorphism and cancer risks, so diet an lifestyle choices play a role.
  • A 2013 study showed that rs1805087 increased the severity of symptoms in schizophrenia. [ref]
  • A small Iranian study found that the MTR A2756G variant was linked to a slightly higher risk of autism.

MTRR Genetic Variants:

Check your 23andMe results for rs1801394 (v4, v5):

  • AA: normal (wildtype)
  • AG: somewhat decreased enzyme efficiency
  • GG: decreased enzyme efficiency

Methionine synthase reductase has several fairly common variants that affect the production of the MTRR enzyme which regenerates vitamin B12 (methylcobalamin) for use by MTR and other enzymes. The variant rs1801394 is also known as A66G, and it decreases enzyme’s efficiency.  It is fairly common and carried by about half the population. It seems that combinations of MTRR polymorphisms with MTHFR or other methylation cycle issues may be more of a concern.

  • A 2011 study showed an increased risk for colorectal cancer (OR = 1.39) for those with rs1801394  GG. [ref]
  • A 2014 study showed an increased risk for metabolic syndrome for those with the A66G polymorphisms and MTHFR C677T.  [ref]
  • A 2014 meta-analysis showed an increased risk for congenital heart disease associated with A66G polymorphism.  [ref]


  • A healthy diet high in folate and B12 seems to be essential for overcoming any deficits created by these two polymorphisms. Foods high in folate include leafy greens, chicken liver, beef liver, asparagus, broccoli, and legumes. Vitamin B12 is only found in animal products with liver being an excellent source.
  • If you have the MTRR polymorphisms and are considering supplementing with B-12, you should first read my article on COMT.  There are four different types of B-12, and some work better than others, depending on COMT polymorphisms.
  • If you are looking for a good adenosylcobalamin and hydroxocobalamin sublingual supplement, I like the Seeking Health brand combo Hydrox-Adeno.  There are many good sources of methylcobalamin, and you may be able to find it at your local health food store as well.

Learn more:

A Little Lithium + B12 may make the world a happier place - depending on your #genetic snps.   



Updated 5/2017

Categories: Methylation Cycle


John DiMaccio · September 21, 2018 at 10:48 pm

I’ve been having a hard time figuring out what supplements I need for my mutations. Unless I read it wrong my mutations would point to me having high homocysteine but I got my blood work and it’s actually on the lower end. It’s 4.6 range 0-15
My mutations are
MTHFR GT risk allele G (A1298C)
MTHFR AG risk allele A (C677T)
MTRR GG risk allele G (A66G)
MTRR CT risk allele T (C524T)
MAOB C risk allele T +/+*(male)
COMT AG risk allele A (V158M)
COMT CT risk allele T (H62H)
GSTP1 GG risk allele G (lle105Val)
APOE CC risk allele C (Arg176Cys)

    Debbie Moon · September 27, 2018 at 11:06 am

    Hi John-
    Thanks for reading and commenting on this blog post. Yes, it looks like you have several genetic variants that are linked to a higher risk for increased homocysteine levels. But diet, lifestyle, age, and other genes also come into play for histamine levels. That is why you do the blood test :-) I also carry several of the risk factors for high homocysteine, but have normal homocysteine levels.

    Stacy · October 21, 2018 at 5:48 am

    There are also other SNPs that up-regulate the processing of homocysteine, such as CBS. I have several paradoxical SNPs like that, which make it really difficult to address deficiencies. While MTHFR mutations generally respond well to methyl groups, I don’t tolerate them well at all due to CBS and possibly other SNPs. It is all very complex! So, in short, the low homocysteine may be due to other SNPs, which may create their own issues! And the low homocysteine may not necessarily be a good thing. Definitely check your CBS.

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