Methylation genes: what MTHFR, COMT and the rest really tell you
You have probably seen it: a "methylation panel" of 13 genes, a colorful report full of words like slow, blocked and overactive, and a supplement plan for every gene. Methylfolate for one, methyl B12 for another, betaine for a third, a warning about sulfur foods for a fourth.
It sounds precise. Most of it is not. Here is every gene on the panel, what large studies actually found, and the few simple things that do help.
The problem: 13 genes, 13 supplements
First, what methylation is
Methylation is one of the most common chemical jobs in the body. An enzyme sticks a tiny tag, one carbon and three hydrogens, onto a molecule, and the tag changes what that molecule does. Tags on DNA switch genes off. Tags help break down dopamine and adrenaline. Tags help build creatine and cell membranes.
The tags come from food. Folate (from leafy greens, beans and fortified grains) and vitamin B12 (from animal foods) keep a small cycle turning: the cycle hands out tags and recycles the leftover, an amino acid called homocysteine. When folate or B12 runs short, homocysteine builds up in the blood. That is the part of the story that is solid.
Then, the panel
The popular panel took the enzymes from a drawing of this cycle, added a few more around it, and paired each one with a supplement. It spread once consumer DNA tests let people download their raw data. The logic was: if a gene on the chart has a variant, the step it controls must be slow, so take something to push it.
The missing step was checking whether those variants change anything in real people.
Why most of the panel says so little
The best test is simple: measure homocysteine in tens of thousands of people, read their whole genome, and see which spots actually move the number. A study of 44,147 people did exactly that. It found 13 places in the genome that shift homocysteine. Three of them sit in or near panel genes: MTHFR, MTR and CBS. The rest of the panel, MTRR, BHMT, SHMT1, MTHFD1 and AHCY, did not show up.
And even the spots that did move homocysteine moved it a little. People in the top tenth of the combined genetic score had homocysteine about 3 units (µmol/L) higher than people in the bottom tenth, and no more heart trouble.
Every gene on the panel: what is true and what is not
MTHFR C677T: real, and food handles it
What you will hear: you have an MTHFR mutation, you can't use folic acid, take methylfolate.
What studies show: this one is real. MTHFR, the enzyme that turns folate into its active form, comes out less active and more fragile with the T version. People with two T copies, roughly 1 in 10 people of European descent, have higher homocysteine than people with none. But how much depends on food. In a combined analysis of 59,995 people, two T copies meant homocysteine about 3.1 units higher than no copies in low-folate parts of Asia, and only about 0.1 units higher in countries that add folic acid to flour.
The CDC is clear on the supplement question: people with this variant process all forms of folate, including ordinary folic acid. Genetics doctors (ACMG) advise against testing MTHFR at all as part of a clotting workup, because the result rarely changes what anyone should do. We wrote more about it in MTHFR: the most oversold gene on the internet.
MTHFR A1298C: matters only next to C677T
What you will hear: a second MTHFR mutation, so double the problem.
What studies show: on its own, this version did not raise homocysteine or lower folate, even with two copies. One copy of A1298C together with one copy of C677T looked about like two copies of C677T: a modest shift that folate intake covers.
MTR: real, very small
What you will hear: you burn through B12, take methyl B12.
What studies show: MTR makes the enzyme that uses folate and B12 to turn homocysteine back into a useful building block. A spot near MTR is one of the 13 that move homocysteine, but the step is very small, far smaller than what folate and B12 in your diet do. No study showed that people with this variant need a special form of B12.
MTRR: no measured effect
What you will hear: your B12 recycling is slow, take methyl B12.
What studies show: MTRR keeps the MTR enzyme working. Its common variant was not among the 13 spots that move homocysteine in the 44,147-person study.
CBS: a small signal, an unsupported diet
What you will hear: your CBS is "upregulated," avoid sulfur foods like eggs, garlic and broccoli, take molybdenum.
What studies show: a spot near CBS does shift homocysteine a little. Whether the panel's usual marker is the variant behind that signal is not settled, and we found no trial that tested cutting sulfur foods by CBS genotype. Eggs, garlic and broccoli are not the problem.
NOS3: a small blood pressure lean
What you will hear: NOS3 means poor nitric oxide, take arginine.
What studies show: NOS3 makes the enzyme that produces nitric oxide in blood vessels. A marker in front of the gene showed up in a blood pressure study of 21,714 people as a small lean toward higher readings. That is a real, small finding about blood pressure, not a reason for arginine.
COMT: a real enzyme difference, a blurry effect on mood
What you will hear: slow COMT, you are a worrier, avoid methyl donors.
What studies show: the Val158Met variant really does change how fast COMT clears dopamine in the front of the brain, about three to four times between the two versions in the lab. How much that changes mood and thinking in everyday life is small and inconsistent across studies. No trial showed that people with slow COMT should avoid methyl donors. More in our COMT article.
MTHFD1, SHMT1, BHMT, AHCY: no measured effect
What you will hear: each one blocks a step, each one needs a supplement (choline, folinic acid, betaine).
What studies show: none of them was among the 13 spots that move homocysteine in the large study. Earlier small studies, often a few hundred people, point in different directions. For AHCY, rare broken copies of the gene cause a serious childhood condition that doctors diagnose; the common variants on consumer chips are not that.
ACAT: a name mix-up
What you will hear: ACAT affects cholesterol and B12, so watch both.
What studies show: two different enzymes have been called ACAT. The gene on the panel, ACAT1, works in energy metabolism inside mitochondria. The cholesterol enzyme people often mean is a different gene. We found no study linking the panel's marker to methylation or B12.
MAO-A: the wrong variant
What you will hear: slow MAO-A means a short temper and trouble with serotonin.
What studies show: the "warrior gene" behind those headlines is a repeat-length difference that consumer DNA chips cannot read at all. The single letter the panel reads has only small studies behind it that were never confirmed.
VDR: not the vitamin D gene
What you will hear: your vitamin D receptor is weak, take more vitamin D, and it affects dopamine too.
What studies show: the largest study of vitamin D genetics, 79,366 people, found the genes that actually set your vitamin D level: GC, CYP2R1, DHCR7, CYP24A1 and two more. VDR is not among them. More in our vitamin D genes article.
What to do instead
The useful advice is the same for every genotype, and it is cheaper than any panel.
How to support methylation for real
Leafy greens, beans, lentils and fortified grains. Any form works, including folic acid, whatever your MTHFR result.
It comes from meat, fish, eggs and dairy. If you are vegan, or over 50 when absorption drops, a B12 supplement or a check of your level makes sense.
A homocysteine blood test shows whether your cycle is actually keeping up. Ask for B12 and folate in the same draw. One number beats 13 genes.
The CDC advice is 400 mcg of folic acid a day for anyone who could become pregnant, with or without an MTHFR variant.
No trial has shown that matching supplements to methylation genotypes helps healthy people. If someone selling the supplements also sells the test, ask why.
What your Helisoma report shows
We read the parts of this story that hold up, and leave out the rest on purpose:
- Folate and homocysteine: your MTHFR C677T result, with the honest size of the effect and what food does about it.
- Homocysteine level: MTR and a marker near MMUT, the B12 enzyme, read together.
- Vitamin B12 level: six markers, including the ones that can make a standard B12 test read high or low.
- Vitamin D level: GC, CYP2R1 and DHCR7, the genes that actually set it, instead of VDR.
- Dopamine clearing: your COMT version, Warrior or Worrier, and what it does and does not mean.
- Blood pressure: the NOS3 marker, as one small piece of a bigger picture.
If you carry two MTHFR C677T copies, the Lab tests page in your report adds a homocysteine and folate test to your list. MTRR, BHMT, SHMT1, MTHFD1, AHCY, ACAT and MAO-A are not in the report, because no large study found an effect worth showing you.
Sources
- Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nature Genetics, 1995. PubMed 7647779
- Holmes MV, Newcombe P, Hubacek JA, et al. Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk. Lancet, 2011. PubMed 21803414
- van Meurs JB, Pare G, Schwartz SM, et al. Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease. American Journal of Clinical Nutrition, 2013. PubMed 23824729
- van der Put NM, Gabreëls F, Stevens EM, et al. A second common mutation in the methylenetetrahydrofolate reductase gene. American Journal of Human Genetics, 1998. PubMed 9545395
- Hickey SE, Curry CJ, Toriello HV. ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing. Genetics in Medicine, 2013. PubMed 23288205
- Centers for Disease Control and Prevention. MTHFR gene variants and folic acid. cdc.gov
- Lachman HM, Papolos DF, Saito T, et al. Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism. Pharmacogenetics, 1996. PubMed 8807664
- Salvi E, Kutalik Z, Glorioso N, et al. Genomewide association study using a high-density single nucleotide polymorphism array and case-control design identifies a novel essential hypertension susceptibility locus in the promoter region of endothelial NO synthase. Hypertension, 2012. PubMed 22184326
- Wang TJ, Zhang F, Richards JB, et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet, 2010. PubMed 20541252
- Jiang X, O'Reilly PF, Aschard H, et al. Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels. Nature Communications, 2018. PubMed 29343764
