Dads matter: MTHFR variants in fathers affect miscarriage risk

There are quite a few studies showing that women carrying certain MTHFR variant combinations are at a somewhat higher risk for miscarriage, but I recently ran across a study that added a new twist to the topic.  It turns out that the father’s MTHFR variants can also play a role in recurrent miscarriages.

The study from 2015 looked at 225 couples with more than three consecutive pregnancy losses compared with 100 control couples with successful pregnancies.  All 225 mothers in the pregnancy loss group carried either compound heterozygous MTHFR C677T and A1298C variants or homozygous C677T or homozygous A1298C. The study defined carrying just one copy (heterozygous) of either C677T or A1298C as being at a low risk for miscarriage.

When the researchers looked at the fathers MTHFR variants, they found that in the pregnancy loss group the men were more likely to carry the risk variants.[study]  This backs up the work of other, smaller studies that also found that the male’s MTHFR status combined with the mother’s MTHFR variants does seem to statistically increase the risk of miscarriage.[study]



How to check your MTHFR variants on 23andMe

Check your 23andMe results for rs1801133 for the MTHFR C677T:

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


Check your 23andMe results for rs1801131 for the MTHFR A1298C:

  • TT: normal (wildtype)
  • GT: one copy of A1298C allele (heterozygous), MTHFR efficiency reduced
  • GG: two copies of A1298C (homozygous), MTHFR efficiency reduced




There are a couple of things that could be going on here:
First, fathers who carry the MTHFR variants are likely passing them on to the baby.  There are a couple of studies showing that the baby’s MTHFR variants may play a role in miscarriages, but there are other studies showing no effect from the baby’s MTHFR gene. Overall, the meta-studies tend to show little to no effect from the baby’s MTHFR status, so this is probably not the reason.[study]

The second possibility of why the father’s MTHFR variants matter could tie in with the fact that men carrying homozygous MTHFR variants are also at a higher risk for infertility.  A meta-analysis pooled the results of 20+ studies and showed that men carrying either the homozygous MTHFR C677T or A1298C variants were at a higher risk for infertility (29 – 63% increase).  Statistics here…  Keep in mind that this is the just the increase in the risk of infertility compared to the normal risk. For example, if the risk of male infertility is 1 in 20, a 69% increase would make the risk 1.69 in 20.[study]

Dads matter – in conception, pregnancy, and throughout life! It is easy to see how prospective moms need to clean up their diets, exercise, and sleep well before getting pregnant, but I think these studies are a good reminder that prospective fathers need to pay attention to their own health as well!

MTHFR variants (read more here) increase the need for ensuring adequate folate consumption. This means leafy green veggies, legumes, and other organic food sources of folate need to be eaten daily. If you won’t make the necessary dietary changes, there are methyl folate supplements as well. A quality B12 is also important, and many people find it convenient to take a B-complex to cover all the bases.  Here is one that I like: Jarrow B-Right. But you may find other options that are a better fit for you.

This may be a ‘talk to your doctor’ situation if you have a physician working with you on family planning.  I know – telling some guys to talk to a doctor is like banging your head against the wall, but if recurrent miscarriages or infertility are a problem, this really may be a time to get some professional help.

I didn’t find any specific studies looking at men supplementing with folate for recurrent miscarriage, but there are studies showing that it is effective for women. One recent (small) study found that 5mg of methyl folate along with B6 and B12 decreased the risk of miscarriage.[study]

Please note that methyl folate is likely the better form of supplemental folate vs. folic acid,[study]  but that some studies show that a folate-rich diet is as effective as either methyl folate or folic acid. [study]  One reason for methyl folate instead of folic acid is that there have been several recent studies linking high doses of folic acid to things like an increased risk of allergies[ study] and some epigenetic changes that are a bit of an unknown.[study]

Studies on miscarriage risk for women carrying MTHFR variants:




MTHFR Coffee with Eggs and Kale for Breakfast

MTHF-R CoffeeQuick post this morning to recommend a good podcast to anyone looking into MTHFR variants.  Chris Masterjohn put out a well balanced and well-researched podcast a few weeks ago titled Living with MTHFR.  For those of you who don’t have two hours to listen to it, there is a transcript of the show, which is a much faster read.

The podcast goes in-depth on the methylation cycle and includes quite a bit of information on the need for creatine, glycine, and choline.  It is a good summation of the big picture of the methylation cycle, and it does a good job of pointing out the food sources of all of the nutrients involved.

While I’m joking a bit about “MTHFR coffee”, I actually do drink my coffee with gelatin in it each morning.  Gelatin is an excellent source of glycine, an amino acid that is often short-changed in our modern diet.  Bone broth is another great source of glycine, but I tend to get histamine reactions from bone broth if it is cooked for a long time.  (Yes, I can and do make a quicker cooked bone broth in the pressure cooker sometimes, but it is not an everyday thing for me.)  To get gelatin (glycine) in my diet on a more regular basis, I add a spoonful of grass-fed, pasture raised beef gelatin to my morning coffee.  The trick to getting it to dissolve well is to put the gelatin in the cup first, along with a little cold water.  Make sure that the gelatin and cold water are combined before adding in the hot water.  If you add sugar to your coffee, it works great to stir the sugar and gelatin together first before adding water.

If you aren’t getting enough creatine in your diet, it is an easy supplement to add.  It doesn’t really have any flavor and easily mixes into coffee or other drinks.  I’ve read several places that it does degrade in liquid over time, so it may be better to add it to something that you are going to drink somewhat quickly rather than a drink that you sip on for hours at a time.  If you add it to your coffee with gelatin in it, you are pretty much guaranteed not to be sipping on it all day since your coffee/gelatin mixture will set up like Jello when it gets cold!

Eggs from my happy backyard chickens plus some kale from my mom’s garden round out an ‘MTHFR breakfast’. I get some choline from the egg yolks and folate from the kale.  A good start to the day!

If you are just getting started in looking into how your genes play a role in your nutrition, you could start with these pages:

I am currently using a Creatine Monohydrate from Bulk Supplements since it has no fillers or extras in it, and I’m using Zint Beef Gelatin.  There are other brands that are good as well.  I tried a hydrolyzed collagen product at one point, but to me, there was a stronger taste to it.  The gelatin is fairly flavorless, and a strong cup of coffee hides any hint of flavor for me.

One final note to leave you with is a headline from a couple of days ago: Higher coffee consumption associated with lower risk of early death.

MTHFR and Vaccinations

MTHFR and VaccinesI recently read, for the million-teenth time, that anyone with MTHFR variants should not be vaccinated.  The argument always seems to be that those with decreased MTHFR enzyme activity cannot detoxify or handle a vaccination. This seems to be accepted as fact by some, but I hadn’t really read anything other than anecdotes about it.  So I decided to look into the scientific studies on the topic.

**Note that I’m not weighing in on whether or not kids should be vaccinated on the currently advised pediatric vaccination schedule — just addressing the science behind MTHFR variants causing adverse reactions to vaccines **

Looking into the studies on MTHFR variants and vaccination injuries and/or adverse events lead me to exactly one study.  The study was small, with less than 200 people included in it.  It looked at several different variants as related to adverse events from a smallpox vaccination.  It did find that those individuals with an MTHFR C677T variant were more likely to have an adverse event.  It also linked a couple of other variants with an even greater likelihood of adverse events.   Again, though, this is a small study using a vaccination that is not normally in use today.  (Smallpox vaccines have not been used on the general public in the US for about 45 years.)

Could there be other studies on MTHFR and vaccination adverse events?  Possibly, but I couldn’t find any that have been published.  If you know of any, please leave a comment below.

Going after the idea that excipients in the vaccine are what cause those with MTHFR variants (i.e. half the population) to be harmed by vaccines, I did find a very small study (50 participants) showing that those with the MTHFR C677T variant might be more sensitive to mercury.  But that really isn’t much of an issue since mercury has been removed from children’s vaccinations since 2001.  (Seasonal flu vaccines for those over 6 years old can still contain mercury.)

I didn’t find any other links between MTHFR variants and other excipients in vaccines.

In digging into the topic, I did find several studies looking at the interplay between genetics and vaccination reactions.  So there has been work done looking at genetic variants and the role they play in both the effectiveness of vaccines and in regards to adverse events, but those studies do not mention MTHFR as being involved in vaccine events.

One study found quite a few HLA gene variants as well as other immune system gene variants that do play a role in how vaccines work.  The study sums up: “We predict, based on the type of work discussed herein, a time when it will be possible to determine what diseases an individual is at risk for, what vaccine(s) they should receive, at what doses and the chance that they may experience any significant adverse event. This is a very different experience than the current situation where essentially everyone gets every vaccine, given in the same manner, at the same dose and the same number of doses – ignoring the reality that we are genetically preprogrammed to immunologically respond in predetermined differing patterns.”

To sum it up:

There is not a lot of evidence pointing to common MTHFR variants playing a role in vaccination adverse events.  There are other genetic variants that have been found to increase the risk of either adverse events or vaccine effectiveness.  I’ve listed some of the studies below.   Someday, hopefully, we will be at the point where those who are most susceptible to a disease will be able to get a vaccine that is genetically right for them.

More to read:


Choline – An Essential Nutrient

Choline-An Essential NutrientI just finished listening to an interesting podcast featuring Dr. Zeisel, a researcher at the NC Nutrition Research Institute.  The interview discussed the body’s need for choline and the impact of some genetic variants on our ability to produce it in the body.  So I decided to dig into this a little more and look at some of the SNPs covered by 23andMe data related to choline.

A little background information…

Choline is involved in several critical roles in the body including:

  • supporting methylation reactions through donating a methyl group (TMG/betaine)
  • formation of acetylcholine, a neurotransmitter and cell-signaling molecule
  • formation of phosphatidylcholine which makes up cell membranes[ref]
  • muscle function [ref]
  • deficiency in choline contributes to non-alcoholic fatty liver disease

Recent studies of choline levels show:

  • academic achievement in 15-year olds is significantly associated with plasma choline levels [ref]
  • choline plus B-vitamins may increase neuroplasticity and speed recovery after a stroke [ref]
  • crocodile choline may be a treatment of gastric cancer [ref]
  • choline deficiency is correlated to lower bone mineral density [ref]
  • high serum choline concentrations may increase the risk of colon cancer [ref]
Role of Choline in Methylation Cycle. Wikimedia Commons, Public Domain

Generally, people can make some choline in their liver; a percentage of people have genetic variants that reduce their ability to make choline and need to ensure adequate intake through food or supplements.

Choline is the precursor to acetylcholine, which is a neurotransmitter.  Acetylcholine controls muscles, heart rhythm, and other function.

The FDA gives a recommended adequate intake for adults as 425-550 mg/day.   [ref]

Genetic Variants Related to Choline

PEMT – phosphatidylethanolamine N-methyltransferase

The PEMT pathway is responsible for the body’s production of phosphatidylcholine which is part of the phospholipid bilayer making up the membranes surrounding our cells.  Note that 23andMe does not cover all of the SNPs in PEMT that are relevant to choline levels.

rs7946: (v.4 and v.5) CT and TT variants have somewhat decreased PEMT enzyme activity [ref]

CHKA – Choline kinase alpha

The first step of the CDP-PC pathway.

rs10791957: (v.4 and v.5) AA and AC variants have a lower turnover of methionine to PC
“Specifically, the variant appears to decrease the use of dietary choline for PEMT-PC synthesis relative to CDP-PC synthesis. Variant individuals displayed decreased turnover of choline-derived methionine → PEMT-PC over the study period, indicating decreased activity of PEMT relative to women without the variant, and also tended to exhibit lower relative PEMT-PC/CDP-PC enrichment as compared to non-variants.”[ref]
In another study, those with CC were found to be “less likely to have clinical symptoms after consuming a low-choline diet.” [ref]

BHMT – Betaine-homocysteine S-methyltransferase

rs3733890: (v.4 and v.5)   AA and GA variants have lower conversion of choline to betaine and more conversion of choline to CDP-PC
“Together, these results indicate that the variant favors the use of dietary choline for CDP-PC synthesis at the expense of betaine synthesis.” [ref]

FMO3 – Flavin-containing monooxygenase

rs2266782:  (v.4 and v.5) GA and AA variants have greater turnover of betaine to methionine and greater turnover of choline-derived methionine to PEMT-PC
“While a previous study from our group suggested that the variant might be associated with increased use of choline as a methyl donor in men (based on increased DMG pool size) [43], results from the present study, indicate that women with the variant actually use choline less as methyl donor. Variant women tended to have a lower turnover of betaine → methionine over the study period. In addition, variant women exhibited a greater turnover of choline-derived methionine → PEMT-PC over the study period, which is consistent with previous findings from our lab that have identified lower methionine excretion among variant individuals (i.e., a greater use of methionine may reduce excretion)” [ref]

MTHFD1 – methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1

rs2236225 (G1958A): (v.4 and v.5) Carriers of the A allele are more likely to have choline deficiency on a low choline diet (modified by folate intake) [ref] [ref]  In one study with premenopausal women, those with an A-allele were 15 times more likely to show choline deficiency symptoms on a diet low in choline.

Food and supplements:

Excellent (egg-cellent :-) sources of choline in foods include:  eggs, liver, shitake mushrooms, milk, and various meats.  [ref]  Raw egg yolks are a better source of choline than cooked, but there are drawbacks, especially if you don’t know the source of your eggs.

Choline supplement options include CDP-choline, phosphatidylcholine, alpha-GPC, and choline citrate. is a good source of information on the different types of choline.

More to read:

Dr. Amy Yasko also has a lot of information about the role of choline in the methylation cycle.  Her view is that MTHFR variants can be bypassed using choline if a person doesn’t have BHMT or PEMT variants. Her free book Companion Guide: Feel Good Nutrigenomics is a good place to start, and her full book Feel Good Nutrigenomics as well as videos, etc can be found on her website.

Linus Pauling Institute (University of Oregon) – Choline

MTHFR, Depression, and Homocysteine Levels


An interesting study came out this year in the Journal of Clinical Psychiatry.  The study, Correlation of Clinical Response With Homocysteine Reduction During Therapy With Reduced B Vitamins in Patients With MDD Who Are Positive for MTHFR C677T or A1298C Polymorphism: A Randomized, Double-Bind, Placebo-Controlled Study, is available in full on the journal’s website.

The study included 330 adults with major depressive disorder who had either MTHFR C667T or A1298C variants.  (Check your status on these SNPS)   While the study report focuses on the marked reduction in homocysteine levels in the vitamin-treated group, it also reports very impressive reduction in depression scores.

The vitamin treated group were taking high doses of three forms of folate (1mg folic acid, 2.5 mg folinic acid, and 7mg of l-methylfolate), magnesium,  zinc, phosphotidylserine, and iron, along with microgram doses of the active forms of thiamine, B6, adenosyl-B12, NADH, and TMG.  Please see the study for the specific types of each of these vitamins and minerals.

The results of the 8 week trial showed that the vitamin treated group had an average reduction in homocysteine levels from 9.6 at baseline to 7.2 umol/L while the placebo group had a slight increase.

The study included a MADRS (Montgomery-Asberg Depression Rating Scale) score at baseline and after 8 weeks.  The vitamin treated group saw a decrease from an average score of 27 at baseline to 15 after 8 weeks, while the placebo group only saw a 1.3 point drop.

Again, I encourage you all to read through the study for yourselves, but to me, it seems to show a significant improvement for those with MTHFR variants and major depressive disorder.


Other recent studies on MTHFR, methylfolate, homocysteine, and depression:

  • Effectiveness of add-on l-methylfolate therapy in a complex psychiatric illness with MTHFR C677T genetic polymorphism. [link]
  • Association between MTHFR C677T polymorphism and depression: a meta-analysis in the Chinese population.  [link]
  • Homocysteine excess: delineating the possible mechanism of neurotoxicity and depression [link]
  • MTHFR: Genetic variants, expression analysis and COMT interaction in major depressive disorder [link]

Folic Acid supplementation and your genes

There is a lot of talk online about MTHFR variants and the need to avoid folic acid. I’m digging into the topic a bit and see what is found in research studies, as well as look at the history of folic acid supplementation. Then I will go into some of the research studies on MTHFR, DHFR, and SLC19A1 variants.

How the body breaks down folic acid…
Folic acid is a synthetic form of folate that is temperature and pH stable, allowing it to easily be added to processed foods and multivitamins.  The chemical name for folic acid is pteroylmonoglutamic acid or PteGlu.

A 2014 review in Preventive Nutrition and Food Science thoroughly explains the breakdown of folic acid:

“However, since PteGlu is not a natural form of folate, it requires additional metabolic steps before it can enter the circulating plasma folate pool as 5-methyltetrahydrofolate (5-CH3H4PteGlu). In order to enter folate metabolism, PteGlu needs to be reduced first to dihydrofolate (H2PteGlu) and then to the active form, tetrahydrofolate (H4PteGlu) which is the methyl group shuttle required for the de novo synthesis of purine, thymidylate and methionine. This additional step is exclusively mediated by dihydrofolate reductase (DHFR) (33). The main role of DHFR is to catalyse the reduction of H2PteGlu to H4PteGlu. It is also responsible for the conversion of PteGlu to H2PteGlu, but with a higher Km. In addition, H2PteGlu allosterically modulates the activity of methylenetetrahydrofolate reductase (MTHFR) which is one of the key enzymes of folate metabolism (34). Therefore, DHFR is critical for both the continuous circulation of reduced folate in the body and synthetic PteGlu metabolism “

Another study in 2012 explains the concerns with un-metabolized folic acid:

There is much debate as to whether exposure to unmetabolized folic acid poses a health risk [17]. Theoretically, folic acid could interfere with normal folate metabolism through competition with reduced, coenzymatic folates for transporters, binding proteins, and folate-dependent enzymes [18–20]. For instance, both folic acid and H2PteGlu are substrates for DHFR. Although the affinity of DHFR for H2PteGlu is higher than its affinity for folic acid, in the presence of high concentrations of folic acid, folic acid could competitively inhibit the conversion of H2PteGlu to H4PteGlu [19]. As neither folic acid nor H2PteGlu is metabolically active, this could theoretically create an intracellular folate deficiency [19]. Another study observed a downregulation of folate transporters in intestinal and renal epithelial cells cultured in growth media that were oversupplemented with folic acid

A study from 2007 looked at the dosage at which un-metabolized folic acid would appear in the bloodstream.  This study was completed in the UK, which had not mandated fortification of flour, so the participants had no unmetabolized folic acid in their bloodstream prior to beginning the study.  The study concluded: “Based on the cumulative evidence to date in this and other studies [4-6] it seems that the threshold dose above which unmetabolised folic acid appears in serum lies around 200 μg. The intervals between repeated exposures also seem to be an important factor [6] as an accumulative effect is observed if repeated doses are consumed close together. These are important considerations for policy makers planning an intervention.” [ref]

Finally, a 2012 study looking at the effects of supplementing with either 1.1mg or 5 mg of folic acid found that there is a great variation in people’s capacity for metabolizing folic acid.[ref]

Genetic Variants Related to Folic Acid Metabolism

DHFR – Dihydrofolate reductase

The DHFR gene codes for the enzyme that converts dihydrofolate (from folic acid or folate) into tetrahydrofolate.

rs1677693 (the minor allele is C)

  • A 2010 study looked at the risk of colon cancer based on DHFR genotype in a ‘post-fortification’ era.  It found that rs1677693 (C allele) was associated with a decreased risk of colon cancer.  [ref]
  • Another 2010 review also looked at DHFR in relation to colon cancer.  It also discusses the lower risk of colon cancer for carriers of the variant, especially in those who didn’t supplement with multivitamins.   [ref]

rs1643649 (the minor allele is C)

  • A study showed the minor allele increased susceptibility to spina bifida.  [ref]

rs1650697 (the minor allele is A)

  • A 2010 study found that in a Chinese population the minor allele gave a slightly more favorable prognosis for nonsmall cell lung cancer.  [ref]

rs1232027 (the minor allele is G) (v.4 and v.5)

  • A study from 2010 found that this variant gave and OR=2.99 as far as response to methotrexate (cancer drug that suppresses folate metabolism). [ref]


MTHFR is a well researched and much talked about variant.  (See my post on MTHFR if you need to check your 23andMe data)  While at first glance it may seem that those with MTHFR 677 and 1298 variants may gain some kind of benefit from folic acid as long as their DHFR gene is working well, more studies need to be done to determine if unmetabolized folic acid negatively affects those with MTHFR variants.

A 2014 mouse study found that mice bred to be Mthfr +/- had liver issues consistent with non-alcoholic fatty liver disease when fed a diet high in folic acid (10 fold higher than recommended).

Another recent study showed that, regardless of MTHFR status, [6S]-5-MTHF (methyl folate) had higher bioavailability than folic acid.[ref]

SLC19A1 – folate transporter gene
This gene is responsible for making the protein that transports folate compounds into the cell.[ref]

rs1051266 (T is the minor allele)

  • The minor allele is associated with reduced plasma folate levels.  [ref]
  • The minor allele  increased the risk for colon adenoma for those with MTHFR 677C, but decreased the risk for those with MTHFR 677TT (minor allele) [ref]

Linking folic acid to autism…
A study in May 2016 found that high levels of folate in the mother after birth doubles the risk of autism for the child. The combination of high B12 and high folate levels gave an even greater risk. Here is an article about the study: Excessive Folate, B12 in Pregnancy Dramatically Ups Autism Risk. 

Other studies in the past have found that prenatal vitamins (most likely with folic acid) reduced the risk of autism, especially in those with MTHFR677 TT.[ref]  More studies are needed to determine what, if any, role folate metabolism plays in Autism.

Other interesting studies…

  • Preterm births: A 2014 study looked at 66,014 Norwegian mothers and risk of spontaneous preterm delivery.  It found “The initiation of folic acid supplementation more than 8 weeks before conception was associated with an increased risk for spontaneous PTD (HR 1.18; CI 1.05-1.32) compared to no folic acid supplementation preconception.” [ref]
  • Prostate cancer: A 2009 randomized placebo-controlled trial for colorectal adenomas found that folic acid supplementation (1 mg/day) more than doubled the risk of prostate cancer.  “Among the 643 men who were randomly assigned to placebo or supplementation with folic acid, the estimated probability of being diagnosed with prostate cancer over a 10-year period was 9.7% (95% confidence interval [CI] = 6.5% to 14.5%) in the folic acid group and 3.3% (95% CI = 1.7% to 6.4%) in the placebo group (age-adjusted hazard ratio = 2.63, 95% CI = 1.23 to 5.65, Wald test P = .01).” [ref]
  • Weight gain: A recent rat study found that excess folic acid along with a higher fat diet caused increased weight gain and inflammation. [ref]

History of how Folic Acid came to be supplemented in the US

Widespread folic acid fortification began in the US in 1996 and then became mandatory in 1998. It is currently added to all “enriched bread, flour, cornmeal, rice, pasta, and other grain products”. [ref]  This mandate was made to reduce the risk of neural tube defects, which happened at the rate of  2,500 babies with NTD/year in the US in 1992. A 2015 CDC article claims: “The birth prevalence of NTDs (proportion of babies in the population born with an NTD) has decreased by 35% in the United States since folic acid fortification was required in 1998.”   [ref]

The history of the FDA decision to mandate fortification with folic acid is interesting to read.  It states that:
Folic acid fortification, for all practical purposes, was not even on the regulatory horizon when it was first included in the 1990 Nutrition Labeling and Education Act (NLEA). FDA scientists at the time felt that the charge to consider the link between folic acid and neural tube defects literally came “out of the blue.” Later, they concluded it probably started with a science workshop hosted by CDC in the late 80s in which unpublished data on folic acid and neural tube defects were presented and seized upon by the supplement industry.” The article goes on to explain that a British study published in 1991 showed that women who already had a child with neural tube defects reduced their risk of having a second child with NDT when they supplemented with 4 mg of folic acid per day. This study was in contrast to the FDA contracted report in 1991 which stated that studies had failed to show the connection between folic acid and NTD.

By August of 1992, the FDA is changing its stance on folic acid.  The article goes on to say:

“In August and September 1992, FDA reviewed results obtained from two additional, unpublished studies, and worked closely with authors and journals publishing them to ensure that the results were made public early. The first, a Hungarian research study, showed a reduced risk of ntd’s in women consuming .8 mg. of folic acid as part of a multivitamin/mineral supplement. The study had been conducted with a sample of women in the general population without a previous history of an ntd pregnancy. The second study was a case control study of women in the general population of Boston, Toronto, and Philadelphia and was referred to as the “Werler study.” This study suggested that .4 mg. of folic acid daily from multivitamin/mineral supplements was associated with a reduced risk of ntd. It also suggested that a diet adequate in folate with more than .25 mg. daily was protective. The new preponderance of scientific evidence on folic acid created a platform from which the Public Health Service (PHS) spoke on September 14, 1992. PHS formally recognized the link between folic acid intake and ntd’s as a compelling public health issue. It recommended that all women of childbearing age should have adequate folate intakes (.4 mg. daily) throughout their childbearing years, but warned that the total intakes should not exceed 1 mg.”

The Werler study that the FDA used for their recommendation looked at 436 cases of NTD with a control group of 2615 babies that had other birth defects. The study threw out 17% of cases and 3% of controls because they knew about the hypothesis that folic acid prevented neural tube defects.  Then they based the conclusion on the reported use of daily multivitamins that also contained folic acid. I admit that I am confused by this study, specifically by why the control group was only babies with birth defects and how the conclusion was reached that it was the folic acid in the multivitamin that lowered the risk of NTD. I’m also unclear as to why you would throw out 17% of the cases because they knew to supplement with folic acid. That seems like it would skew the data.

I found a copy of a second study by the same author, Martha Werler, on on the Oxford Journal website published a few years later using the same study population, I think. The study group consisted of 303 babies with oral clefts while the control group was 1,167 babies who had other birth defects not related to oral clefts or neural tube defects. The study talks about how neural tube defects and oral clefts are related and then broke the data down by the number of mothers supplementing with multivitamins before and during the first trimester.  The study’s conclusion reads “We found no significant protective effect for folic acid supplementation in relation to the risk of all oral clefts, cleft palate, or cleft lip with or without cleft palate.

Please don’t get me wrong…  I am not questioning a link between NTD and folate levels, but rather I’m surprised at how little data the FDA used in making the decision to force the fortification of folic acid on the public. I had rather naively assumed that there were lots of good studies showing without a doubt that 400 μg/d  of folic acid was exactly what we all needed.

Colon cancer and folic acid
Colon cancer rates increased around the same time that fortification programs for folic acid began.  Of course, correlation doesn’t equal causation, and the rise in colon cancer rates could be due to another factor.  Except– several studies link folate status to colon cancer, and inhibition of DHFR via pharmaceuticals is one method of slowing certain cancer.  Also, the MTHFR 677-TT variant which impairs the enzyme’s activity also decreases the risk of colon cancer. [ref] [ref]

A 2007 article in the journal Cancer Epidemiology, Biomarkers & Prevention sums up the correlations between the increase in colon cancer and the implementation of folic acid fortification:

“There is a very close chronological relationship between these increases in the incidence of CRC and the remarkable increase in systemic folate status that occurred among adults as a result of folic acid fortification. As mentioned above, both countries experienced approximately a 100% increase in plasma folate levels between 1996 and 1999 (5, 6).” …. “Although mandatory fortification did not begin until 1998, it is important to recall that voluntary fortification in the United States began almost immediately after the March 1996 report. Voluntary fortification began somewhat later in Canada because the legislation did not allow for it until December 25, 1996. Thus, the increase in the incidence in CRC in each country was nearly contemporaneous with the increase in dietary folic acid intake and blood folate level.”  [ref]

MTHFR C677T: Not All Bad!

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 CT or TT have less MTHFR enzyme function than those who have the CC 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 23andMe results for rs1801133 for the MTHFR C677T:

  • GG: normal (wildtype)
  • AG: one copy of C677T allele (heterozygous), MTHFR efficiency reduced by 40%
  • AA: 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:

  • A 2015 meta-analysis (study that looked at several previous studies) found that for Asian men, the TT 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 TT 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 CT and TT 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 TT 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 TT genotype vs CC genotype had a significantly reduced prostate cancer risk (OR=0.47).

Mixed results:

  • A 2013 meta-analysis found that while MTHFR 677TT homozygous was found to have a higher susceptibility to lung cancer in smokers, the TT “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 TT allele had a lower risk of cervical cancer, but Asian women with TT 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 CT and TT 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 677TT 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]

MTR / MTRR – Homocysteine, methionine, and B12

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

COMT – Genetic Connections to Neurotransmitter Levels

The COMT gene encodes the enzyme catechol-O-methyltransferase which is involved in breaking down the neurotransmitters dopamine, epinephrine, and norepinephrine. This enzyme adds a methyl group (from SAMe) to the dopamine, epinephrine, or norepinephrine molecules, thus changing them into a different substance. COMT is also involved in the metabolism of some drugs used for asthma, Parkinson’s, and high blood pressure.

There are several well-studied polymorphisms of COMT.  Some of the psychiatric disorder with increased risk associated with COMT polymorphisms include schizophrenia, depression, anxiety, and bipolar disorder.  Outside of the brain, COMT is also involved in the methylation of catechol estrogens.[ref][ref]

There are several blogs and clinicians online that write about the effects of using supplements that are ‘methyl donors’ on people who have lower COMT activity. [ref][ref] The logic is that the slower COMT variant uses fewer methyl groups, and pushing it with a quick influx of methyl groups can dopamine levels to build up and then fall, causing mood swings.  I’m not finding any studies that back this up (doesn’t mean there aren’t any, just that I haven’t read them), but there seems to be a lot of anecdotal reports on the web that indicate that people who have the low activity variant (listed below) may want to be careful when supplementing with methyl donors such as theanine, SAMe, methyl B12, curcumin, TMG and more.

COMT rs4680, Val158Met
One of the most studied variants of the COMT gene is rs4680, often referred to as Val158Met.  In looking at research studies, the G is “Val” and the A allele is usually noted as “Met”.

The G allele has higher COMT enzymatic activity, causing a more rapid breakdown of the neurotransmitters and thus lower levels of dopamine. In most populations, the G allele is the most common.[ref]

The A allele has lower COMT enzyme activity and thus higher levels of dopamine.

Check your 23andMe results for rs4680 (v.4 and v.5):

  • GG: higher COMT activity, lower dopamine & norepinephrine, higher pain tolerance (Val)
  • AG: intermediate COMT activity
  • AA: lower COMT activity, higher dopamine & norepinephrine, lower pain tolerance (Met)

Here are the findings from a few recent studies on this COMT variant:

  • A 2015 study of cognitively normal adults found that those with GG genotype had lower Neuroticism scores and higher Agreeableness and Conscientiousness scores than those with AG or AA.[ref]
  • A 2015 study of self-administered morphine in 973 patients following surgery found that the minor (A) allele was associated with more morphine use.  This result backs up the many other studies showing that those with rs4680 AA often have a lower pain tolerance than those with rs4680 GG.[ref]
  • A 2015 study of approximately 800 young adults looked at the combined effects of gender and COMT polymorphisms on schizophrenia and psychosis proneness traits.  Males carrying the G allele scored higher on the negative symptoms and traits of schizophrenia and psychosis. [ref]
  • A small 2014 study looked at the differences in fat oxidation and energy expenditure with green tea based on COMT genotype.  Those with the rs4680 GG genotype had significantly increased energy expenditure and fat oxidation with green tea, while those with the AA genotype had no increase. [ref]
  • Lots of other studies are listed on SNPedia including several that look at the response to antidepressants.  There are hundreds of studies in PubMed on this COMT polymorphism.
  • Dr. Amy Yasko looks at COMT in reference to which type of B-12 works best for an individual. In general, she suggests that methylcobalamin (B12) usually works well for those with the GG genotype, and those with the AA genotype may find that hydroxycobalamin or adenosylcobalamin work better.

COMT rs4633
This common variant is also involved in the activity level of COMT. T is the less common version with lower COMT enzyme activity; C is the more common version with higher activity. It correlates with the rs4680 polymorphism, and thus most people will have the same activity levels on both.

Check your 23andMe results for rs4633:

  • CC: higher COMT activity, lower dopamine, norepinephrine
  • CT:  medium COMT activity
  • TT: lower COMT activity, higher dopamine, norepinephrine

Recent studies on this variant have found:

  • A small 2015 study showed that rs4633 was associated with disc degeneration and lower back pain.  Other studies have also found this result. [ref] [ref]
  • A 2014 study looked at the effects of mercury exposure on boys and girls in relation to COMT status.  Boys with the T polymorphism had impaired test performance in response to increasing acute mercury exposure.  This was in contrast to girls with the polymorphism who showed fewer effects from acute mercury exposure.  [ref]
  • A 2012 study of atherosclerosis in elderly Japanese found that the CC genotype was associated with atherosclerosis, especially in women.  [ref]
  • A study found that those with TT had a higher risk of endometrial cancer.  [ref]

Other COMT Polymorphisms:
There are a couple of other COMT variants that may add to (or subtract from) the effect of the main COMT variants listed above.

Check your 23andMe results for rs6267 (v.4 and v.5):

  • GG: normal
  • GT: risk of higher pain sensitivity, somewhat lower COMT activity [ref]
  • TT: risk of higher pain sensitivity, somewhat lower COMT activity [ref]

Check your 23andMe results for rs165599 (v.4 and v.5):

  • AA: increased risk of anxiety, schizophrenia[ref] [ref][ref]
  • AG: increased risk of anxiety, schizophrenia[ref] [ref][ref]
  • GG: normal

Diet and Lifestyle:
A study in mice found that COMT deficiency led to glucose intolerance on a high-fat diet.  Keeping in mind that this is just a mouse study, if you have blood sugar regulation issues and have COMT rs4680 AA, you may want to look at the amount of fat in your diet.  Again, mouse study caveat… but it is interesting to see the link.

It is often suggested by clinicians (and online anecdotes) that those with rs4680 AA (lower COMT levels) should avoid going overboard with foods and supplements that are considered methyl donors.

Magnesium is a cofactor for the COMT enzyme. A study found positive effects for liver COMT levels and heart health from supplementing with magnesium. A good quality magnesium supplement, such as Jigsaw MagPure, may be worth trying if you aren’t getting enough magnesium from food sources.

More to read about COMT and the methylation cycle:
There are quite a few websites that give suggestions for actions to take if you are having problems balancing out your dopamine and other neurotransmitter levels. Knowing if you are genetically predisposed to breaking down dopamine either quickly or slowly may help you and your doctor to understand which route to take to help balance out your neurotransmitters.


Updated 10/2017

Histamine intolerance and the methylation cycle

Histamine Intolerance - The genes and pathways of breaking down histamine.
Histamine Intolerance – The genes and pathways of breaking down histamine.

Are you itching by the end of the day?  Miserable in the evening due to heartburn?  Nose constantly stuffy and drippy? Plagued by migraines? All of these (and more) can be related to histamine intolerance.

First, symptoms of histamine issues can be more than just watery eyes and sneezing when the pollen count rises each spring.

From The American Journal of Clinical Nutrition:

[Histamine] causes smooth muscle cell contraction, vasodilatation, increased vascular permeability and mucus secretion, tachycardia, alterations of blood pressure, and arrhythmias, and it stimulates gastric acid secretion and nociceptive nerve fibers. In addition, histamine has been known to play various roles in neurotransmission, immunomodulation, hematopoiesis, wound healing, day-night rhythm…

Symptoms of histamine intolerance can include:

  • headaches
  • migraines
  • dark circles under the eyes
  • itching, hives
  • congestion, sneezing, runny nose
  • acid reflux
  • anxiety, irritability, hyperactivity
  • digestive issues
  • tachycardia or arrhythmia
  • fatigue

I like the way the author of Peeling Back the Onion Layers explains it:

Everyone has a different tolerance for histamines. Some have serious mast cell disorders and need to be extremely vigilant about histamines in the diet. Some people need to restrict histamines in their diet to avoid migraines and terrible insomnia. Others just need to watch their histamine load to avoid crossing their threshold and feeling a little cranky or noticing a decline in their digestion.

A lack of the diamine oxidase (DAO) enzyme can cause issues with histamines.  The gene AOC1 codes for the production of diamine oxidase.  There are a couple of AOC1 polymorphisms included in 23andMe data that have been linked to reduced production of DAO.

Check your 23andMe results for rs10156191:

  •  CC: Normal DAO production
  •  CT: Reduced DAO production [ref]
  •  TT: Reduced DAO production


Check your 23andMe results for rs1049742:

  •  CC: Normal DAO production
  •  CT: Reduced DAO production [ref]
  •  TT: Reduced DAO production


So how does this tie together with the methylation cycle?  From Chapter 2: Nutrigenomics and the Methylation Cycle by Dr. Amy Yasko:

The functional areas impacted by improper methylation are in a dynamic relationship with one another—that is, they are mutually interactive. So it is with the relationship of your immune cells to digestive issues. Since many of your immune cells reside in the digestive tract, there’s a close relationship between methylation, immunity, and such digestive problems as leaky gut, allergies, and various forms of digestive distress that the children commonly experience. Briefly, if methylation is low and T cell production is low, then histamine levels tend to be high. Histamine is linked to inflammation, a contributing factors to leaky gut as well as allergies.

With the underactivity of T cells, B cell activity can take over, which can lead to autoimmune issues like allergies and food sensitivities.

This makes sense when you look at the big picture of how methylation cycle problems can affect the health of the whole body.  I do need to note, though, that this is not something for which I can find any research studies to back up Dr. Yasko’s position.

So for those who have MTHFR polymorphisms or other methylation cycle problems, histamine intolerance can be tied into overall immune health.   As your health overall improves, often histamines will become less of a problem.

A diet of low histamine foods can help to get you back on track and manage the symptoms that too much histamine is causing you.  But getting to the root of the matter will require a healthy gut.  For those with methylation cycle issues, a diet rich in green vegetables will help increase folate levels, and there are supplements for methylfolate and B12 that may help as well.* Another avenue to look at for gut health and inflammation is the role that surfactants in our foods play in our gut microbiome.

Additional Reading:

Updated Feb. 2017