In the first part of this article, I discussed what SNPs are and how they occur, what’s included with a 23andme genetic test, and the very basics of MTHFR.
I also clarified the difference between folic acid and folate.
Let’s Continue On, Shall We?
Methylfolate is a form of folate, which is also called vitamin B9. Folate helps to rebuild and repair DNA, it helps to convert homocysteine (a marker for cardiovascular disease) back into the amino acid methionine, it plays a part in neurotransmitter production and is essential for growing a fetus.
It is also well known for playing an integral part in the methylation pathway.
What the Heck is Methylation?
The simple definition of methylation is the addition of a methyl group (CH3 – one carbon with three hydrogens) to DNA. This methyl group helps to determine how a gene expresses. Just because you “have the breast cancer gene” (everyone has the gene, but as I described in the first post, “having a gene” usually means having the risk allele/defect copy) doesn’t mean it will express, but having a lack of methyl groups increases the likelihood that it will express… Got it?
Methylation is critical for a seemingly endless amount of essential functions in the body, including DNA synthesis and repair, neurotransmitter functioning (mental/emotional health), expression of genes, detoxification (especially of heavy metals) and immune system regulation.
It affects numerous other pathways and cycles in the body, including the urea cycle and the Krebs Cycle that is responsible for energy production.
So, yes, super important.
The body uses folate for many chemical reactions related to methylation.
The Two Main MTHFR SNPs
There are numerous MTHFR variants, with even more genes & variants involved in the folate conversion pathway, but most of the research conducted has been on two forms of MTHFR: A1298C and C677T.
To strip MTHFR down to bare-naked layman’s terms, the C677T variant has been highly associated with cardiovascular issues and poor detoxification, while the A1298C variant has been linked with mood disorders/neurotransmitter imbalances and issues associated with elevated ammonia levels.
To recap, if you are heterozygous (defined in Part 1) for one of these variants, your MTHFR gene is working at about, roughly, a 30% reduced efficiency. If you are homozygous, that can be reduced as much as 70%. If you have one copy of each, you are considered “compound heterozygous” and efficiency can run anywhere in between those percentages.
It has been estimated that 40-60% of our population has some form of MTHFR variant. That’s quite a lot of people that don’t effectively process folic acid and therefore likely have less than optimal detoxification or other factors associated with methylation. This variant also has been associated with miscarriage.
Check out this article from the US National Library of Medicine/NIH on issues surrounding folic acid fortification (among which are autism, colorectal cancer, Alzheimers and other neuropsychiatric disorders, and insulin resistance in offspring). I bet it’ll make you feel as disconcerted as it made me feel.
Now that you’ve determined you have an MTHFR SNP, a little folate supplementation might not do any harm for some, but might cause others to drop some of their marbles like Crispin Glover on Letterman… And it may not happen immediately. You might feel pretty great at first, but then crash and burn after a week or two. This is because there are other SNPs that should be addressed before addressing MTHFR or the rest of the folate pathway.
There is an order of action to remediating or compensating for MTHFR SNPs. Just throwing methylfolate into your picture can make your protocol backfire.
I like to use the analogy that if a building is on fire, you wanna call the fire department, not the construction crew (folate is needed to build and repair). If there is some degree of inflammation in the body, that is what most definitely needs to be extinguished first and foremost. Throwing folate into the mix right off the bat can surely exacerbate issues.
Mitigating inflammation is a pretty hefty first step, as it can come from a gazillion different things with diet and lifestyle – food sensitivities, gut issues, toxicants, stress, etc. But from a genetic perspective, one’s genes can cause a predisposition to inflammation from issues like:
Mitochondrial dysfunction (symptomized by low energy/chronic fatigue)
Poor fatty acid utilization/metabolism (which also affects mitochondrial energy production, since fat is needed for the mitochondria to make ATP).
Iron oxidation (iron that is not properly used by the body can oxidize and cause inflammation. This can happen even if you have been diagnosed as anemic!)
Excess free radical production – Free radicals cause oxidative stress, which has been inked to chronic diseases and disorders of all kinds. Similarly, free radicals and oxidative stress can come from many different sources. **Go ahead and Google “Oxidative Stress and disease” and have your mind blown by scientists for an afternoon.
Elevated ammonia levels
Poor detoxification – either from not enough antioxidants, or levels of toxins above the body’s ability to clear them.
I generally recommend that clients work to lower inflammation for at least a few months before beginning to target methylation issues (lowering inflammation alone will begin to enhance methylation capacity).
Rather than reducing MTHFR (or any SNP for that matter) to a single problem that needs one nutrient to help compensate, it is crucial to look at groups of SNPs, or even more importantly, entire biochemical pathways and the diet/lifestyle of the person to determine a route of action.
The SNPs just give clues as to what could be causing an issue.
Once the so called fire is extinguished, it still would be jumping the gun to start with folate supplementation if, for instance, B12 levels are low, or if there are SNPs that could possibly be causing an increase in sulfites, glutamate and/or ammonia.
Also, unless you have adequate glutathione levels, taking methylfolate will make you more inflamed. If detox abilities or pathways are not up to par, stimulating methylation will spur detoxification and can cause problems if the body isn’t able to adequately deal with the toxins that are stirred up. The reason for this is because if you are low in glutathione and start taking methylfolate, you stimulate Phase 1 liver detox and that creates toxins that have to be cleared by Phase 2, which involves glutathione.
If B12 levels are low and someone supplements with a higher dose of folate than the body can handle, “methyl trapping” can occur. Methyl trapping is problematic because methylfolate cannot work without cobalamin (B12). The folate is not properly utilized and serum folate rises while intracellular folate levels suffer.
Having SNPs in certain genes can indicate potential problems with B12 (TCN, GIF, FUT2, MTR, MTRR). These SNPs may affect the body’s ability to produce B12, transport it, or absorb it. The form of cobalamin to supplement with is also something to consider, but that may be a topic for a future post.
Regarding Ammonia and Glutamate
Quite a few different SNPs can predispose people to elevated ammonia and/or glutamate levels (in addition to other factors, like inadequate beneficial gut bacteria), both of which can cause anxiety, quick irritation, brain fog and adrenal fatigue. These genetic predispositions seem to manifest when someone has multiple SNPs in the related genes, such as the CBS and BHMT genes, or SNPs involved with glutamate precursors and conversions in the urea cycle*. These issues need to be addressed prior to adding folate because, first, elevated ammonia is very inflammatory, and second, because adding methyl donors like methylfolate will “fuel” the ammonia production if there are SNPs in something called the transsulfuration pathway.
So, what I’m basically saying is that this shiz is complex and it’s probably a good idea to have a practitioner guide you through your results and interpretation.
While there are some specific supplements that can help target and compensate for SNPs, lifestyle and diet upgrades are at the heart of healing.
Making Use and Making Sense of Your Interpretation
There is a rapidly growing number of genetic testing interpretation services. They all vary in how many SNPs they include and which ones. Many are solely done via computer, leaving you sitting in front of your computer for hours Googling yourself down deep, deep rabbit holes to piece together a not-so-clear picture of what the hell is going on with your particular SNP ensemble.
The software I use is the MethylGenetic Nutrition Analysis software. It currently looks at over 1,500 SNPs, grouped into areas of genes and SNPs involved with:
- The Krebs cycle/ATP production
- Gut health predisposition
- Histamine clearance
- Detoxification capacity
- The folate and methionine cycles
- The potential for elevated ammonia and glutamate levels
- Proper neurotransmitter degradation.
These results contain different types of information than the health report that 23andme provides for their $199 package (more on that below). But the best part is, you get to talk to a practitioner face to face (or phone, Skype, etc) to walk you through the report. My consults are generally 1 1/2 hours because the report is so chock-full of info.
The info that is used for interpretation services is the “raw data” that looks like a bunch of mumbo jumbo coding. The raw data can quickly and easily be uploaded to the MethylGenetic Nutrition Analysis software. Getting the report only takes about 2 minutes. The raw data comes with the $99 kit from 23andme that offers the ancestry but not the health reports.
How the 23andme Health Reports Vary From the MethylGenetic Nutrition Analysis Reports
The 23andme health reports vary from the MethylGenetic Nutrition Analysis reports and other interpretation services in that 23andme’s health reports tell you information like whether or not you are a carrier for certain diseases and syndromes (such as Maple Syrup Urine disease and Tay-Sachs disease), or if you likely flush when consuming alcohol or if your ear wax is wet or crumbly. It does not give an idea of what could be causing your inflammation or neurotransmitter imbalance.
A variety of clients come to me in regards to interpreting their raw data. Some just want me to help them make sense of it, so they are the "one and done" type of clients. Other clients want to go deeper into lifestyle, diet and supplementation upgrades so they can improve their situation, like how to improve detoxification capacity, slash inflammation, or learn what order of action should take place to support their genetic variants.
Whatever your interest is in genetic testing, know that it is rapidly becoming the rate limiting factor in personalized health care – whether from an allopathic approach (called pharmacogenetics) or from a naturopathic/functional/integrative approach that uses targeted supplementation combined with dietary, environmental, and lifestyle upgrades.
Feel free to drop me a line if you have any questions or interest in learning more!
*(Michael McEvoy of Rebel Health Tribe and Metabolic Healing has written more in depth posts on both of these topics, for those that want to delve a lot deeper)