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Methylation Genes – How They Can Be Modified To Improve Your Health

The addition of one carbon and 3 hydrogens (a methyl group) to a molecule in order to convert it into a completely different molecule is called methylation. It is a chemical reaction that is basic and critical to life. Dozens of these critical reactions exist in our bodies, which perform many diverse tasks. Notable examples are the synthesizing of melatonin to help with sleep, making special lipids (phospholipids) that cell membranes are primarily composed of, and slowing down cell division to prevent cancer. Most importantly, methylation of the main fight/flight neurotransmitter in the brain, noradrenalin, in order to metabolize it away, is especially important for relaxation, sleep and inner peace.

Generally, those who are genetically less capable of methylation are often labeled as having “methylation defects,” as if such people are genetic misfits. In fact, having some hypomethylation tendencies can confer benefits. These so called “defective” people are often more productive, robust workers, emotionally sensitive and creative individuals, because they are less capable of metabolizing away the primary, fight/flight neurotransmitter, noradrenalin, from their brains. They tend to worry and care more about themselves and others.

Is It Genetics or Just Your Personality?

The down side to being a hypomethylator is a tendency to be more compulsive, perfectionistic, anxious, addiction-prone and moody. In our younger years, when we are more physiologically able to withstand extra fight/flight, sympathetic stress, there is a tendency to become over-achievers. We are driven by our genes to work harder and make more money. We can appear to be extroverted movers and shakers, and be attractive as mates, which is why these genes are so common. We pass them on during our reproductive years to produce unsuspecting, hypomethylating children. Later, after midlife and the child-bearing years, the extra sympathetic stress can take its toll in the form of higher cancer and heart disease rates.

A little more genetic “high energy” can be helpful, but too much of a good thing can be a bad thing. The same is true of the hypomethylators. We all get 2 sets of genes from each parent, and those of us who get one abnormal methylation gene and one normal gene can get the benefits of more productivity and success, even though we can pay somewhat of a downside price by experiencing some extra stress. Being less capable of methylating away the fight/flight neurotransmitter noradrenalin, we are thus more likely to incur a heightened and sustained stress response from stressors of any cause (emotional, metabolic (e.g., low blood sugar), infectious (e.g., candida), toxic (e.g., mercury) or energetic (e.g., wi-fis and microwaves). But having a heightened tendency to be motivated by extra stress, the up-side of having these defects can compel us to have increased drive to succeed and be more productive.

The Process is Like a Relay Race

The mechanism of methylation is like runners handing off the baton in a relay race. Methyl groups come from various sources or donor molecules, which wind up on a type of folic acid called 5-MTHF or 5-methyl-tetra-hydro-folate. The MTHFR gene is usually a rate limiting step in the race, and it is responsible for getting the 5-MTHF into its final, active form. The 5-MTHF then hands off the methyl groups to B12, which in turn hands them off like a runner in a race to homocysteine which then becomes methionine, which turns into SAMe or s-adenosylmethionine which then hands off the methyl groups to dozens of different molecules, including noradrenalin, the anxiety-, perfectionism-, compulsivity-causing, fight/flight neurotransmitter to make it go away. Another important job of 5-MTHF is to methylate a serotonin metabolite to synthesize melatonin so we can sleep better.

If one has quirky substitution in MTHFR (methylene-tetra-hydro-folate-reductase) which is blueprinted from a gene by the same name, it is like having a slower runner in the first leg of the race. Ultimately the dozens of possible methylations that could happen at the end of the race don’t happen as well. Again, a runner who is a little slower may confer advantages, while a very slow runner in the beginning of the race can lead to serious problems.

At the end of the race, another common, quirky gene (polymorphism is the proper term) called the COMT (catechol-O-methyl transferase) gene can slow things down too. Some unfortunate people have serious methylation problems at both ends, that is, a slow runner in the beginning and at the end of the race, and they often face a lifetime of struggle with mental problems, addictions and other medical issues as they age. I personally believe it is important for anyone suffering from a mental disorder or an addiction to test for methylation defects. Likewise, every middle-aged and older patient who has cancer or heart disease should determine if their genetic makeup could be playing a role. The MTHFR and COMT SNPs (actually the proper term – single, nucleotide polymorphisms ) are very common, potentially very serious and their expression is extremely modifiable.

Looking at MTHFR in More Depth

How can a little bit of a genetic “defect” be good, and having too much be bad? Consider another common genetic quirk which you may be more familiar with, sickle-cell disease. The genetic abnormality which causes hemoglobin to be made in a different way provides protection against malaria, a disease which has been so devastating that some medical anthropologists suggest it has killed more human beings in history than all other diseases combined. Those who have one sickling gene from one parent and a normal gene from the other parent – called sickle-cell trait – have the best of both worlds. Their hemoglobin is fairly functional because the normal gene from one parent covers up the expression of sickling gene. The sickling gene however, confers protection against malaria.

A much smaller proportion of people have two abnormal genes (called homozygous), and they then become prone to developing sickle cell disease, a potentially disabling condition. But since malaria is so common and devastating, and because the more common, partial inheritance condition (called heterozygous) offers protection, a selective advantage exists for this gene to be commonly expressed in those whose ancestry originated from malaria-infested parts of the world. Since the percentage of those with the homozygous inheritance are much less common, that selective disadvantage is over-ridden by the selective advantage of having sickle cell trait.

Similarly, those who have some methylation problems, can have a selective advantage, while those who are severe hypomethylators, a much smaller group, can have some serious disadvantages. Hypomethylation has been associated with alcoholism and addictions, bipolar disorder, cancer and heart disease, which altogether accounts for the lion’s share of chronic diseases. Again, I believe it is incumbent on all healthcare practitioners to determine who the more severe hypomethylators are, and modify their genetic expression to achieve prevention and a better state of wellness.

MTHFR is probably the most important of the hypomethylation genes because its effects are potentially very powerful in disrupting methylation, and it is the most common. There are 2 independent and important SNPs on the MTHFR gene, the 677CT and the 1298AC, and these names designate the locations (addresses) on the gene where the quirky substitutions exist. There are 7 possible variations of the MTHFR gene caused by these 2 SNPs which cause progressively slower methylation as indicated in the table below.1 A designation of (-/-) is the normal variant, (-/+) is the heterozygous condition and (+/+) is the potentially more serious expression of the SNPs indicating that the inheritance of the SNP came from both parents.

methylation table

Note: The table above was extracted from a document at Genova Diagnostics:

Genova also provides genetic testing and other excellent educational resources for you and your healthcare provider.

As you can see from the chart, the weaker 1298AC only causes problems in the homozygous inheritance pattern (+/+), which can slow methylation by 30% to 40%. As you move to the right to increasingly more severe inheritance patterns, a combination homozygous 677CT (+/+) and heterozygous 1298AC (+/-) on the far right can cause a 60% to 70% decrease in methylation abilities.

Generally, those who are in the 30% to 40% category can get by with one or two mg. of methylfolate twice a day, while those in higher categories of hypomethylation should probably receive the “pharmaceutical” Deplin (3.5 – 7.5 mg. twice a day of methyl folate) or an equivalent higher dosage. (Note: Deplin, although prescribed like a drug, is actually a nutrient)

If one falls into the more serious MTHFR SNPs categories and no other information is known, I usually suggest the following in order to handle other methylation SNPs (like COMT which we discussed above) which may be lurking behind the scenes.

1) B Complex – 1 twice a day,

2) SAMe 400 mg. twice a day, 1 hour before meals (start with lower doses and slowly work up),

3) B12 sublingual – 5,000 mcg. a day),

4) Betaine 500 mg. – 1 with meals,

5) Optizinc 20 mg. – 1 a day,

6) Magnesium taurate 1000 mg. – 1 twice a day.

The best option is to work with a healthcare provider who regularly evaluates important, common and modifiable SNPs like those involving the MTHFR gene, and build this information into your overall treatment plan. If you have trouble locating a healthcare practitioner who does this work, the Academy of Functional Medicine and Genomics provides educational and wellness consults by phone to discuss your genetic testing. The MTHFR, COMT, other methylation SNPs, as well as dozens of other important SNPs which can influence your wellness, are all available in a $99 consumer-friendly, saliva test provided by 23 And Me ( ).

Review this page – Wellness Education –  for more information about consumer testing and  changing the genetic expression of your SNPs.

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