A Closer Look at Genetic Mutations and How They Work – or Don’t

I’ve written before about the genetic testing I did with 23andMe <–my referral link, and especially about my MTHFR mutation, but it’s far more complicated than that. (And MTHFR is pretty complicated!) There are a host of other genetic mutations that make dealing with my DNA far more nuanced than just taking methylfolate and methyl-B12 supplements.

Here is a brief summary of some of the SNPs that cause me trouble with methylation, according to Genetic Genie:

• +/+ MTHFR A1298C, VDR Taq, BHMT-08, CBS A360A
• +/- COMT V158M, COMT H62H, MTRR A66G, BHMT-02, BHMT-04, AHCY-01, AHCY-02, AHCY-19

I decided to put this blog post together to summarize how each of these things specifically affects my body. I’m going to tackle the homozygous SNPs first, the ones where I have two copies of the “bad” SNP. I’ll tackle the heterozygous SNPs after those, the ones where I only have one copy of the “bad” SNP.

+/+ MTHFR A1298C

This is the one I’ve spent the most time and word count on. The MTHFR gene (methylenetetrahydrofolate reductase) is responsible for part of the body’s methylation process, in part by converting homocysteine to methionine.

MTHFR A1298C converts 5-methylfolate (5MTHF) to tetrahydrofolate (THF), without elevating homocysteine levels, to generate BH4. BH4 aids the body in ammonia detoxification and is a limiting factor in neurotransmitter production. (For all of the research I’ve done on MTHFR so far, this is the first time I’ve made a connection with my bad reaction to most hair color. I can only use ammonia-free hair dye because of my bad reaction to ammonia fumes.) Being homozygous for the MTHFR A1298C mutation can lead to a decrease in levels of serotonin, melatonin, dopamine, norepinephrine, and epinephrine. These neurotransmitters are crucial for energy levels, sleep, and mood regulation, which helps explain my chronic fatigue syndrome (CFS) with its accompanying insomnia, as well as my major depression and generalized anxiety disorder. Mercury, lead, and aluminum can further inhibit BH4, and I am well aware of my exposure to lead at various points in my life.

Nutritionally, this lends itself to methylfolate and methyl-B12 supplementation.

+/+ VDR Taq

VDR stands for Vitamin D Receptor. Vitamin D deficiencies are not uncommon, particularly in the northeastern United States where I’ve lived my entire life, but my homozygous VDR Taq status is apparently related to my heterozygous COMT status. I had to visit a page on a site called HeartFixer.com to find that this particular combination of genes results in: lowest dopamine levels, poor tolerance to toxins and microbes, lowest susceptibility to mood swings (ha!), and the both the need and tolerance for dopamine precursors and methyl donors.

Nutritionally, I already knew I need to supplement with Vitamin D3. It looks like I should also look into gingko biloba and tyrosine as dopamine precursors, and possibly melatonin, TMG, turmeric, and theanine as additional methyl donors.

+/+ BHMT-08

BHMT stands for betaine homocysteine methyltransferase, acting as a methylation shortcut by helping convert homocysteine to methionine. The BHMT-08 mutation can be linked to elevated glycine levels. “[Dr.] Yasko also believes that BHMT-08 is related to the impact that psychological stress has on a patient’s attention levels.” Hmm, yeah, I have attention problems, especially when I’m stressed.

Nutritionally, I don’t see any advice concerning this one.

+/+ CBS A360A

CBS stands for cystathionine beta synthase. It acts as a catalyst in the first step of the transsulfuration pathway from homocysteine to cystathionine. My homozygous mutation means this enzyme works too fast, leading to low levels of cystathionine and homocysteine but high levels of taurine and ammonia. It can be associated with sulfur intolerance, but at least when it comes to my Epsom salt baths (magnesium sulfate) I haven’t noticed an issue with this. But my CBS mutation further depletes my BH4, which is already a problem due to my MTHFR mutation.

The upshot for this one is that I need to pay attention to whether or not I develop a sensitivity to sulfur.

+/- COMT V158M, COMT H62H

COMT stands for catechol-O-methyltransferase. It break down certain neurotransmitters and catecholamines, like dopamine, epinephrine, and norepinephrine. Just to be contrary about that whole “less susceptible to mood swings” thing with VDR Taq, being COMT+ can work the other way around. I guess that’s the complicating factor for my temperament. This enzyme messes with the prefrontal cortex of my brain, which is responsible for personality, inhibition of behaviors, short-term memory, planning, abstract thinking, and emotion. Oh, and pain sensitivity. I have a very low tolerance for pain. Since COMT also aids in estrogen regulation, it can be associated with breast cancer risk.

COMT V158M has been described by worrier vs. warrior. I have a copy of each side of the coin, though those who know me are more familiar with the worrier side.

COMT H62H seems to be associated with an increased risk of endometrial cancer, though personally, I only carry one copy of the risk gene.

Nutritionally, my COMT status can give me some trouble with methyl donors.

+/- MTRR A66G

MTRR is the gene responsible for the regulation of the enzyme 5-Methyltetrahydrofolate-Homocysteine Methyltransferase Reductase, also known as MTR. MTR recycles vitamin B12 in order to convert homocysteine to methionine. There would be more for me to worry about if I was homozygous instead of heterozygous, but since there’s not, I’m not going to get into that here.

Nutritionally, this increases my need for methyl-B12.

+/- BHMT-02, BHMT-04

I have already mentioned my homozygous BHMT-08 mutation above, but I am heterozygous for two other mutations. These two SNPs are “thought to play a role in gut environment,” which is a frustratingly vague description.

My best guess is that I should eat more yogurt and/or take probiotics. Honestly, shouldn’t we all?

+/- AHCY-01, AHCY-02, AHCY-19

AHCY stands for S-adenosylhomocysteine hydrolase, which helps break down methionine. I’m just going to quote this passage from SNPedia to break this down:

It controls the step that converts S-adenosylhomocysteine hydrolase to adenosine and homocysteine. Adenosine plays an important role in energy transfer as ATP and ADP. It helps promote sleep and suppress arousal. Dysfunction of this enzyme can affect levels of homocysteine and ammonia. Some physicians claim AHCY mutations may actually take the strain off the CBS enzyme and may even prevent taurine from becoming very elevated.

So…more homocysteine and ammonia troubles. And since a copy of each of three mutations on this gene live in me, it makes sense that I experience difficulties with energy and sleep. I had to look up this graph to make more sense of the whole thing.

Nutritionally…this is where things get murky. It’s suggested that methylfolate and methyl-B12 could exacerbate AHCY mutation problems. I don’t know how much weight to place on this complication since I have homozygous mutations demanding supplements and only heterozygous mutations suggesting to avoid them.

BUT I’m not doing badly with a low-methionine diet, since I don’t eat a lot of meat. Bonus? I might be doing myself a favor with my caffeine consumption, which can counteract too-high levels of adenosine.

Other SNPs of Note

A 2009 study titled A comparison of classification methods for predicting Chronic Fatigue Syndrome based on genetic data listed 42 SNPs associated with chronic fatigue syndrome, so I took a look at my 23andMe raw data to identify which of them I possessed copies of. Unfortunately, 23andMe did not include all 42 of these on my report, but I made note of those that were of clinical significance and not considered my “ancestral alleles.” I’ll list them by gene:

• COMT (break down certain neurotransmitters and catecholamines)
  • rs4646312 (CT)
  • rs6269 (AG)
  • rs4633 (CT)
  • rs165722 (CT)
  • rs933271 (CT)
  • rs5993882 (GT)
• CRHR1 (a mediator of endocrine, autonomic, behavioral, and immune responses to stress)
  • rs110402 (AG)
  • rs1396862 (AG)
  • rs173365 (AG)
  • rs242924 (GT)
  • rs7209436 (CC)
• CRHR2 (a mediator of endocrine, autonomic, behavioral, and immune responses to stress)
  • rs2267710 (TT)
  • rs2284217 (AG)
• MAOA (breaks down neurotransmitters and can be related to inflammation)
  • rs979605 (AA)
• MAOB (mainly breaks down dopamine)
  • rs3027452 (AG)
  • rs1799836 (CT)
  • rs2283729 (GG)
• NR3C1 (glucocorticoid receptor, regulates genes controlling the development, metabolism, and immune response)
  • rs2918419 (TT)
  • rs852977 (AA)
  • rs6188 (CC)
  • rs258750 (AA)
• SLC6A4 (involved in serotonin reuptake)
  • rs2066713 (AA)
  • rs140701 (CC)
• TH (helps make dopamine)
  • rs2070762 (AG)
• TPH2 (helps make serotonin, causally involved in CNS, and aids in maintenance of vascular tone and gut motility)
  • rs2171363 (AG)
  • rs4760816 (CT)
  • rs1386486 (AG)

I would like to point out that, despite 23andMe not giving me data for several of the important SNPs, I contain at least one copy of 27 of the risk alleles, two copies (homozygous) for 10 of them.

I can’t provide much more information about these SNPs, because not many of them have much information publicly available at this time. It may be worth noting, though, that research connects many of these same polymorphisms to autism and mental illness.

Read my Big Fat Medical Update for more details.

Christina Gleason (976 Posts)

That’s me: Christina Gleason. I’m a writer, editor, and disability advocate. I'm a multiply disabled autistic lady doing my best in this world built for abled people. I’m a geek for grammar, fantasy, and casual gaming. I hate vegetables. I cannot reliably speak, so I’ll happily conduct business over email or messaging instead.