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Interesting COMT Variations

Valentijn

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Instead of "risk", as used thus far in other methylation lists, I'm marking the slower versions. The reason for this is because slow and fast COMT genes each have different medical risks, but for the purposes of methylation, it's the slow versions which can make things trickier, as the slow versions may result in reduced tolerance of methyl groups in supplements.

"Implied" slow alleles are based on studies where novelty seeking is associated the other allele, as novelty seeking has been associated with up-regulation. I'm not as confident in those sorts of studies, as they're basically making a lot of assumptions based on questionnaires and interpretations of behavior. Two haplotypes are listed at the end. These are only relevant when all of the alleles are present.

SNP names are underlined, bolded, and orange when they indicate a missense mutations. Rare missense mutations lacking research have a "?" after the rare allele, as it's not known if that rare allele is a down-regulation or an up-regulation.

rsID.........NAME....SLOWER...ETC
rs737866.....T689C...C.......Implied
rs737865.....A701G...G
rs4646312....T385C...T.......Implied
rs165722.....C201T...C.......Implied
rs6269.......A98G....A
rs6270.......C34S....C?
rs4633.......H62H....TT
rs6267.......A72S....T
rs13306281...V92M....A?
rs61910731...V100L...T?
rs5031015....A102T...A?
rs4986871....A146V...T?
rs4680.......V158M...AA.....1/3 activity
rs13306279...P199L...T?
rs174696.....C1354T..C.......Implied
rs9332377....C367T...T
rs165599.....G522A...G

Haplotype I (only relevant when all of these versions are present):
rs4646316....C310T...C
rs9332377....C367T...T

Haplotype II (58-fold reduction in function when all of these versions are present):
rs6269.......A98G....A
rs4633.......H62H....C
rs4646312....T385C...T......See Note
rs4680.......V158M...G

Note: rs4646312 in Haplotype II is reported with the more common allele of rs4818 as the risk factor. 23andMe doesn't contain that SNP, but rs4646312 has identical and nearly identical prevalence rates in the various groups genotyped, hence is likely usually inherited in a "chunk" with rs4818. So the results of rs4646312 will usually be applicable, but might not be in some cases.
 

Valentijn

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So what is COMT and why is it worth discussing in the context of methylation?

Basically it's involved in the breakdown of some neurotransmitters, and when those neurotransmitters break down, they use a methyl group in the process. Thus someone with faster COMT will use up more methyl groups and have a greater tolerance for supplements involving methyl groups, such as methylfolate and methylB12.

Conversely, someone with slower COMT won't be using up methyl groups as quickly, and might need to be careful about adding too many into the mix via supplementation.

PS - I really hate this gene. It's one huge mess, with a ton of research to sort though. And too much of it reminds me of the "this personality type is associated with developing CFS" BS :mad:
 

Sea

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Are you sure of the alleles for haplotype 2 Valentijn? Rs4633 is listed with T as the slower version in the top list but with C as the version for the haplotype.
 

Valentijn

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Are you sure of the alleles for haplotype 2 Valentijn? Rs4633 is listed with T as the slower version in the top list but with C as the version for the haplotype.
Yup. A lot of things change quite a bit in haplotypes.
 

Critterina

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Valentijn,

I really like all the work you do and post like this. I saw the rare MTHFR and this one. Have I missed any?

I tolerate methyl groups very well, so no surprise that my only result was

COMT...rs165722.....C201T...C.......Implied +/+

Thank you!
 

Valentijn

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So I have :
rs4680.......V158M...AA.....1/3 activity

Do I lose 1/3 activity or only have 1/3 activity. Is this why I appear to be tolerating methyl groups?

I also have H62H TT
AA has one-third of the activity as the other homozygous genotype for the SNP. So it's running at 33%. But that's not necessarily saying that AA is "too slow", just that it's slower than than the other version, which might just as easily be considered "too fast".

H62H probably has less of an impact than V158M, since H62H isn't a missense or other mutation resulting in a change in the structure of the gene.

There's probably a lot of factors that go into tolerating methyl groups, and frankly I haven't see any proof that slower COMT results in less tolerance of methyl groups - but I also haven't looked, and it does make some sense in theory at least.
 

Al Klein

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Valentijn,

I really like all the work you do and post like this. I saw the rare MTHFR and this one. Have I missed any?

I tolerate methyl groups very well, so no surprise that my only result was

COMT...rs165722.....C201T...C.......Implied +/+

Thank you!
Hey!
What did you use that reported the above? Just intrigued. rs165722 TT is listed in my 23andme full genome list, but then not reported from livewello - just wondered if I'm missing anymore (although struggling to keep up with the ones that I have!)
 

Creekee

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Thanks for all the info, Valentijn! I am a bit COMT confused here. Genetic Genie says:

COMT V158M AA +/+
COMT H62H TT +/+
COMT P199P AG +/-


Started a methylation protocol for the first time in early March. Ever-tweaking, but so far unable to trigger any over-methylation.

I do have +/+ VDR Taq. Maybe that's compensating some?

Really appreciate all the research you're sharing. So interesting!
 

musicchick581

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In haplotype 2, I have all of those but I have heterozygous risk alleles, ex.

rs4680, you say G is a slower COMT, well I have AG. I have that pattern for all of those under haplotype 2. Does this mean I don't have the 58 fold reduction? Do they have to be homozygous?
 

Valentijn

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rs4680, you say G is a slower COMT, well I have AG. I have that pattern for all of those under haplotype 2. Does this mean I don't have the 58 fold reduction? Do they have to be homozygous?
No idea ... the research never specifies that when they're looking at haplotypes.
 

taniaaust1

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I thought I'd put the following link here rather then starting a new COMT thread . I just come across the following and thought it may be of interest to some who have COMT mutations http://www.mayomedicallaboratories.com/test-catalog/Clinical and Interpretive/83301 (sorry if this is already here somewhere).

A single nucleotide polymorphism in exon 4 of the gene produces an amino acid change from valine to methionine (Val108/158Met). This polymorphism, COMT*2, reduces the maximum activity of the variant enzyme by 25% and also results in significantly less immunoreactive COMT protein, resulting in a 3-fold to 4-fold decrease in activity compared to wild type *1.

A second functional polymorphism has been identified in exon 4 that results in a threonine substitution for alanine (Ala52/102Thr). This polymorphism, COMT*3, reduces the maximum activity of the variant enzyme by 40% compared to the wild-type enzyme.
For those who dont know terms.. the term "wild type" is refering to anyone who doesnt have a mutation.

All the below info is out of the link I put before.

COMT Allele
Amino Acid Change
Effect on Enzyme Activity/Metabolism

*1
None (wild-type)
Normal/Extensive
*2
Val108/158Met
Reduced/Poor
*3
Ala52/102Thr
Reduced/Intermediate

Drugs that undergo metabolism by COMT:

-Alpha-methyl DOPA
-Apomorphine
-Benserazide
-Bitolterol
-Dihydroxyphenylserine
-Dobutamine
-Dopamine
-Epinephrine
-2-Hydroxyestrogens
-4-Hydroxyestogens
-Isoetherine
-Isoprenaline
-Isoproterenal
-Norepinephrine
-Rimiterol

Coadministration may decrease the rate of elimination of other drugs metabolized by COMT.

Drugs that undergo structural modification but are not metabolized by COMT:

-Albuterol
-Metaproterenol
-Methoxamine
-Phenylephrine
-Perbuterol
-Terbutaline

Coadministration will not decrease the rate of elimination metabolism of other drugs metabolized by COMT.

Drugs known to inhibit COMT activity:

-Entacapone
-Tolcapone
-Nitecapone

Dietary Components that inhibit COMT activity:

-Quercetin
-Tea catechins

Coadministration will decrease the rate of metabolism of COMT metabolized drugs, increasing the possibility of toxicity, including in heterozygous individuals.
 
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AA has one-third of the activity as the other homozygous genotype for the SNP. So it's running at 33%. But that's not necessarily saying that AA is "too slow", just that it's slower than than the other version, which might just as easily be considered "too fast".

H62H probably has less of an impact than V158M, since H62H isn't a missense or other mutation resulting in a change in the structure of the gene.

There's probably a lot of factors that go into tolerating methyl groups, and frankly I haven't see any proof that slower COMT results in less tolerance of methyl groups - but I also haven't looked, and it does make some sense in theory at least.
@Valentijn

I hoped you could help clear up some confusion. I am homozygous for both SNP's, and assume therefore I'm working slowly (H62H) + 1/3 of slowly (V158M). But I don't understand how to interpret the V158M by reference to the H62H in real terms. How can we describe H62H as "too fast" in any sense if we are homozygous for the "slower" H62H genotype? Surely, we are just running slowly.

I also don't really understand how we are able to compare V158M by reference to H62H when H62H may have less of an impact that V158M, because it isn't a missense or other mutation? I'm left wondering what 1/3 of the activity of H62H means in practice. :thumbdown: Perhaps the most useful genotype is V158M? If you're homozygous for this, you can reasonably assume that methyl donors could prove problematic - or at least tread carefully, bearing in mind there are those mutations, such as rs13306279...P199L...T?) for which there is no reliable evidence that it's an up- or down-regulation).

Any thoughts would be great!
 

Valentijn

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I am homozygous for both SNP's, and assume therefore I'm working slowly (H62H) + 1/3 of slowly (V158M). But I don't understand how to interpret the V158M by reference to the H62H in real terms. How can we describe H62H as "too fast" in any sense if we are homozygous for the "slower" H62H genotype? Surely, we are just running slowly.
I meant that being homozygous for the "slow" version doesn't necessarily mean that you're running slow. You could just as well think of it as running at "normal" speed, which people homozygous for the opposite version are "fast". There's really not any indication that the fast or slow version is at all abnormal, hence having the "slow" (or normal?) version isn't anything to get worried about "treating".

H62H and V158M look like they're in complete linkage disequilibrium - so if someone is +/+ for one, they're almost always +/+ for the other. Hence any research linking H62H to different gene function is probably a bit of a false positive, and it really is just showing an association due to study participants having the identical version of V158M. So H62H is useless for determining gene function, unless you don't have access to your V158M alleles.
 

Lynn_M

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Valentijn,
I think I qualify as Haplotype II, if heterozygous conditions qualify.

Haplotype II (58-fold reduction in function when all of these versions are present):
rs6269.......A98G....A Me: AA
rs4633.......H62H....C Me: CT
rs4646312....T385C...T Me: TT
rs4680.......V158M...G Me: AG

I have high levels of 4-hydroxyestrogen, so I suspect I do have reduced COMT function. 58 fold seems questionable.

I tried to find info about Haplotype II, but didn't see anything that matched your info. Can you provide any leads as to where to find more info?
 

Lynn_M

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Valentijn,
Thanks for the link. Figure 1 of http://molehr.oxfordjournals.org/content/17/7/439.full is a table of 4 different haplotypes for COMT. Low activity COMT is designated as comprising rs6269 (A), rs4633 (C), rs4818 (C), and rs 4680 (G).

Your note said rs4646312 (T) could be substituted for rs4818. Does the rs4646312 (T) substitute for rs4848 (T)? If so, I believe you made a mistake when you listed rs4646312 (T) as the inclusion criterion for Haplotype II, and it should be rs4646312 (C).
 

Valentijn

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Your note said rs4646312 (T) could be substituted for rs4818. Does the rs4646312 (T) substitute for rs4848 (T)? If so, I believe you made a mistake when you listed rs4646312 (T) as the inclusion criterion for Haplotype II, and it should be rs4646312 (C).
No, in the original study it lists the C (major) allele for rs4818 being the one in the low activity haplotype. That corresponds with the T (major) allele for rs4646312.
 

Lynn_M

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Thanks for confirming that Valentijn. I was hoping maybe I didn't fall into that low activity haplotype, but it appears that I do. Although with heterozygous alleles with rs4633 and rs4680, I'm probably don't have the full 58-fold reduction in function.