Interesting COMT Variations

[Pope]

I'm new here, but I'm hoping you're still reading through these notes! I'm new to the SNP world as well and and am confused about COMT, based on 23andme data.

1. If we have rs4633 (H62H) CC and rs4680 (V158M) GG, does that mean that they counteract each other? Is H62H CC a slow version and V158M GG a fast version?

2. Why would wild type COMT V158M (rs4680) GG and H62H (rs4633) CC be associated with low activity in haplotype II? I thought they were "normal" activity alleles? We have rs6269 AG, rs4646312 CT, rs4633 CC and rs4680 GG. Would that be haplotype II (or do you need to be homozygous for all 4?)? If so, does that mean we should avoid methyl donors because COMT is too slow?

3. We also have CBS A360A (AA), which supposedly suggests avoiding methyl donors. But then MTHFR A1298C (GT) and MTHFR P39P (AG) suggest to add them, as do MTRR A66G (AG) and MTRR C524T (CT) and MTR rs1805087 (AG). Very confusing. How do you know which SNPs are stronger than others?

4. Are there any blood tests that can tell you if your COMT is working properly, or whether you should take or avoid methyl donors? We are getting tested this weekend for pyroluria and Lyme disease among other things and I want to cover our bases.

Thanks everyone!

 

[alicec]

If we have rs4633 (H62H) CC and rs4680 (V158M) GG, does that mean that they counteract each other? Is H62H CC a slow version and V158M GG a fast version?

These are the ancestral, wildtype or unmodified versions of the SNPs.

The H62H SNP, whether the wildtype or variant form, does not result in any change to the protein. The variant and the wildtype gene produce the same protein so it makes no sense to talk of faster and slower versions. The proteins are identical.

V158M does affect the protein. The variant gene produces an enzyme with about 1/3 the activity of the wildtype protein. So the wildtype version which you have is indeed faster than the variant.

This is not necessarily a good or bad thing. Both versions are so common in the population that who is to say what rate is normal?

Suffice to say that each variant appears to have advantages and disadvantages.

Why would wild type COMT V158M (rs4680) GG and H62H (rs4633) CC be associated with low activity in haplotype II? I thought they were "normal" activity alleles?

These haplotypes are the result of the effect of nucleotide changes on the three dimensional structure of the mRNA formed from the gene. Some combinations of nucleotides are more destabilising than others, resulting in premature breakdown of the mRNA and hence less protein product (not an abnormal protein). This means less enzyme activity.

These kinds of effects can occur when a number of SNPs, which might be spread out on the gene, happen to be close together in the 3-D shape of the mRNA. Several nucleotide changes are needed, not one in isolation and the effect is not one on protein structure.

In contrast, the many studies on V158M in isolation do relate to changes in protein structure. The single nucleotide change in the gene results in a change in amino acid in the enzyme produced by the gene (valine changes to methionine). This produces an altered protein which is more unstable than the wildtype protein at normal body temperature.

Here is the original paper defining the haplotypes. Not that they were defined in relationship to pain tolerance.

If so, does that mean we should avoid methyl donors because COMT is too slow?

There is no evidence that COMT status has anything to do with tolerance of methyl donors.

Although it is repeated ad nauseum on the internet, it was just a theory of Amy Yasko that became self-fulfilling.

Plenty of people have put it to the test and found the theory wanting. Some people who are COMT +/+ have no problems with methyl groups. Some people who are COMT -/- do.

We also have CBS A360A (AA), which supposedly suggests avoiding methyl donors. But then MTHFR A1298C (GT) and MTHFR P39P (AG) suggest to add them, as do MTRR A66G (AG) and MTRR C524T (CT) and MTR rs1805087 (AG). Very confusing. How do you know which SNPs are stronger than others?

You need to read the research that determined whether or not the SNP has any effect on enzyme activity - and don't believe everything you read on the internet, particularly if they are trying to sell you supplements based on the information.

Here are some threads which discuss SNPs known to do something. CBS, MTHFR, MTR, MTRR.

That CBS SNP has no effect. The first MTHFR SNP has a small effect if +/+, +/- negligible. The combination of the first MTRR and the MTR SNP does slow the enzyme, but +/- is not great.

 

[Pope]

Thank you so much!!