Summarise further report pros and cons after 23andme?

[Jenny TipsforME]

@PennyIA lovely to think a baby has come out of your knowledge

 

[Jenny TipsforME]

@caledonia don't worry I also have the Warrior gene and rs53576(G;G) the gene that means I'm more likely optimistic, empathetic and handle stress well. Which will win out?!

I better avoid depression though because I have 5 different variations that mean I'm less likely to respond to anti-depressants (all homozygous and most 7x less likely to respond)...

 

[alicec]

hetero in MTHFR A1298C

This would slow the enzyme very slightly. The Yasko stuff about this SNP affecting the backwards reaction of the enzyme in which a molecule of BH4 is generated, and thus that the SNP compromises BH4, is yet another of her total misreadings of research.

The enzyme does not run backwards and it does not regenerate BH4, though methylfolate does act as a peroxynitrile scavenger so it could have a BH4 sparing effect.

The SNP simply has a small slowing effect on the normal (forward) action of the enzyme. Here is a post about this SNP.

though don't understand VDR relationship with COMT yet

Don't fall for the Yasko stuff that COMT = too much dopamine and hence intolerance of methyl groups and that VDR Taq offsets this somehow since it lowers vit D which in turn stimulates dopamine production.

COMT and intolerance of methyl groups is pure speculation and plenty of people have put it to the test and found it not to be the case.

VDR Taq affects the VDR, not vit D and acutally has been shown to have little effect.

I also have the Warrior gene

There's a lot of nonsense written about this MAO A SNP, which in itself does nothing at all. Here is a post about it.

Good luck - you are on an interesting journey.

 

[Jenny TipsforME]

@alicec thanks interpretation is confusing. I was a bit tongue in cheek about the warrior gene, although it has a nice ring to it! There could be a value in perceiving yourself that way.

My main impression today is that I have protectors and susceptibility to same things which mostly seems to cancel out. Some things might be worth following up where I have related symptoms eg a few autoimmune conditions.

Also if lifestyle can help, eg one with magnitude of 3 said can be reversed with raw veg and fruit. This seems worth being consistent with (no harm anyway).

Celiac confused me, a couple of susceptible snps including a main one. Had blood test 16yrs ago which was negative. Does that measure expression rather than dna?

 

[Valentijn]

Celiac confused me, a couple of susceptible snps including a main one. Had blood test 16yrs ago which was negative. Does that measure expression rather than dna?

Usually the research is showing a very small increase in risk, and does not say if someone will get a disease or not. Some SNPs do cause disease directly, but most SNP research is showing very little effect, and is very vulnerable to false positives.

 

[Jenny TipsforME]

Usually the research is showing a very small increase in risk, and does not say if someone will get a disease or not. Some SNPs do cause disease directly, but most SNP research is showing very little effect, and is very vulnerable to false positives.

I was curious about what the coeliac blood test I had tested, looked up it's

• Total immunoglobulin A (IgA)
• IgA Tissue transglutaminase antibody (shortened to tTG)

It is possible to test false negative for coeliac eg if have IgA deficiency. I cut out gluten anyway. Don't fancy eating it to redo the test so perhaps it doesn't matter. Except people wouldn't roll their eyes if I was officially coeliac...

What would your attitude be for conditions you have symptoms for and relevant SNPs? Is this worth raising with a doctor? For example, I noticed a number of autoimmune conditions. Probably this is better interpreted as a general vulnerability to autoimmunity and ME should be on the list. Don't have details in front of me but there's a few rheumatoid ones, lupus, Sjorgens, asthma reaction to dust mite (know that's EXPRESSED, IL10 related), IBD, Crohns (Inc a 0% frequency one). Some of these are magnitude 3 risk (my highest).

I don't have risk for EDS which was one of my main questions.

Also I thought my settings on Promethease were to leave out locked results on 23andme but it seemed to include everything. In the end that worked out alright. Parkinsons risk much lower than expected (my grandfather and aunt died of this). It's not impossible for me to get it but I expected it right at the top of the list. I was dreading idea I might go from ME to Parkinsons so this gives piece of mind.

The more serious possibilities for me are ones it is good to know for preventative action or it's so muddled it makes little sense (protective and risk for same thing).

Queries, has anyone looked into :

• rs1045642 (TT yesterday 23andme says AA today confused) to do with pumping foreign bodies out of cells, magnitude 3
• TNF-308 (A, G) difficult to understand A is TNF1 G is TNF2
• IL6'-174' polymorphism (IL6 rings bell from ME research)
• Missense variant Q141K/C421A on ABCG2 (gout and diarrhoea)
• NAT2 slow metaboliser
• CYP2D6*10 reduced Metabolism
• CYP3A5 non expressor

With my 5 homozygous difficulty responding to anti-depressant SNPs, does that point to anything else? Eg serotonin problems. It seems to be to do with blocking the blood brain barrier from what I've read so far.

 

[alicec]

Celiac confused me, a couple of susceptible snps including a main one. Had blood test 16yrs ago which was negative. Does that measure expression rather than dna?

The SNPs reported for celiac susceptibility are usually for HLA. They are not complete and you can't actually work out your relevant HLA type from them so I don't think they mean a lot.

Some HLA subtypes types are known to be strongly associated with celiac but not 100% - however if you don't have the relevant HLA types you are highly unlikely to have celiac. You would need to have proper HLA testing to know if you had these - as far as I have been able to work out, there is no way of determining them from reported SNPs.

Your blood tests did not involve HLA typing but they do show you are not making the antibody characteristic of celiac.

Unless you had other reasons to suspect celiac I wouldn't be placing too much weight on the SNPs.

What would your attitude be for conditions you have symptoms for and relevant SNPs? Is this worth raising with a doctor? For example, I noticed a number of autoimmune conditions

If you have symptoms then definitely raise it with your doctor. The SNPs would maybe provide a small amount of support depending on what they are, but for the most part the reported risks are very small, an association, which may or may not mean anything.

My rule of thumb is to ignore lone association studies that were done some years ago. Usually they are far too small and used inadequate statistics.

More recent studies are finding many of the associations are disappearing and it is just not the case that single genes have strong effects on particular diseases. It seems that many genes may contribute small effects.

With most diseases for which a genetic contribution has been observed (from twin studies), the situation is getting even murkier. Better and larger gene studies are just not accounting for the magnitude of the effect - ie genes encoding proteins don't tell the whole story.

• NAT2 slow metaboliser

• CYP2D6*10 reduced Metabolism

• CYP3A5 non expressor

There is a lot of research on these detox enzymes and Promethease does a fair job of translating SNPs into research on effect of alleles.

Just make sure that you really do have the appropriate combinations of SNPs, then be familiar with the things metabolised by the enzymes. This could be relevant, eg, for use of certain drugs.

As far as I could work out being a CYP3A5 non-expresser doesn't mean much since so are the majority of Caucasians.

 

[Jenny TipsforME]

Lymphatic issues:
@Valentijn @alicec thanks for your help. I was hoping to be more independent in my search but it gets amazingly confusing.

Something I noticed, a cluster of issues with is lymphatic problems. These don't panic me in themselves but curious about possible ME connection.

Eg Acute Lymphoblastic leukaemia I seem to have more than 1 risk for including a 7% freq, 2.4 mag, monozy one (rs4132601gg) and rs11980379cc which is B cell precursor also 7% frequently. Treatment could be (drum roll) rituximab.

Overall 12 'bad' risks when type in lymph. No 'good' news on IKZF1 which seems related.

Fortunately I've already passed over a couple of childhood leukaemia risks.

 

[Jenny TipsforME]

The above brought to mind this Jo Cambridge and Fane Mensah Invest in ME research

"we did find an increase in a molecule expressed on ‘new’ B cells, that is the ones most recently exiting the bone marrow.

This is a differentiation marker called CD24.

CD24 polymorphisms (genetic changes) have also been described in different autoimmune diseases.

CD24 is a cell ‘adhesion’ molecule which is involved in the way B cells interact with other cells and with their surroundings" http://www.ukrituximabtrial.org/Rituximab news-Mar16 01.htm

I can't find CD24 in my data though I don't think it's included.

I don't pretend to understand this biology but from English comprehension b cell precursor sounds related to new B cells.

 

[Jenny TipsforME]

This seems potentially useful for pwme

Supplementary Data 1. List of investigated genes implicated in human immune response and inflammation. (spreadsheet)
Gene list was taken from the nCounter GX Human_Immunology Kit and nCounter GX Human Inflammation Kit (NanoString® Technologies, Seattle, WA, USA). Some SNPs may be represented in more than one gene.

 

[Jenny TipsforME]

I feel like I deviated from the initial purpose of this thread which is to summarise how to make sense of the dna data.

Something I find helped (after reading through the results just sorted by magnitude) is adjusting the filters on Promethease to something like this:
Magnitude more than 0.1 (could make higher, this shows how important the result is known to be)
References more than 5 (to avoid making conclusions based on little research)
Frequency under 45% (some of my results are 100% frequency, in other words what it is to be human!)

You could also try sorting by frequency to spot the more unusual SNPs.
Does this sound helpful to more knowledgeable people?

 

[Jenny TipsforME]

I'm finding the way information is presented in https://www.infino.me/genetics/ helpful. This is free.

 

[alicec]

I'm finding the way information is presented in https://www.infino.me/genetics/ helpful. This is free.

I did look at that site and also found it helpful. However I had energy for just a short time on the site and didn't find any way of saving results so I could come back later. Maybe I missed something in my exhaustion.

Yes I can download 23andme again but it seems a bit silly to do this every time I want to look at the site. Again maybe I missed something.

 

[Jenny TipsforME]

@alicec I haven't closed the tab yet on my browser, when I went back after dinner it didn't have to reload the data. It seemed like Promethease in that way (although you can download from Promethease and I didn't see that option either on infinite).

 

[Jenny TipsforME]

@alicec sorry should have read Infino (my tablet has weird keyboard settings that are usually helpful)

Since leukemia stuff came up in Promethease I'm having a look at that in Infino. Just peeking at my childhood leukeamia risks - I had 18 SNPs associated with that including 7 monozygous ones. Something to remember when I feel unlucky with ME - there's a version of me out there in the multiverse that went down with childhood leukemia.

[Edit: see next post, this isn't quite correct but I've left the error here because I think other pwme might read this the same as me]

What Significance -log pvalue matters for genetic results? Can't find straightforward answer on Google. For this condition the p-values range 45 to 5 for the relevant research. From the Coursera course I've started I think they said it should be a higher p-value than for most things because it's essentially a large fishing expedition.

I've just counted 27 of my SNPs associated with Chronic lymphocytic leukemia (vs 16 I don't have, although the ones with higher p values I have mostly hetero for). This doesn't seem like it would be normal, although I haven't seen other people's results. What do you think?

I'm presuming there aren't actually 'genes for leukemia' but that this association is something to do with how the white blood cells are functioning. My curiosity is about a link with ME? ie if more research had been done, would ME be listed alongside CLL and ALL as an association with these SNPs?

"There are three different types of lymphocytes:

• T cells, which fight infection by triggering other cells in the immune system and by destroying infected cells
• B cells, which make antibodies
• Natural killer (NK) cells, which fight microbes and cancer cells"

I'm not very good at remembering details (despite reading the ME research as it's released) but aren't all 3 types of lymphocytes coming up as problematic in ME research?

Perhaps I'm reading too much into it?

 

[Jenny TipsforME]

*** @alicec I realise I was reading the tables in View SNP Catalogue wrongly! On Infino each row of the table is about each SNP in a study not necessarily unique SNPs (some of the SNPs have been studied repeatedly and appear more than once on the table with different p values). This is a bit less remarkable. I should have said that SNPs I have are associated with CLL 27 times in research and SNPs I have have been associated with childhood leukemia 18 times in research. I think this is still 'a thing' but I'll have to check more carefully about the indvidual SNPs.

eg rs735665 has been studied 4 times in CLL and the p value ranged 38-11. Also there's a study associated with Follicular Lymphoma. Infino will tell you which genes a SNP is near (how useful is this?). This one is near 'SCN3B - sodium channel, voltage gated, type III beta subunit' gene where Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle.

 

[sb4]

This would slow the enzyme very slightly. The Yasko stuff about this SNP affecting the backwards reaction of the enzyme in which a molecule of BH4 is generated, and thus that the SNP compromises BH4, is yet another of her total misreadings of research.

The enzyme does not run backwards and it does not regenerate BH4, though methylfolate does act as a peroxynitrile scavenger so it could have a BH4 sparing effect.

The SNP simply has a small slowing effect on the normal (forward) action of the enzyme. Here is a post about this SNP.



Don't fall for the Yasko stuff that COMT = too much dopamine and hence intolerance of methyl groups and that VDR Taq offsets this somehow since it lowers vit D which in turn stimulates dopamine production.

COMT and intolerance of methyl groups is pure speculation and plenty of people have put it to the test and found it not to be the case.

VDR Taq affects the VDR, not vit D and acutally has been shown to have little effect.



There's a lot of nonsense written about this MAO A SNP, which in itself does nothing at all. Here is a post about it.

Good luck - you are on an interesting journey.

Hey, Just interested in why you think yasko is wrong. I have +/+ on both COMTs and MAO-A and have ruined sleep with methylfolate. Do you think my poor sleep is due to some other reason?

 

[bertiedog]

As you will see from my signature I have both those 2 SNPS (Homozygous) and I also am very sensitive to more than 500 mcg added methyfolate and also to any extra amino acids I take because they seem to give me unbalanced neurotransmitters so from my experience COMT plus MAO A homozygous definitely cause problems of overstimulation there is no question because it's happened every time I have taken these things. It's like being on speed (not that I have ever tried that).

Pam

 

[alicec]

Just interested in why you think yasko is wrong. I have +/+ on both COMTs and MAO-A and have ruined sleep with methylfolate. Do you think my poor sleep is due to some other reason

You may well be sensitive to methylfolate and it may be responsible for your poor sleep but this has nothing to do with COMT and MAO A.

There is no research to support Yasko's claims about COMT and sensitivity to methyl donors. It was pure speculation on her part which became self-fulfilling. People with COMT+/+ were not given methyl donors just in case, then this quickly morphed into they don't tolerate methyl donors and this soon proliferated all over the internet.

Plenty of people, including myself, put it to the test and found that it didn't hold. Yes many are sensitive to methyl groups but it has little to do with COMT.

As for MAO A (and I'm assuming you mean R297R), again there is no research supporting Yasko's claims, though there is a lot of garbled nonsense written about this SNP.

Just looking at the name is enough to tell us that it doesn't amount to much. The arginine (R is an abbreviation for this amino acid) at position 297 remains as arginine. In other words the wildtype and variant proteins are identical. It is just not possible that the SNP produces a slower enzyme.

This SNP in itself does nothing.

There is some research suggesting it might be a proxy for some other SNP - I did try to chase this down, since I have this SNP, but didn't come up with anything convincing.

There is also research showing that, in combination with other SNPs, the nucleotide change, even though it doesn't result in protein change, can contribute to mRNA instability and so result in less protein. But this is in combination with several other SNPs and only in the right combination.

Finally there is the misinterpreted stuff about the warrior gene which is also used to make claims about this SNP. The warrier gene stuff refers to a repeat motif in the promoter region of the gene (this is upstream of the coding region) which affects the amount of enzyme formed - ie more or less MOA A, not faster or slower versions of the protein.

It was found that several SNPs, including R297R, might be proxies for the number of repeats in the promoter - but it is several SNPs in just the right combination, not R297R in itself.

Still this didn't stop the internet rumour mill from adding to the mythology about this SNP supposedly meaning a slower form of the enzyme.

So I repeat, in itself, the SNP has no effect. It may do something in combination with a number of other SNPs but it has to be in just the right combination.

 

[alicec]

so from my experience COMT plus MAO A homozygous definitely cause problems of overstimulation

I have both these SNPs and can take deplin-like doses of methylfolate without problem. In fact too little methylfolate causes insomnia for me.

I don't have any doubt that for some people, methylfolate can cause problems, but it has nothing to do with these SNPs.