Looking for Mast Cell disease - Genetic Data help

[Fogbuster]

Hey guys,

I'd really appreciate your help.

I have suspected for a while that I have a histamine related disorder being Mast Cell Activation Disorder and at the very least histamine intolerance that has been causing my huge array of symptoms and bizarre functional symptoms.

My issues

I "react" (a stress response goes off to) literally everything I eat; all foods, spices, cigarettes, alcohol, hair sprays, any (stressor) exercise more than walking and of course stress whilst also having severe cognitive dysfunction. The list could go on in regards to symptoms and things I react to, but I won't bore you with that, I'll just bore you with my data instead! (Worth noting that alot of my worst triggers are histamine triggers/liberators, such as cigarettes, spinach, kefir, sauerkraut, aged cheese, alcohol.

But on a serious note, I'm really desperate and need some experienced minds to chime in to help me analyse these results. I need to get to the bottom of what is causing my severe cognitive dysfunction and "reaction" to everything I ingest.

I have 7 ABP1 genes of which one of them is the "rs10156191" one.

I only seem to have a heterozygous mutation on CBS C699T. CBS mutations are involved in Mast Cell Activation disorder.

Is that hetero CBS mutation indicative enough to suggest I possibly have Mast cell issues?

And what I would like to know is does this suggest that it's likely I have a histamine based disorder based on these genetic findings? Thanks for reading.

 

[Valentijn]

@Fogbuster - How are CBS SNPs involved in mast cell activation? Additionally, CBS C699T will have very little or no impact when heterozygous.

To the best of my knowledge, the methylation SNPs aren't helpful in indicating a histamine disorder.

 

[Fogbuster]

Sorry I'm away from the computer atm but will get the piece of info when I'm back.

So bottom line is 23andme data is not helpful at indicating a histamine related disorder?

I had a histamine test which came back negative but from what I understand it simply tests for histamine levels in your blood at that current moment in time; when I was seeing my doc for a consult and histamine test I would not ingest a food/substance I "react" to for obvious reasons so when I took it I wouldn't be symptomatic.

So my plan is to get another histamine test and ingest a couple of triggers like 10-15mins before the test.

 

[Valentijn]

I have 7 ABP1 genes of which one of them is the "rs10156191" one.

There's only one ABP1 (AOC1) gene. The alleles on it are called SNPs. Is the rs10156191 SNP heterozygous or homozygous for you? It's a very common missense mutation, with 10% of the general population being homozygous. What are the other AOC1 SNPs which you "have"?

There is some indication that rs10156191 being +/- or +/+ results in lower DAO activity, but the only paper I can find which discusses it (http://onlinelibrary.wiley.com/doi/10.1111/j.1398-9995.2011.02548.x/full#f3) refuses to say what the activity levels were for controls, and only divides them as >10 and <10. So they're screwing around quite a bit in that paper, and it's impossible to tell how much of an impact those genotypes are actually having.

Another gene implicated in histamine issues thus far is KIT. A list of genes which interact with KIT (CD117) is at http://en.wikipedia.org/wiki/CD117#Interactions

 

[taniaaust1]

Hi, I personally think I have a mast cell disorder too, I have an uncle with systemic mastocytosis and his daughter is sick just like myself (my uncle believes I have masto like himself) but her doctors don't believe in ME/CFS so my cousin, she goes undiagnosed though she was on disability (and may be still) for her illness.

I've been trying to find out if I have systemic mastocytosis through my 23andME results. There is often mutations in KIT genes with systemic mastocytosis and a mutation there could aid in an instant diagnoses of it as it having this mutation can be included as part of the diagnostic criteria. My uncle with masto does have the KIT mutation which is used to diagnose masto but I haven't been able to work out myself though the KIT genes come up on the 23andME (well at least some).. I'm yet to figure out directly which KIT results are mutations and which are the normal ones (Im not that smart so don't understand things like Valentijn does)

I hence used Valentijns program which picks out the rarer genes (10% and under) from ones 23andME raw data and have been going through those mutations but yet haven't found the KIT one. I'm only though half way through going through all the mutations the program picked out so still could come across it and end up with a mastocytosis diagnoses through doing this.

I suggest you run yours through Valentijns program too if you have time to go through each mutation individually looking for mast cell ones). I did though this find have one of the common connected with mastocytosis gene mutations come up (but its not the one which would give me that diagnoses)
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@Valentijn Im wondering if you would accept someone paying you to go through their KIT genes to tell them if they have a mutation there or not and which it is? What would you change for something like that if you were willing to do this?

The way Im going it's going to take me over another year as Im having to go through EVERY10% or rarer mutation rather then going through the KIT genes on my 23andME test directly as I cant get my head myself around how to figure out mutations of those so Im having to go through that 17? page list of all my mutations and research each (its taken me a 12-18 months to get through 7 pages of the mutations).


I was looking at the following http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3279709/

"Mastocytosis is a heterogenous group of diseases characterized by the growth and accumulation of neoplastic mast cells.1 Based on the clinical presentation of the disease, cutaneous mastocytosis (CM) and systemic mastocytosis (SM) have been defined as the two main subtypes of mastocytosis.1 CM primarily occurs in children, and the mast cell infiltration is confined to the skin.1

In contrast, almost all adult patients with mastocytosis have SM, which is characterized by involvement of at least one extracutaneous organ and may involve multiple hematopoetic cell lineages.1,2

In the vast majority of cases with SM, the clonal nature of the disease can be established through demonstration of a somatic A to T missense mutation at position 2447 of the coding sequence in the KIT gene.1,3,4 The resulting substitution of aspartate (D) to valine (V) at position 816 in the kinase domain leads to autoactivation of the KIT receptor tyrosine kinase.5

Studies with transgenic mice and mast cell lines have suggested that this mutation alone is sufficient to cause SM.6–8 However, the KIT D816V mutation is not specific for mastocytosis, as gastrointestinal stromal tumors, acute myeloid leukemia, and germ cell tumors have also been demonstrated to carry this mutation"

I find it interesting that mutation also is connected to acute myeloid leukemia as that cancer appears in higher rates in ME/CFS.

@Valentijn can you tell from that what rs number in the KIT gene stuff that would be? I feel like its telling me where to look but its like reading chinese to me. And does that mean that whatever one it is, it's TT instead of AA on my 23andME results if I have this mutation?

I do have several double copy mutations to do with tyrosine kinase in the 23andME raw data in the rarer genes from your program but none KIT so far.

Also Im confused by the abstract of that pubmed article.

"The vast majority of patients with systemic mastocytosis (SM) carry the somatic D816V mutation in the KIT gene. The KIT D816V mutation is one of the minor criteria for a diagnosis of SM according to the 2008 World Health Organization classification of myeloproliferative neoplasms. In the present study, we present a real-time qPCR assay that allows quantification of as little as 0.003% KIT D816V mutation-positive cells. A total of 61 samples from 31 cases of SM were included in the study

. We detected the mutation in skin or bone marrow in 95% of the cases of SM. We demonstrate the clinical relevance of the assay by identifying as little as 0.03% mutation-positive cells in bone marrow aspirates from SM patients and calculate the analytical sensitivity of negative samples to determine the reliability of the result. We further demonstrate that this method also detects the KIT D816V mutation in peripheral blood in 81% of the mutation-positive cases with SM."

I don't understand seeing this is a gene mutation why they need to look for for the gene mutation in the bone marrow?? Do you understand this?????

 

[Valentijn]

Valentijn, Im wondering if you would accept someone paying you to go through their KIT genes to tell them if they have a mutation there or not and which it is? What would you change for something like that if you were willing to do this

Ethically I really couldn't accept money from other sick ME/SEID patients, and I also don't have the time for it. I'm trying to work on some bigger projects regarding SNPs, and they're taking up most of my limited cognitive power currently

The way Im going it's going to take me over another year as Im having to go through EVERY10% or rarer mutation rather then going through the KIT genes on my 23andME test directly as I cant get my head myself around how to figure out mutations of those so Im having to go through that 17? page list of all my mutations and research each (its taken me a 12-18 months to get through 7 pages of the mutations).

We can probably make that faster, but again it's going to take some time and a new PC where we can download and process some very large databases. Basically we need to cross-reference the chromosome locations of the rare SNPs (or entire 23andMe file) with all of the gene locations. We also might be able to translate the the "i" numbers into more useful "rs" numbers, and automatically flag missense mutations. Hopefully we can do that in the next month or two. But no guarantees.

 

[taniaaust1]

Ethically I really couldn't accept money from other sick ME/SEID patients, and I also don't have the time for it. I'm trying to work on some bigger projects regarding SNPs, and they're taking up most of my limited cognitive power currently

oh so I cant even bribe you . It's frustrating as I know I may have the answer right in front of me with these gene mutations but I cant figure things out. Its not unethical when it will save some one over a year of stress and using their better times up, trying to figure it out. But yeah, can completely understand the not having the time!!!

We can probably make that faster, but again it's going to take some time and a new PC where we can download and process some very large databases. Basically we need to cross-reference the chromosome locations of the rare SNPs (or entire 23andMe file) with all of the gene locations. We also might be able to translate the the "i" numbers into more useful "rs" numbers, and automatically flag missense mutations. Hopefully we can do that in the next month or two. But no guarantees.

That went right over my head, I don't even know or don't remember what "i" numbers are but whatever you are doing, sounds good best luck with it. That cross referencing sounds a huge job, I'd offer to give you a hand with at my better times if I understood it.

 

[Valentijn]

That went right over my head, I don't even know or don't remember what "i" numbers are but whatever you are doing, sounds good best luck with it. That cross referencing sounds a huge job, I'd offer to give you a hand with at my better times if I understood it.

"i" numbers are the labeling system which 23andMe uses, supposedly just for SNPs which don't have an "rs" number yet. But they're lying through their teeth, because they also routinely use "i" numbers to hide pathogenic mutations.

As for the rest, there are databases which essentially say which SNP "rs" number or location (position on a chromosome) is associated with a gene or missense mutation. And 23andMe also provides location information, so it's possible to have the program match up locations and list what gene a SNP is on, and to indicate if it's a missense mutation.

This would automate the process considerably. So instead of having 18,000 results from the 10% file, it could possibly be filtered down to 5,000 which are on genes, and maybe 200 which are missense mutations, and maybe even flag a handful that are pathogenic. This could make things a lot easier, because the missense mutations are likely to be where the interesting SNPs are.

 

[Pope]

Where do you find the 10% file?

 

[Critterina]

@Fogbuster, did you ever get any help? Find anything in your genes? I was wondering if you had hypermobility Ehlers Danlos Syndrome (EDS) because that makes mast cell activation a different critter, maybe with different solution...sorry to have found this out.