Ion Channel SNP Paper

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A.B.

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In my case there is definitely some problem with glucose utilization, blood sugar regulation, or something in that area.

What other functions does this channel have?

Does magnesium have anything to do with TRPM3 function? Because magnesium seems to often be somewhat helpful.
 

adreno

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From the paper:

TRPM channels are mostly permeable to magnesium and calcium. Only TRPM4 and TRPM5 are impermeable for divalent cations. TRPM3 is permeable for cations including Ca2+ and Zn2+. However, the permeation profile highly depends on the expressed spliced variant.55 No hereditary TRPM3 channelopathy has been described to date. TRPM3 has been implicated in inflammatory pain syndromes, rheumatoid arthritis, and secretion of proinflammatory cytokines.

As pancreatic β cells also have a high proportion of TRPM3 channels,44,56–58 there is the likelihood of perturbations in insulin/glucose regulation in CFS patients. Metabolic disturbance has also long been identified as a cardinal feature of CFS.

The most characterized TRPM3 in humans is in the central nervous system (CNS) and eye55 where missense mutation of the TRPM3 gene has also been found to underlie the development of cataract and glaucoma.59 TRPM3 is involved in the detection of heat and in pain transmission. TRPM3-deficient mice exhibit clear deficits in their avoidance responses to noxious heat and in the development of inflammatory heat hyperalgesia.55 Dysregulation in thermoregulatory responses has been reported in CFS patients.60 Generalized pain is a characteristic of CFS and occurs in the absence of tissue damage, and this is suggestive of potential CNS impairments.61

As TRPM3 has a role in nociception and thermoregulation, it may have a role in the pathomechansim of CFS. Additionally, TRPM3 is activated by pregnenolone sulfate, suggesting that it has neuroendocrine effects62,63 and might also be involved in the regulation of glutamatergic signaling in the brain.64
 

Simon

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Has anyone flagged this up yet?
Examination of Single Nucleotide Polymorphisms (SNPs) in Transient Receptor Potential (TRP) Ion Channels in Chronic Fatigue Syndrome Patients
From Marshall Gradisnik and Staines.

Ion channels would seem interesting possibilities as genetically based thresholds for disturbed responses. I guess that the importance of the findings is critically dependent on the statistics. Any thoughts - maybe from @user9876 ?
Unfortunately the paper gives very little detail on the statistical analysis used, and they don't explicityly state they have corrected for multiple comparisons (eg by some kind of False Discovery Rate correction, FDR).
A two column χ2 test was used to determine significance, where a P-value of <0.05 was determined to be significant.
If they haven't used FDR it would throw into doubt the findings, since with 233 SNPs analysed there would be expected to be 12 false positives, compared with 13 positives found in this study. The p values were hardly stunning, with only 3 SNPs making it below 0.01 (best was for TRMP3, 44% in patients v 29% in controls, p=0.003).

That said, the study used the open-source PLINK: Whole genome data analysis toolset developed by researchers at Harvard and MIT amongst others, and this may have multiple comparison corrections built into it. I will try to find out what the authors did re multiple comparison corrections.
 

taniaaust1

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TRPM channels are mostly permeable to magnesium and calcium.
I don't know if its the TRPM channels or not but in my 23andme raw data when I was looking at my double copy mutations in the past, I found I had double copy gene mutations in the ion channels to do with calcium. It was one of the things which had interested me in my results which I wondered how it was affecting me. I found those mutations when my raw data was put through through Valenjtns program picking out the more uncommon gene mutations.

I'll have to take another look at exactly what those mutations were so others can check these ion channel ones out too.
 

Marco

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That said, the study used the open-source PLINK: Whole genome data analysis toolset developed by researchers at Harvard and MIT amongst others, and this may have multiple comparison corrections built into it. I will try to find out what the authors did re multiple comparison corrections.
That's what I'd assumed but possibly not a safe assumption to make.

ETA - The software offers corrections for multiple comparisons such as Bonferroni but like anything else I guess you have to understand the data, software and the most appropriate analysis.
 
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taniaaust1

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This info may interesting to someone
The three main groups of ion channels are

1) the voltage-gated channels such as the sodium and potassium channels of the nerve axons and nerve terminals,

2) the extracellular ligand-activated channels which includes channels such as GABA and glycine receptor channels, most of which are regulated by ligands that are "neurotransmitters". These channels are often named according to the ligand they bind to.

3) Intracellular ligand-gated ion channels. These include CFTR and some other ABC family members as well as ion channels involved in sense perception. These are often activated indirectly by GCPRs. Other common intracellular ligands which activate these kinds of channels include calcium ions, ATP, cyclic AMP and GMP as well as phosphadidyl inositolIon channels
http://www2.montana.edu/cftr/ionchannelprimers/beginners4.htm (has a lot more supposedly "beginners" info explaining different ion channels)

TRPM channels are mostly permeable to magnesium and calcium.
Has anyone else noticed a lot of mutations around calcium or the calcium ion channel in their results compared to the other stuff if you are analysing all the more uncommon mutations? I have many calcium ones showing up among my results, its one of the most common types of mutations seen in my test results. (I still got a lot of my more uncommon mutations to analyse)

I have homozygous mutations in the following areas

ABC B4 I have lots of mutations in it (affects ATP)
rs6977539 CC,
rs6957680 GG,
rs6956661 AA,
rs11768699 TT,
rs10487804 AA ,
rs17149547 GG
LONP1 (mitochrondria, ATP) rs11085147 TT
CROT (transport of Acyl-CoA which converts to ATP) rs7786781 CC

CACNA1S - Calicum channel rs12239772 GG
RIMS1 - regulates calcium channels and insulin rs9442770 AA
RYR3 - encodes a receptor to release calcium rs16971754 CC
SSR1 - binds calcium to the cell ER membrane rs11243152 AA

SCN2B (sodium channel activity in muscle cell action protential and sodium channel regulation) rs11216799 AA
SLC9A2 (several of these) Its involved in PH regulation and plays important role in colonic sodium absorption rs11674245 AA, rs1016160 AA

SLC4A4 (has pathways for all kinds of things, metal ions, regulates bicarb secretion, intercellular PH, glucose) rs13147721 AA

TRPM3 is activated by pregnenolone sulfate, suggesting that it has neuroendocrine effects62,63 and might also be involved in the regulation of glutamatergic signaling in the brain.64
HOMER2 This family regulates glutamate receptors rs7170046 TT
 
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Simon

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Nothing gets past you, @Simon.
Maybe that's why I started the thread!
Thanks :)

Good news: just waiting for final confirmation from Prof Sonya Marshall-Gradisnik, but it appears the authors DID correct for multiple comparisons - and there are more papers to come on this work. Which means we can all get on with discussing this paper's findings.
 
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The finding is interesting, but with caveats - ME/CFS is not a purely genetic disorder, or patients would have it from birth. So at most, this suggests increased susceptibility to inducing some as yet unknown immunological loop. Is it a clue perhaps, or a red herring?

Speaking of which, and this is a good thread as any to mention this, @Jonathan Edwards, what do you think about the following paper (and the hypothesis that the SNP leads to increased risk of autoimmune illness?)

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982386/
 

Gondwanaland

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As TRPM3 has a role in nociception and thermoregulation, it may have a role in the pathomechansim of CFS. Additionally, TRPM3 is activated by pregnenolone sulfate, suggesting that it has neuroendocrine effects62,63 and might also be involved in the regulation of glutamatergic signaling in the brain.64
Can someone please rephrase this paragraph for the cognitively impaired?
 
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The finding is interesting, but with caveats - ME/CFS is not a purely genetic disorder, or patients would have it from birth. So at most, this suggests increased susceptibility to inducing some as yet unknown immunological loop. Is it a clue perhaps, or a red herring?

Speaking of which, and this is a good thread as any to mention this, @Jonathan Edwards, what do you think about the following paper (and the hypothesis that the SNP leads to increased risk of autoimmune illness?)

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982386/
The Fc-gamma-RIIc paper is just what I would have expected on the basis of our model of autoimmunity. If there is a functional polymorphism it ought to affect autoimmunity rates - probably in a fairly broad fashion.

I have not yet worked out in my mind how a genetic ion channel variant would be likely to predispose to ME if based on an immune loop. It might alter B cell thresholds, again in a broad fashion, but why would it then only be linked to ME (and maybe migraine?). If the ion channel was acting as antigen then it would perhaps be odd for several SNPs to turn up. One could build a model but it seems awkward to me. What seems maybe more likely is that an ion channel variant could predispose to a neural loop - that might be set of either immunologically or otherwise. That makes more sense to me but it suggests that the ion channel might not have any direct relevance to immunology here.
 

Marco

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The finding is interesting, but with caveats - ME/CFS is not a purely genetic disorder, or patients would have it from birth. So at most, this suggests increased susceptibility to inducing some as yet unknown immunological loop. Is it a clue perhaps, or a red herring?
I agree that it's unlikely that this is a direct cause of ME/CFS - more likely that it may contribute risk for developing a range of conditions involving nociception. I don't agree necessarily though that 'patients would have it from birth'. Whatever the mechanism I could imagine SNPs like this might predispose one to nociceptive 'wind up' (or long term potentiation) that might then trigger a self-perpetuating loop. You do not have 'it' from birth but you may have a risk factor that interacts with environmental stressors/stochastic mechanisms.
 
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