Hi, all.
I’m writing this post to ask for input from those of you who have run the 23andme genotyping panel, to help in elucidating details of the genetic predisposition of ME/CFS. Here’s the story:
As many of you know, I am convinced, based on consistency with known biochemistry, confirmation by lab testing, and treatment experience, that the Glutathione Depletion-Methylation Cycle Block hypothesis for the pathogenesis and pathophysiology of ME/CFS is very likely to be valid. As you also may know, this model proposes that for sporadic (non-cluster, non-epidemic) cases of ME/CFS, there is a genetic predisposition.
There is considerable evidence for a genetic predisposition in this disorder, including twin and family studies as well as specific polymorphism frequency studies.
This model also proposes that a variety of stressors (including physical, chemical, biological and psychological/emotional stressors) act as the etiological factors (root causes) to bring about the depletion of glutathione as the initial event in the cause and effect sequence of the pathogenesis.
In this model, therefore, glutathione depletion serves as the “trip wire” that brings the onset of ME/CFS. Once glutathione goes low enough, it sets in motion a “row of dominoes” consisting of a functional B12 deficiency, a partial block of the enzyme methionine synthase and hence of the methylation cycle, loss of folates from the cells, and draining of the sulfur metabolism. This sequence in turn forms a vicious circle, and that is what makes ME/CFS chronic. The various features of ME/CFS stem from this vicious circle as well as from the pathogens and toxins that either served as etiological factors or that accumulated after onset, because of the resulting dysfunction of the immune system and the detox system.
Assuming that glutathione depletion is indeed the “trip wire,” it seems to me that in seeking to discover the details of the genetic predisposition, we should look for polymorphisms in the enzymes associated with the glutathione system.
A person has two ways of raising their level of glutathione: they can either make new glutathione, or they can recycle oxidized glutathione. Of course, they do have to make some new glutathione to replace what is lost over the longer term, but in the short term,
recycling oxidized glutathione can meet an immediate need.
Given this, the people who would be expected to be most vulnerable to depletion of glutathione would be those who, for genetic reasons, have difficulty either in making new glutathione or in recycling oxidized glutathione, or, particularly, both.
There are many genes and many polymorphisms that have the potential to influence the ability to make and recycle glutathione, so that tracking down which ones might be most influential in the ME/CFS population would be a major effort. However, this has already been done for autism, and as you may know, I have argued for several years that the biochemical abnormalities in ME/CFS and autism are very similar, particularly in that both involve glutathione depletion and a partial methylation cycle block. On that basis, I think it might be helpful to examine what has been found in autism in this regard, and to check to see if the situation in ME/CFS is similar.
In the paper by Bowers, et al., (2011)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188290/pdf/11689_2011_Article_9077.pdf
the authors write:
“Our three-SNP model showed that having both minor allele variants of either rs12737233 (CTH) or rs3750834 (GLRX3) combined with at least one variant allele of rs11135434 in GLRX increases the risk for autism almost fourfold.”
Note that CTH is cystathionase, also called cystathionine gamma lyase. It is the enzyme in the transsulfuration pathway that produces cysteine, which is usually the rate-limiting amino acid for making glutathione. CTH is therefore important in the formation of glutathione.
GLRX3 and GLRX are glutaredoxins. One of the main roles of the glutaredoxins is to retrieve glutathione that has become oxidized by binding with cysteine residues of proteins, forming disulfide bonds. Thus, the glutaredoxins play major roles in recycling glutathione.
If SNPs in these enzymes inhibit their operation, they will impact the formation and recycling of glutathione, respectively, and make it more likely that glutathione will become depleted when heavy demands are placed on it. This appears to be why they increase the risk of developing autism.
Perhaps these same SNPs will be found to increase the risk of developing ME/CFS.
To find out, I would like to ask those of you who have run the 23andme genotyping panel to post your results for these three SNPs. I realize that the results will not have statistical significance unless we have a large number of them, but I think it would be interesting to make a start, anyway. I have posted mine below for comparison. Note that I do not have autism or ME/CFS, and I appear to have the dominant genotype makeup for Europeans, for all three of these SNPs, indicating that I do not have this risk factor for autism.
rs12737233
ANKRD13C
70784935
rs12737233
C or T
TT (TT is dominant)
rs3750834
GLRX3
131978358
rs3750834
A or G
AA (AA is dominant)
rs11135434
intergenic
95143598
rs11135434
C or T
CT (CT is dominant)
I note that 23andme has assigned two of these SNPs to other than CTH and GLRX, respectively. I don’t know what to make of this, but I’m assuming that the rs numbers do identify the correct SNPs for comparison to the paper by Bowers et al.
If some of you would like to post your results, maybe we will learn something by comparing one to another.
Best regards,
Rich
I’m writing this post to ask for input from those of you who have run the 23andme genotyping panel, to help in elucidating details of the genetic predisposition of ME/CFS. Here’s the story:
As many of you know, I am convinced, based on consistency with known biochemistry, confirmation by lab testing, and treatment experience, that the Glutathione Depletion-Methylation Cycle Block hypothesis for the pathogenesis and pathophysiology of ME/CFS is very likely to be valid. As you also may know, this model proposes that for sporadic (non-cluster, non-epidemic) cases of ME/CFS, there is a genetic predisposition.
There is considerable evidence for a genetic predisposition in this disorder, including twin and family studies as well as specific polymorphism frequency studies.
This model also proposes that a variety of stressors (including physical, chemical, biological and psychological/emotional stressors) act as the etiological factors (root causes) to bring about the depletion of glutathione as the initial event in the cause and effect sequence of the pathogenesis.
In this model, therefore, glutathione depletion serves as the “trip wire” that brings the onset of ME/CFS. Once glutathione goes low enough, it sets in motion a “row of dominoes” consisting of a functional B12 deficiency, a partial block of the enzyme methionine synthase and hence of the methylation cycle, loss of folates from the cells, and draining of the sulfur metabolism. This sequence in turn forms a vicious circle, and that is what makes ME/CFS chronic. The various features of ME/CFS stem from this vicious circle as well as from the pathogens and toxins that either served as etiological factors or that accumulated after onset, because of the resulting dysfunction of the immune system and the detox system.
Assuming that glutathione depletion is indeed the “trip wire,” it seems to me that in seeking to discover the details of the genetic predisposition, we should look for polymorphisms in the enzymes associated with the glutathione system.
A person has two ways of raising their level of glutathione: they can either make new glutathione, or they can recycle oxidized glutathione. Of course, they do have to make some new glutathione to replace what is lost over the longer term, but in the short term,
recycling oxidized glutathione can meet an immediate need.
Given this, the people who would be expected to be most vulnerable to depletion of glutathione would be those who, for genetic reasons, have difficulty either in making new glutathione or in recycling oxidized glutathione, or, particularly, both.
There are many genes and many polymorphisms that have the potential to influence the ability to make and recycle glutathione, so that tracking down which ones might be most influential in the ME/CFS population would be a major effort. However, this has already been done for autism, and as you may know, I have argued for several years that the biochemical abnormalities in ME/CFS and autism are very similar, particularly in that both involve glutathione depletion and a partial methylation cycle block. On that basis, I think it might be helpful to examine what has been found in autism in this regard, and to check to see if the situation in ME/CFS is similar.
In the paper by Bowers, et al., (2011)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188290/pdf/11689_2011_Article_9077.pdf
the authors write:
“Our three-SNP model showed that having both minor allele variants of either rs12737233 (CTH) or rs3750834 (GLRX3) combined with at least one variant allele of rs11135434 in GLRX increases the risk for autism almost fourfold.”
Note that CTH is cystathionase, also called cystathionine gamma lyase. It is the enzyme in the transsulfuration pathway that produces cysteine, which is usually the rate-limiting amino acid for making glutathione. CTH is therefore important in the formation of glutathione.
GLRX3 and GLRX are glutaredoxins. One of the main roles of the glutaredoxins is to retrieve glutathione that has become oxidized by binding with cysteine residues of proteins, forming disulfide bonds. Thus, the glutaredoxins play major roles in recycling glutathione.
If SNPs in these enzymes inhibit their operation, they will impact the formation and recycling of glutathione, respectively, and make it more likely that glutathione will become depleted when heavy demands are placed on it. This appears to be why they increase the risk of developing autism.
Perhaps these same SNPs will be found to increase the risk of developing ME/CFS.
To find out, I would like to ask those of you who have run the 23andme genotyping panel to post your results for these three SNPs. I realize that the results will not have statistical significance unless we have a large number of them, but I think it would be interesting to make a start, anyway. I have posted mine below for comparison. Note that I do not have autism or ME/CFS, and I appear to have the dominant genotype makeup for Europeans, for all three of these SNPs, indicating that I do not have this risk factor for autism.
rs12737233
ANKRD13C
70784935
rs12737233
C or T
TT (TT is dominant)
rs3750834
GLRX3
131978358
rs3750834
A or G
AA (AA is dominant)
rs11135434
intergenic
95143598
rs11135434
C or T
CT (CT is dominant)
I note that 23andme has assigned two of these SNPs to other than CTH and GLRX, respectively. I don’t know what to make of this, but I’m assuming that the rs numbers do identify the correct SNPs for comparison to the paper by Bowers et al.
If some of you would like to post your results, maybe we will learn something by comparing one to another.
Best regards,
Rich
