Hi, all.
As many of you know, I have proposed the Glutathione DepletionMethylation Cycle Block (GD-MCB) hypothesis, which suggests that the onset of ME/CFS is caused by depletion of glutathione by some combination of a variety of physical, chemical, biological and/or psychological/emotional stressors, in a person who is genetically predisposed.
Though there is considerable evidence from twin and family studies as well as individual polymorphism studies that a genetic predisposition exists, at least for the sporadic (non-cluster) cases, it has not been well-defined up to the present. I have suggested that it must consist of polymorphisms in genes that code for enzymes that are involved in the early part of the pathogenesis of ME/CFS. Otherwise, they would not be accessed, and would not have an impact on the likelihood of onset of ME/CFS.
Based on these considerations, it would seem that the genetic predisposition toward developing ME/CFS must involve polymorphisms in genes coding for enzymes associated with glutathione. These have not yet been studied in ME/CFS.
As many of you also know, I have argued that the basic biochemistry of ME/CFS is the same as that of autism. If this is true, one might expect that a similar genetic predisposition might be involved in autism.
A recent paper reports on a study of glutathione-related polymorphisms in autism. Here is the abstract:
J Neurodev Disord. 2011 Jun;3(2):132-43. Epub 2011 Mar 5.
Glutathione pathway gene variation and risk of autism spectrum disorders.
Bowers K, Li Q, Bressler J, Avramopoulos D, Newschaffer C, Fallin MD.
Source
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe St. room W6509, Baltimore, MD, 21205, USA.
Abstract
Despite evidence that autism is highly heritable with estimates of 15 or more genes involved, few studies have directly examined associations of multiple gene interactions. Since inability to effectively combat oxidative stress has been suggested as a mechanism of autism, we examined genetic variation 42 genes (308 single-nucleotide polymorphisms (SNPs)) related to glutathione, the most important antioxidant in the brain, for both marginal association and multi-gene interaction among 318 case-parent trios from The Autism Genetic Resource Exchange. Models of multi-SNP interactions were estimated using the trio Logic Regression method. A three-SNP joint effect was observed for genotype combinations of SNPs in glutaredoxin, glutaredoxin 3 (GLRX3), and cystathione gamma lyase (CTH); OR=3.78, 95% CI: 2.36, 6.04. Marginal associations were observed for four genes including two involved in the three-way interaction: CTH, alcohol dehydrogenase 5, gamma-glutamylcysteine synthetase, catalytic subunit and GLRX3. These results suggest that variation in genes involved in counterbalancing oxidative stress may contribute to autism, though replication is necessary.
PMID: 21484198
As the abstract reports, the study found that a combination of polymorphisms in three genes associated with glutathione predicts having almost a fourfold higher risk of developing autism. They were the genes that code for the enzymes glutaredoxin, glutaredoxin 3 and cystathionine gamma lyase (also called cystathionase). The study also found that a combination of polymorphisms in four genes related to glutathione had a marginal association with greater risk of developing autism.
Note that cystathionine gamma lyase is the second enzyme in the transsulfuration pathway. One of its reaction products is cysteine, which is usually the rate-limiting amino acid for the synthesis of glutathione. A polymorphism in this enzyme would thus impact the ability to synthesize glutathione.
The glutaredoxins are small proteins that catalyze glutathione-dependent disulfide oxidoreduction reactions in a coupled system with NADPH, GSH, and glutathione reductase. They use glutathione to reduce low molecular weight disulfides and proteins. Polymorphisms in these enzymes may impact the demand for glutathione or the ability to recycle glutathione when it becomes oxidized.
Two additional genes that were involve in a marginal association with the risk of developing autism were the genes that code for alcohol dehydrogenase 5 and gamma- glutamylcysteine synthetase.
The former is also known as formaldehyde dehydrogenase. It oxidizes formaldehyde-glutathione conjugates, releasing glutathione to be used again. A polymorphism in this gene may therefore cause glutathione to be sequestered as this conjugate, making less of it available for other purposes.
Gamma-glutamylsynthetase (also called glutamate cysteine lygase) is the rate-limiting enzyme for the synthesis of glutathione. A polymorphism in this enzyme would affect the ability to synthesize glutathione.
I suggest that if a similar study were done in ME/CFS, similar results would be found. While this would not directly affect treatment of ME/CFS, I think it would draw more research and clinical attention to this proposed causal mechanism, and in the long run, I think that would improve treatment.
Best regards,
Rich
As many of you know, I have proposed the Glutathione DepletionMethylation Cycle Block (GD-MCB) hypothesis, which suggests that the onset of ME/CFS is caused by depletion of glutathione by some combination of a variety of physical, chemical, biological and/or psychological/emotional stressors, in a person who is genetically predisposed.
Though there is considerable evidence from twin and family studies as well as individual polymorphism studies that a genetic predisposition exists, at least for the sporadic (non-cluster) cases, it has not been well-defined up to the present. I have suggested that it must consist of polymorphisms in genes that code for enzymes that are involved in the early part of the pathogenesis of ME/CFS. Otherwise, they would not be accessed, and would not have an impact on the likelihood of onset of ME/CFS.
Based on these considerations, it would seem that the genetic predisposition toward developing ME/CFS must involve polymorphisms in genes coding for enzymes associated with glutathione. These have not yet been studied in ME/CFS.
As many of you also know, I have argued that the basic biochemistry of ME/CFS is the same as that of autism. If this is true, one might expect that a similar genetic predisposition might be involved in autism.
A recent paper reports on a study of glutathione-related polymorphisms in autism. Here is the abstract:
J Neurodev Disord. 2011 Jun;3(2):132-43. Epub 2011 Mar 5.
Glutathione pathway gene variation and risk of autism spectrum disorders.
Bowers K, Li Q, Bressler J, Avramopoulos D, Newschaffer C, Fallin MD.
Source
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe St. room W6509, Baltimore, MD, 21205, USA.
Abstract
Despite evidence that autism is highly heritable with estimates of 15 or more genes involved, few studies have directly examined associations of multiple gene interactions. Since inability to effectively combat oxidative stress has been suggested as a mechanism of autism, we examined genetic variation 42 genes (308 single-nucleotide polymorphisms (SNPs)) related to glutathione, the most important antioxidant in the brain, for both marginal association and multi-gene interaction among 318 case-parent trios from The Autism Genetic Resource Exchange. Models of multi-SNP interactions were estimated using the trio Logic Regression method. A three-SNP joint effect was observed for genotype combinations of SNPs in glutaredoxin, glutaredoxin 3 (GLRX3), and cystathione gamma lyase (CTH); OR=3.78, 95% CI: 2.36, 6.04. Marginal associations were observed for four genes including two involved in the three-way interaction: CTH, alcohol dehydrogenase 5, gamma-glutamylcysteine synthetase, catalytic subunit and GLRX3. These results suggest that variation in genes involved in counterbalancing oxidative stress may contribute to autism, though replication is necessary.
PMID: 21484198
As the abstract reports, the study found that a combination of polymorphisms in three genes associated with glutathione predicts having almost a fourfold higher risk of developing autism. They were the genes that code for the enzymes glutaredoxin, glutaredoxin 3 and cystathionine gamma lyase (also called cystathionase). The study also found that a combination of polymorphisms in four genes related to glutathione had a marginal association with greater risk of developing autism.
Note that cystathionine gamma lyase is the second enzyme in the transsulfuration pathway. One of its reaction products is cysteine, which is usually the rate-limiting amino acid for the synthesis of glutathione. A polymorphism in this enzyme would thus impact the ability to synthesize glutathione.
The glutaredoxins are small proteins that catalyze glutathione-dependent disulfide oxidoreduction reactions in a coupled system with NADPH, GSH, and glutathione reductase. They use glutathione to reduce low molecular weight disulfides and proteins. Polymorphisms in these enzymes may impact the demand for glutathione or the ability to recycle glutathione when it becomes oxidized.
Two additional genes that were involve in a marginal association with the risk of developing autism were the genes that code for alcohol dehydrogenase 5 and gamma- glutamylcysteine synthetase.
The former is also known as formaldehyde dehydrogenase. It oxidizes formaldehyde-glutathione conjugates, releasing glutathione to be used again. A polymorphism in this gene may therefore cause glutathione to be sequestered as this conjugate, making less of it available for other purposes.
Gamma-glutamylsynthetase (also called glutamate cysteine lygase) is the rate-limiting enzyme for the synthesis of glutathione. A polymorphism in this enzyme would affect the ability to synthesize glutathione.
I suggest that if a similar study were done in ME/CFS, similar results would be found. While this would not directly affect treatment of ME/CFS, I think it would draw more research and clinical attention to this proposed causal mechanism, and in the long run, I think that would improve treatment.
Best regards,
Rich