@mariovitali
Of the relatively common SNPs in GCHI, like those we're looking at here, the most well-studied and most significant (for European ethnicities) seem to be
rs841, and a haplotype of three SNPs comprised of:
rs10483639
rs3783641
rs8007267
That 3-SNP haplotype is referred to by SNPedia/Promethease as "gs224." The risk alleles for each of the three SNPs above are C, A and T, respectively. (The risk allele for rs841 is A.)
Rs841, in European ethnicities, is in strong "linkage disequilibrium" with gs224 (see the reference in this
post). This means that, typically, the overall genotype (homozygous or heterozygous) a person has for gs224 should match pretty well with the result for rs841. (Note that 23andMe no longer tests for rs841 with their latest test, which is why I'm mentioning this for other people.)
So, for example, you're heterozygous for both rs841 and for gs224. (For other people, it often won't necessarily happen that all 3 SNPs within gs224 each perfectly matches the genotype for rs841; e.g., see this
post.)
I think rs841 is probably the actual, functional, detrimental SNP (affecting gene expression), but it may be gs224 as a whole, instead, that is the problem - or both, or neither (it's still not perfectly clear, I don't think). In any event, gs224 can be used as a good substitute for rs841, and vice versa, for people of European ethnicity.
GCH1 is the rate-limiting step for the production of BH4, and rs841 (or gs224) appears to affect how much BH4 is made. That SNP (or haplotype) may be detrimental, especially in diseases involving oxidative stress. At a minimum, it probably exacerbates oxidative stress (by promoting uncoupling of the nitric oxide synthases to produce superoxide and peroxynitrite), but it might also possibly contribute to the development of disease in the first place (by working in conjunction with other "bad" SNPs and/or epigenetic factors, including diet driven) or to perpetuate a disease. Or, in the words of the authors of the reference given above (at p.198 of the article):
[Rs841/gs224]'s phenotypic consequences are decreased GCH1 upregulation upon stimulation or tissue inflammation but not a complete loss of GCH1 function. Decreased BH4 production mainly manifests in pathophysiological situations when its production would be normally increased due to upregulation of GCH1, e.g. at inflammatory sites or in injured neurons [8,10] or in blood vessels exposed to high blood pressure, high cholesterol or other cellular stress factors [12,18,19].
It wouldn't be possible to tell for certain whether a person might actually have a problem with reduced BH4 production from the results of rs841/gs224 alone, I don't think. And in your case, being heterozygous makes that less likely than being homozygous. But it may be worth exploring to see if something might help.
I don't have enough energy to go into too much more detail, but obvious categories of things to try are (there's some overlap):
1. Increase GCH1 expression
2. Prevent inhibition of GCH1 expression
3. Decrease loss (degradation) of the enzyme (GTPCH1)
4. Decrease loss (oxidation) of BH4
5. Increase BH4
I think losartan might hold some promise to increase BH4 based on this study (and others not directly related to BH4):
Angiotensin II type 1 receptor blocker ameliorates uncoupled endothelial nitric oxide synthase in rats with experimental diabetic nephropathy
In theory, direct BH4 supplementation would seem to have some significant potential problems, but
@Mimi has apparently had some success in that regard. (I'm curious if it's still working for her?)
The problem is that it turns out that the
ratio of BH4 to its oxidized form, BH2, is just as important as the absolute amount of BH4, in terms of keeping NOS coupled. And keeping a high BH4:BH2 ratio while supplementing BH4 would seem very tricky given how much oxidative stress is present in ME/CFS. There may be a "Goldilocks" amount, though, that can work. Or alternatively, supplementing a very large amount of BH4 so that it can act as its own "built-in" antioxidant might be possible - except for cost.
A couple of years ago, I tried the "homeopathic" 2.5mg BH4 capsules that are available. I seemingly had a positive response to the very first capsule, but then nothing after that, even trying up to as much as ten capsules at once. Perhaps I was running into the BH4:BH2 ratio problem, and needed to try either less than 2.5mg (seems a bit unlikely), or a lot more than 25mg.
On the other hand, BH4 is extremely easily oxidized when not in the stabilized (patented) Kuvan tablet form. And I'm suspicious that some of the suppliers are simply crushing the tablets to make smaller doses, and they may not be taking great enough care to protect against oxygen. So I might give direct supplementation another try with the actual Kuvan tablets at some point.
As far as trying to prevent loss of BH4 already present, that's going to be partly about decreasing overall oxidative stress, e.g., with antioxidants. Methylfolate in theory should be especially helpful, but too much might contribute to hypermethylation of the promoter region of GCH1 and shut down its expression, especially when used with large amounts of vitamin B12.