Tetrahydrobiopterin

I am starting a new thread for this topic as it may be important. Apparently Tetrahydrobiopterin (aka BH4) has some very interesting associations to Kynurenine pathway, Nitric Oxide production, EBV and many more.

I am tagging @wigglethemouse for the SNPs that i provide :


GCH1

s4411417 (Risk C)
rs752688 (Risk T)
rs10483639 (Risk C)
rs3783641 (Risk A)
rs8007267 (Risk T)
rs10137071 (Risk T)
rs841 (Risk A)

SPR

rs6730083 (Risk G)
rs1876487 (Risk A)




More on BH4 / Tetrahydrobioptrin :


Connection with ME/CFS (?)

https://link.springer.com/article/10.1007/s11011-019-0388-6


Connection with Kynurenine :


http://www.jbc.org/content/291/2/652.full



Connection with NRF2

https://www.sciencedirect.com/science/article/pii/S0891584914010764



BH4 Connection with IDO, Quinolinic acid, Glutamate


https://www.frontiersin.org/articles/10.3389/fnins.2018.00499/full


EDIT : With DRP1

https://www.sciencedirect.com/science/article/pii/S0891584917300126

 

rs4411417: CC
rs752688: TT
rs8007267: TT
rs10483639: CC
rs3783641: AA
rs8007267: TT
rs10137071: TT


rs6730083: AA
rs1876487: CC

So that is 8/9 for me?

 

If the risk alleles are correct , then yes ! Hopefully someone who is far more knowledgeable than me can confirm the alternative (risk) alleles that i found.

 

I made a correction for rs6730083. the Risk allele is G, not A. Apparently on Sequencing.com they had this one wrong :



So they show 'A' as the alternative and Refernce is 'G' when actually it is the other way around after looking at dbSNP. Lesson learned.

I went through all of the rest variants and they are correct. @Lisa108 despite this, i believe that it is interesting that you have many homozygous mutations.

For the record, me and a severely ill patient have heterozygous mutations on all of these variants , apart from rs6730083

 

These are all very common

Gene GCH1

rs4411417
Alleles T>C 22% (Reference>Variant)
https://www.ncbi.nlm.nih.gov/snp/rs4411417

rs752688
Alleles C>T 22%
https://www.ncbi.nlm.nih.gov/snp/rs752688

rs8007267
Alleles C>T 30%
https://www.ncbi.nlm.nih.gov/snp/rs8007267

rs10483639
Alleles G>C 26%
https://www.ncbi.nlm.nih.gov/snp/rs10483639

rs3783641
Alleles T>A 24% / T>C
https://www.ncbi.nlm.nih.gov/snp/rs3783641


rs8007267
Alleles C>T 30%
https://www.ncbi.nlm.nih.gov/snp/rs8007267

rs10137071
Alleles C>G / C>T 41%
https://www.ncbi.nlm.nih.gov/snp/rs10137071


Gene SPR

rs6730083
Alleles G>A 17%
https://www.ncbi.nlm.nih.gov/snp/rs6730083

rs1876487
Alleles A>C 46%
https://www.ncbi.nlm.nih.gov/snp/rs1876487

 

@mariovitali
I don't see much excitement on gnomAD Broad Institute database. No protein coding genes. Some variants have no transcripts...... Here are the links.

Gene GCH1

rs4411417
https://gnomad.broadinstitute.org/variant/14-54853845-T-C?dataset=gnomad_r3

rs752688
https://gnomad.broadinstitute.org/variant/14-54844851-C-T?dataset=gnomad_r3

rs8007267
https://gnomad.broadinstitute.org/variant/14-54912273-C-T?dataset=gnomad_r3

rs10483639
https://gnomad.broadinstitute.org/variant/14-54839739-G-C?dataset=gnomad_r3

rs3783641
https://gnomad.broadinstitute.org/variant/14-54893421-T-A?dataset=gnomad_r3

rs8007267
https://gnomad.broadinstitute.org/variant/14-54912273-C-T?dataset=gnomad_r3

rs10137071
https://gnomad.broadinstitute.org/variant/14-54903622-C-T?dataset=gnomad_r3

Gene SPR

rs6730083
https://gnomad.broadinstitute.org/variant/2-72888868-G-A?dataset=gnomad_r3

rs1876487
https://gnomad.broadinstitute.org/variant/2-72887223-A-C?dataset=gnomad_r3

 

@wigglethemouse Thank you.

Unfortunately i do not understand -since these are all indeed common mutations- why they are shown in Disgenet as having some effect. Example for rs3783641 :

http://www.disgenet.org/browser/2/1/1/rs3783641/

and another

http://www.disgenet.org/browser/2/1/1/rs8007267/

 

@wigglethemouse Another example from dbSNP for rs8007267 and rs10483639 (both on the list i provided). Lower levels of BH4 is what we are looking for !

 

Okay, from GCH1 Haplotype Determines Vascular and Plasma Biopterin Availability in Coronary Artery Disease: Effects on Vascular Superoxide Production and Endothelial Function that you reference above

I interpret this as 2% of study patients with all of the following has BH4 reduced by 80%
rs8007267 AA
rs3783641 TT
rs10483639 GG

These (i.e. AA, TT, GG) are the reference alleles not the variants that you are referencing? The OO haplotype frequency is 70.6% in this study.

Hope I got that right @mariovitali

 

BH4 is the short cut to methionine synthesis if the normal.pathway is compromised ( mthfr mutations being common)
Is there an" order" for BH4 function/ use which would compromise other actions if it was prioritised?

It strikes me that it's not potentially the I.ia t a couple of mutations for conditions but the cumulative effect of many.

 

@wigglethemouse

Yes that is correct. However i am finding information regarding the haplotype mentioned in that paper as gs224

https://www.snpedia.com/index.php/Gs224

I do not know why there is a discrepancy but the text in the link i provided writes :

On my first post i provide the variants along with their alt. alleles which match completely with the ones quoted above. This haplotype is referred as haplotype gs226. In my -limited- understanding there appears to be a discrepancy between the text quoted above and the study. Moreover user nandixon discusses about GCH1 here, quoteing the same alt. alleles :

https://forums.phoenixrising.me/thr...-bh4-relation-to-nos.19570/page-2#post-592334

In that post , angiotensin is being mentioned (something that comes up over and over to my machine learning runs). Also norepinephrine and epinephrine are closely related to BH4. Vitamin C (which replenishes BH4) appears to be useful in POTS :


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3191072/


From all the above i will definitely be looking at this more closely, something i didn't do in the past.

 

@wigglethemouse @Lisa108 I added rs841 (Risk A) to the list.

It is very interessting that in the following link on rs841, lower HRV (Heart rate variability) is mentioned and also decreased baroreflex.

https://www.snpedia.com/index.php/Rs841


FWIW I am heterozygous on rs841 and the severely ill patient is as well.

 

rs 841: AA

Dang, I just wanted to change my avatar...

 

https://www.ncbi.nlm.nih.gov/clinvar/variation/313386/
rs841 is very common - 22%.
https://www.ncbi.nlm.nih.gov/snp/rs841

Clinvar has 3 citations stating benign.
https://www.ncbi.nlm.nih.gov/clinvar/variation/313386/

I followed the link but don't see the scientific source for lower HRV and decreased baroreflex. I did find this though linking rs841 with C+273T
Tetrahydrobiopterin, Superoxide and Vascular Dysfunction
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2852262/

Reference 26

where the text states

So, that paper is all about C+243T, not C+273T. A typo. I guess the first paper meant C+243T.
Just to double check
rs841 is Chr 14 position 54843774 G->A. Lets look it up
https://gnomad.broadinstitute.org/region/14-54843754-54843794?dataset=gnomad_r3
the table at the bottom shows c.*12+8C>T

I've not been able to see what the variant position on the chromosome is for C+243T. Do you know?



When I first started looking at my 23andMe data I got excited about each mutation found. Then it was explained to me that
* the body has many genes affecting the same protein and so backup mechanisms exist in many situations.
* if you do find a gene that is damaging both in studies, and SIFT, that has a high CADD score it doesn't mean it is disease causing in your case.
* Ideally a genetic study is tied with a proteomics study. If in proteomics you see proteins very high or low you can then look at the genetic data to see if there is a link. Unfortunately to date I don't believe we have seen a large proteomics study in ME. And on an individual basis you would want to run a medical test to confirm the disease mechanism explained by the mutation if possible.
* You probably also want to look at your siblings data and parents data to see if any of them have the same mutation/symptom.

I guess what I'm trying to say is that it is all very complicated, way above my head, and easy to jump to assumptions. Sorry to be Debby Downer. We need to follow-up multiple citations where possible.

 

I can only think that the original paper used < rather than > and that confused people reading it. e.g. they wrote G<A rather than the more usual A>G

 

I agree, we should be very careful in not accepting but also not dismissing things easily and Thank you once again for this detective work.

Here is a post i made on PR :

https://forums.phoenixrising.me/thr...e-treatment-for-cfs.37244/page-29#post-634381

So back then, i did notice some issues with protein but believed that it was attributed to "protein misfolding". I discuss how by not eating protein for 20 days and then introducing it, i got Sensorineural Hearing Loss (= lost my hearing on one ear).

Also, i felt the worst when i would switch to a low fat, low carb diet (which means that i had to go high-protein). Given the re-visit to GCH1 and Phenylalanine metabolism, i stopped eating meat for the past 9 days and dropped every supplement i take apart from Metafolin and Vitamin C (to replenish BH4). No symptoms so far but i have to pass the 15-days mark. Numerous times in the past i would try to stop the supplements i was taking and within 7-10 days i would get symptoms with the first one being tinnitus.

If this does not happen and when i re-introduce protein i get tinnitus then that will confirm the origin of problems for myself. I will report back.

More potential interesting "signals" are coming up that require further investigation. This i found on the ME association regarding a machine learning approach that was able to differentiate ME/CFS vs Controls :

https://www.meassociation.org.uk/wp...n-MECFS-using-Raman-spectroscopy-06.09.18.pdf

@Andy Dr Morten is being mentioned. Could we ask what is his opinion with Phenylalanine on ME/CFS patients by any chance?


@wigglethemouse I did not have the time to look in the paper discussing the Machine Learning approach extensively. The algorithm they use is Ok but they could have used more advanced algorithms. I will have to elaborate more on the paper :

https://pubs.rsc.org/en/Content/ArticleLanding/2018/AN/C8AN01437J#!divAbstract

 

phenylalanine is definitely on my radar. Chris Armstrong was the first to highlight it.

Metabolic profiling reveals anomalous energy metabolism and oxidative stress pathways in Chronic Fatigue Syndrome patients.
https://www.researchgate.net/public...pathways_in_chronic_fatigue_syndrome_patients

Karl Morten then identified phenylalanine in a model cell and in patients in the work you mentioned. He didn't talk about it in the Q&A here on s4me............

And soon we should expect more data from the Jarred Younger good day bad day paper where samples sent to Chris Armstrong measured metabolites............

 

@wigglethemouse i believe at one point we had a discussion about mast cell activation syndrome (MCAS). Yet one more possible signal regarding BH4 and its role in NO :

So, mast cell degranulation. Then i find this :

 

Very interesting link @mariovitali

There are also papers stating mast cells produce NO as well as react to NO
http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0074-02762005000900003

I wish I knew what Chris Armstrong was working on regarding Nitrogen
https://twitter.com/user/status/1169367659445489664

 

@wigglethemouse

Of course i cannot be sure that this is what he is looking at but many interesting topics we've been discussing. From a Nitrogen metabolism page (link below) :









and (see NMDA, AMPA, Kainate below, related to excitotoxicity)




https://themedicalbiochemistrypage.org/nitrogen-metabolism.php