Only one month at 100mg. It seems like she had no response during titration—probably 25, 50, 75 and then 100mg. It seems a little strange that she had no response until she hit exactly 100mg—but life is strange.
Preprint Spironolactone for ME/CFS in a Patient Homozygous for rs5522 (I180V): A Case Report, 2026, Donnellan et al
- Thread starter forestglip
- Start date
Only one month at 100mg. It seems like she had no response during titration—probably 25, 50, 75 and then 100mg. It seems a little strange that she had no response until she hit exactly 100mg—but life is strange.
jnmaciuch
Senior Member (Voting Rights)
Preferential capture is a biochemical principle that has to do with receptor binding affinity to a ligand. It is a real phenomenon but the basis for invoking it here with such confidence and claiming that it causes cells to be functionally "starved" of GR activity is...entirely unsubstantiated.
Firstly, the mutation does not occur in the ligand binding domain (LBD) of the protein, it's all the way on the other end. There are instances where mutations in other parts of the protein can change the shape of the LBD, but even more likely this mutation affects something that matters after cortisol already binds like nuclear localization. The conclusion from this 2024 preprint was basically that we know this mutation affects enhances the downstream effect of cortisol binding to the MR but we don't know why. And the effect it would have on intracellular GR activity is even less known
Long story short: as far as anecdotal evidence goes it's theoretically plausible that this person's health is affected by this mutation and that the drug did something to counteract it, I just don't think the biological explanation for why can be trusted
Utsikt
Senior Member (Voting Rights)
Thank you!
It also seems a bit weird to me to place the entire illness on one fairly common mutation. Wasn’t it 11 % or something?
11 or 12% is the frequency of the allele. Everyone has two alleles. So out of all the alleles in a population (twice the population), how many are C? That's the allele frequency.
The proportion of people who have two copies of the minor allele is fairly rare - around 1%.
Online calculator for seeing the expected genotype frequencies based on a given allele frequency: https://scienceprimer.com/hardy-weinberg-equilibrium-calculator
jnmaciuch
Senior Member (Voting Rights)
Even a common mutation could be relevant if the mutation worsens a problem that is already under strain from the disease state. That might explain things like how two people end up with very similar disease presentation, except one has debilitating OI as a primary symptom and the other doesn't. But yeah, I don't have faith it would explain the entirety of the illness
ScoutB
Senior Member (Voting Rights)
I guess C is the 'reference' allele even though it is more rare than the alt allele T. Is that unusual? I guess sometimes your reference genome just happens to contain the more rare variant? Wonder if that's why the AI got confused -- it confused me at least.
FWIW, according to my own sequence data I'm TT, i.e. the common type.
Yeah I am confused by this -- I often see genetics papers mention the location and gloss over which allele was the 'bad' one. Maybe it's obvious to experts for reasons like forestgliph said.
Not advocating for it, but you could get your whole genome sequenced. My sense is, unless the gene is a well established risk factor for some disease, there often isn't a specific test just for it.
FWIW, according to my own sequence data I'm TT, i.e. the common type.
I think that reference genomes are assembled from bits and pieces of genetic code of different people. So if those people have the minor allele, that's what gets included in the reference. Looking at DecodeME's Table 3, two of the eight lead SNPs are like this, where the reference allele is the minor allele.
Venicequeenf
Established Member
I contacted the author and asked which alleles the patient had, ahe said she think it was TT. That’s confusing, so she probably remembers it wrong? Because TT is the common type
Hopefully if and when it gets peer-reviewed, someone will ask that it be explicitly specified. But it seems to me the paper is saying the variant she has causes valine to be substituted into the gene.
The C allele causes a valine substitution. T leads to the gene having isoleucine instead.
Also, the paper says:
If by "the variant", the paper means the same variant the patient has, then that frequency of 20-25% would match with having at least one copy of C, not T. Closer to 99% of Europeans have at least one T.
Venicequeenf
Established Member
She probably forgot and mixed it up?!
She said it gets peer reviewed ib 2 weeks!
Post in thread 'Spironolactone for viruses - personal experience gathering'
https://forums.phoenixrising.me/thr...sonal-experience-gathering.84082/post-2427192
https://forums.phoenixrising.me/thr...sonal-experience-gathering.84082/post-2427192
DonnellanP
Established Member
Someone notified me this thread exists. What do you want to know?
23 and me
It was raw data.
TT
Other companies report differently
I went from 25 to 100 and did stop at 50 along the way.
Everything was prescribed by a Dr.
I went to 100 x 2
Don’t do this.
After I write the report my RAAS went crazy. Aldosterone went from 7 to 138
Drs won’t believe it’s fluid and not fat because there is no pitting edema. Fluid is 3rd spacing.
I repeat. I am not a Dr. doses higher than 25mg may cause initial improvement but then RAAS activation.
What else can I answer?
Had to stop both spiro and progesterone to starve out the MR receptor. Starting to per out 5-10 lbs this week.
Cholesterol was normalized in first 6 weeks on spiro.
23 and me
It was raw data.
TT
Other companies report differently
I went from 25 to 100 and did stop at 50 along the way.
Everything was prescribed by a Dr.
I went to 100 x 2
Don’t do this.
After I write the report my RAAS went crazy. Aldosterone went from 7 to 138
Drs won’t believe it’s fluid and not fat because there is no pitting edema. Fluid is 3rd spacing.
I repeat. I am not a Dr. doses higher than 25mg may cause initial improvement but then RAAS activation.
What else can I answer?
Had to stop both spiro and progesterone to starve out the MR receptor. Starting to per out 5-10 lbs this week.
Cholesterol was normalized in first 6 weeks on spiro.
DonnellanP
Established Member
Yes. The Katsu paper outlines this substitution. I180v
Why is the prevalence data screwed up? The researchers in 2006 had flawed methodology. He studied in vivo compared it to humans and used 18.7 yr old men as comparison. Excluded women, people with any medications or diseases.
Did use twins, but flawed Methodology
jnmaciuch
Senior Member (Voting Rights)
Hi @DonnellanP , I am a PhD student studying computational biology. If you have the TT genotype, there might be a mistake in your manuscript. You would not have the rs5522 Ile180Val mutation, you would have the common type (Ile180).
This is the location on the genome for the gene encoding the MR at amino acid 180. The nucleotide sequence CAA (the gene is transcribed right to left) codes for the mRNA sequence GUU, which codes for Valine. If you had a T in that rightmost position instead of a C, that codes for amino acid sequence AUU, which codes for Isoleucine. That is the more common genotype, and not the one cited in your study with increased MR activity.
This is the location on the genome for the gene encoding the MR at amino acid 180. The nucleotide sequence CAA (the gene is transcribed right to left) codes for the mRNA sequence GUU, which codes for Valine. If you had a T in that rightmost position instead of a C, that codes for amino acid sequence AUU, which codes for Isoleucine. That is the more common genotype, and not the one cited in your study with increased MR activity.
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DonnellanP
Established Member
With respect. You are not understanding how 23 and me reports the raw data.
The Derijk methodology is flawed too.
20 yrs ago and no one questioned it because he got there first. He has be cited 6,000 times overall in his career.
BBRC has accepted the paper. Peer review any day now.
I know my stuff.
I can’t debate everyone on here.
Believe me or don’t
I was prescribed Spiro a year ago for acne but didn’t take it because I thought LOWER blood pressure? No way.
The pots is from lack of cortisol needed for vascular tone.
The Derijk methodology is flawed too.
20 yrs ago and no one questioned it because he got there first. He has be cited 6,000 times overall in his career.
BBRC has accepted the paper. Peer review any day now.
I know my stuff.
I can’t debate everyone on here.
Believe me or don’t
I was prescribed Spiro a year ago for acne but didn’t take it because I thought LOWER blood pressure? No way.
The pots is from lack of cortisol needed for vascular tone.
As far as I can tell, 23andMe reports based on the positive strand, and on the positive strand at this location, T is the common allele and C is the minor allele.
Can you please explain how you determined that T is the minor allele or codes for valine?
Other preprint including the same author on rs5522:
Comparison of transcriptional activation by corticosteroids of human MR (Ile-180) and haplotype (Val-180)
Comparison of transcriptional activation by corticosteroids of human MR (Ile-180) and haplotype (Val-180)
DonnellanP
Established Member
To clarify:
The Katsu mechanism paper is getting peer reviewed right now.
I tried to get my case report peer reviewed on cureus but they won’t print a pre print as a refrence hence the problem. I am waiting on my own contribution to be peer reviewed before I can get peer review.
I want everyone to feel better.
Honestly, I’m gotten some online harassment since the pre print so if I seem short, I’ve just been through some “ people “ getting really pissy about what I put out in the world. I read every reference throughly.
I think the prevalence is higher in the U.S. than in Europe.
Look at my LinkedIn page if you are curious about me or the orcid Id
The Katsu mechanism paper is getting peer reviewed right now.
I tried to get my case report peer reviewed on cureus but they won’t print a pre print as a refrence hence the problem. I am waiting on my own contribution to be peer reviewed before I can get peer review.
I want everyone to feel better.
Honestly, I’m gotten some online harassment since the pre print so if I seem short, I’ve just been through some “ people “ getting really pissy about what I put out in the world. I read every reference throughly.
I think the prevalence is higher in the U.S. than in Europe.
Look at my LinkedIn page if you are curious about me or the orcid Id
DonnellanP
Established Member
rs5522 SNP
A allele = Codes for ISOLEUCINE (Ile, I) at position 180
G allele = Codes for VALINE (Val, V) at position 180
23andMe rs5522
23andMe notation terms:
They report opposite strand
A/G (forward strand) = T/C (reverse strand)
TT = GG on forward strand
jnmaciuch
Senior Member (Voting Rights)
Thanks for the reply, @DonnellanP. I work with sequencing data regularly.
The complementarity of nucleotides is C=G and T=A, and NR3C2 is a negative strand gene. So A/A reported on the positive strand means T/T in the negative (protein coding) strand. Would you mind sharing what the raw 23 and ME data said? Was it A/A or G/G?
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