Preprint Spironolactone for ME/CFS in a Patient Homozygous for rs5522 (I180V): A Case Report, 2026, Donnellan et al

forestglip

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Spironolactone for ME/CFS in a Patient Homozygous for rs5522 (I180V): A Case Report

Donnellan, Patricia

Abstract
Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition with no consistently effective treatment. The mineralocorticoid receptor variant rs5522 (I180V) is associated with enhanced MR response to cortisol and altered stress responsiveness, but has not been linked to ME/CFS treatment response.

Case: A 48-year-old woman with 28 years of treatment-resistant ME/CFS was found to be homozygous for rs5522. Following initiation of spironolactone, an MR antagonist, she experienced restorative sleep within 48 hours, resolution of post-exertional malaise within 3 days, and sustained functional improvement at one month.

Conclusion: MR overactivity may drive ME/CFS in patients with rs5522. Genetic stratification could identify patients who benefit from MR antagonism.

Web | DOI | PDF | Authorea | Preprint
 
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Only one month so far:
Improvement has been sustained for over one month on 100 mg daily.
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So potentially temporary like a previous intervention:
The patient had previously trialed fludrocortisone (Florinef), an MR agonist sometimes used in ME/CFS for orthostatic symptoms, with initial but unsustained benefit.
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And just noting:
The patient is also the sole author of this report
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The minor allele frequency is approximately 12% in European populations, meaning approximately 20-25% carry at least one copy of the variant (2).
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Can anyone say what homozygot means in that case? Which alleles she had?

I have rs5522 TT

It is interesting because I used tk take spironolactone for a few years for m PCOS and my disease definitely progressed later, which could be due to thousand factors (my disease is very progressive)
 
forestglip said:
Most likely, she has two copies of the minor allele, C, though I don't see her explicitly say that. The T allele is very common.

rs5522 on dbSNP - See the row for European in the Allele Frequency table:

C=0.110877 A=0.000000, T=0.889123
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Thabk you. Unfortunately I am very severe and cognitively not functioning enough to understand or interprete anything in that link.

According to chatgpt:

European populations (most relevant for you)
  • C allele (Ile) ≈ ~89–92%
  • T allele (Val) ≈ ~8–11%
That translates roughly to:
  • CC (Ile/Ile) → ~80–85% (very common)
  • CT (Ile/Val) → ~15–20%
  • TT (Val/Val) → ~1–3% (quite uncommon)
So in Europeans:
TT is rare, but definitely present


But i don’t know ir chatgpt is to be trusted more than you
 
Venicequeenf said:
Thabk you. Unfortunately I am very severe and cognitively not functioning enough to understand or interprete anything in that link.

According to chatgpt:

European populations (most relevant for you)
  • C allele (Ile) ≈ ~89–92%
  • T allele (Val) ≈ ~8–11%
That translates roughly to:
  • CC (Ile/Ile) → ~80–85% (very common)
  • CT (Ile/Val) → ~15–20%
  • TT (Val/Val) → ~1–3% (quite uncommon)
So in Europeans:
TT is rare, but definitely present


But i don’t know ir chatgpt is to be trusted more than you
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Sorry i think you were right!
How is this paper even ofninterest id the don’t say which alleles the patient had
 
Venicequeenf said:
How is this paper even ofninterest id the don’t say which alleles the patient had
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I think it could potentially be inferred from the text:

The rs5522 variant results in a valine substitution at codon 180 in the MR N-terminal domain. Studies have shown this variant is associated with enhanced transcriptional response to cortisol, increased HPA axis activity, and altered stress reactivity (2, 3).
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The rs5522 variant, however, shows enhanced transcriptional response to cortisol (2, 3). Even normal physiological cortisol levels may trigger excessive MR activation.
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The patient’s prior response to fludrocortisone is instructive. Florinef, an MR agonist sometimes used in ME/CFS for orthostatic intolerance, initially helped but failed to sustain improvement. This is consistent with a model in which the underlying problem is MR overactivity, not underactivity.
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It appears that the paper is saying that the patient's problem is consistent with overactivity of the mineralocorticoid receptor (MR). It also says that the variant that causes a valine substitution causes overactivity of the receptor.

According to the HGVS tab on dbSNP, valine is the amino acid seen with the minor (less common) allele, C. If she's saying she has a problem consistent with valine at this position in the gene, then the allele she has is C.
 
Checking the DecodeME summary stats:

1771681781010.png

So the minor allele, C, is the risk allele, consistent with the case report. The p-value is 0.038, which is not very strong evidence, though.

Maybe this is a recessive variant, in which case there would be no effect if there was only one copy of C, and it wouldn't be detected as easily in DecodeME, which used an additive, not recessive model.

Edit: I thought DecodeME said they used an additive model in the paper or analysis plan, but I misremembered. They don't seem to explicitly say which model they used, though additive is the default for the tool they used, regenie.
 
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For who wonders what Spironolactone is

Source: www.drugs.com

What is spironolactone?​

Spironolactone is a potassium-sparing diuretic (water pill) that prevents your body from absorbing too much salt and keeps your potassium levels from getting too low.

Spironolactone is used to treat heart failure, high blood pressure (hypertension), or hypokalemia (low potassium levels in the blood).

Spironolactone also treats fluid retention (edema) in people with congestive heart failure, cirrhosis of the liver, or a kidney disorder called nephrotic syndrome.

Spironolactone is also used to diagnose or treat a condition in which you have too much aldosterone in your body. Aldosterone is a hormone produced by your adrenal glands to help regulate the salt and water balance in your body.


Source: Wikipedia

Spironolactone, sold under the brand name Aldactone among others, is classed as a diuretic medication.[21] It can be used to treat fluid build-up due to liver disease or kidney disease.[4] It is also used to reduce risk of disease progression, hospitalization, and death due to some types of heart failure.[22][23] Other uses include acne and excessive hair growth in women, low blood potassium that does not improve with supplementation, high blood pressure that is difficult to treat, and early puberty in boys.[4][24][25][26] It can also be used to block the effects of testosterone as a part of feminizing hormone therapy.[27] Spironolactone is usually available in tablets, taken by mouth, though topical forms are also available.[4]
 
In the brain, where 11β-hydroxysteroid dehydrogenase type 2 is absent, cortisol is the primary MR ligand (4). Wild-type MR responds to cortisol proportionally and allows the system to return to baseline. The rs5522 variant, however, shows enhanced transcriptional response to cortisol (2, 3).
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Even normal physiological cortisol levels may trigger excessive MR activation. Critically, serum cortisol levels do not reflect what is happening at the receptor level. With cortisol preferentially captured by overactive MR, less may be available to activate the glucocorticoid receptor (GR). GR is expressed in virtually every tissue — brain, liver, kidney, muscle, immune cells — and is essential for basic cellular functions including metabolism, memory, immune regulation, inflammation control, and energy production.
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The result is a body with normal circulating cortisol but functionally starved at the cellular level: organs unable to access the cortisol they need to perform the basic functions of life.
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Can someone explain the bolded part? It seems to be a key part of the reasoning. What does «preferentially captured» mean, and is that something that actually happens?
 
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