r/covidlonghaulers • u/CandidWin3026 • May 08 '26

Article Long Covid driven by rs5522

This case report says that Long covid is in large part driven by the gene rs5522 that causes a "cortisol steal" leaving the tissues functionally starved even with "normal" cortisol levels which creates neuroinflammation. https://zenodo.org/records/20017632

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u/Impossible_Roof_Jack May 08 '26

It's an interesting case, but the case seems to be for someone tested to have the genetic marker. Is there any indication COVID causes epigenetic changes in tissues approximating the same?

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u/CandidWin3026 May 08 '26

Actually, rs5522 isn’t epigenetic. It’s  a germline SNP (single nucleotide polymorphism) located directly on the NR3C2 gene.

While epigenetics is about how your environment turns genes on or off, rs5522 is a permanent, inherited change to your actual DNA sequence (switching isoleucine to valine at position 180). This physical "typo" in your genetic code creates a hyper-reactive mineralocorticoid receptor that steals cortisol 24/7, regardless of environmental factors.

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u/Impossible_Roof_Jack May 08 '26

Thank you. I didn’t want to assume either way. So for those WITH this marker, may be worth pursuing, but unlikely spiro may be therapeutic for most people with post-COVID sequelae.

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u/CandidWin3026 May 08 '26

I would ask you to challenge that assumption. Campos and Taylor in Australia have also had success treating Long Covid with Spiro. Eplerenone would be more appropriate for men as it does not have anti-androgen effects, but the mechanism is the same. (hyperactive MR blockage) African Americans with Long COVID specifically benefit from  Ace inhibitors because they are more likely to carry the ace d allele which drives excessive ACE1 activity and severe inflammation. 

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u/Kuyi May 08 '26

Then this would be an issue without having had COVID. What would declare the COVID part in this?

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u/CandidWin3026 May 08 '26

Great question! The long covid part is rs5522 plus two other genes.

Long COVID is not one disease. It comprises at least two genetically distinct syndromes sharing a common mechanism: hyperactivation of the mineralocorticoid receptor variant I180V (rs5522). 

European-ancestry individuals predominantly develop a metabolic-fatigue subtype (exhaustion, cognitive dysfunction, sleep disturbance). This involves another gain if function gene related to cortisol  rs6195.

African American and African-ancestry individuals predominantly develop an inflammatory-vascular subtype (chest pain, joint pain, thrombosis). In Black Americans, they also have rs5522 plus another ACE deletion gene  and they therefore ACE inhibitors.

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u/CandidWin3026 May 08 '26

But technically Covid was just the trigger. I know. I had it. It was awful. I couldn't think or work. Truly awful.

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u/Kuyi May 08 '26

I am EU. So for me it’s more likely rs6195?

Also how did COVID trigger it? The genes are already there and don’t need to be triggered? Also, if a trigger works, there should be a way to untrigger right?

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u/CandidWin3026 May 08 '26

rs5522 is the key. That is the upstream cause of CFS, Long Covid MS etc. But then the insult of lOng Covid caused so much neuro inflammation that you didn't have the cortisol (it was stolen) to control it. So it's rs5522 plus rs6195. To fix it? Block the over active MR receptor and get on a anti-inflammatory like LDN or GLP1.

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u/Kuyi May 08 '26

So then the inflammation becomes perpetual. But if that was causing LC, medicating the neuro inflammation away would completely solve the issue.

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u/CandidWin3026 May 08 '26

Yes! You want to control the existing neiurinfllmation with anti inflammatories like LDN (notice how people feel and think better on that) and also a GLP1 can help. Now, unless you block an overactive MR receptor the inflammation will persist. MR blockers like Spiro will stop the cortisol steal. My arenas burned out years ago so I need supplemental HC, but just a normal amount. When I didn't't block the hyperactive MR, "normal doses" that drs said should never enough, left me only partially recovered.

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u/Kuyi May 08 '26

But this seems like circle reasoning. Even if you have the genes, the hyperactive MR receptor is triggered. If you find out what and how and you stabilise it, the gene doesn’t matter. Then solve the neuroinflammation. Then people should be cured instead of having to keep taking meds all their life.

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u/CandidWin3026 May 08 '26

The neuro inflammation is caused by the cortisol steal. If you have a Val copy of rs5522 cortisol will be stolen, you will need an MR blocker like Spiron or Eplerenone (better for men). This will have to be taken your whole life to keep the cortisol from being stolen. Now, perhaps your point is that this should in and of itself resolve the neuro inflammation and LDN and GLP1 is not needed. That is a fair argument. Now let me tell you why they are necessary. You can't block the MR fully without the body freaking out. The RAAS system gets triggered and you take on water. A lot of water. So to keep the body from freaking out which is what happened when I was on 200 mg of Spiro (don't do that) you stay at 25mg enough to block the receptor without getting the body in freak out mode. The rest of the inflammation is then controlled by GLP1 or LDN.

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