Genetics: HFE

[Hutan]

DecodeME candidate ME gene
From the Candidate Genes document

In DecodeME, we attempted to link GWAS variants to target genes. Here we discuss the top two tiers of predicted linked genes that we are most confident about –‘Tier 1’ and ’Tier 2’.

We defined genes as Tier 1 genes if: (i) they are protein-coding genes, (ii) they have GTEx-v10 expression quantitative trait loci (eQTLs) lying within one of the FUMA-defined ME/CFS-associated intervals, and (iii) their expression and ME/CFS risk are predicted to share a single causal variant with a posterior probability for colocalisation (H4) of at least 75%. For this definition, we disregarded the histone genes in the chr6p22.2 HIST1 cluster, as their sequences and functions are highly redundant (1). This prioritisation step yielded 29 Tier 1 genes.

For the intervals without Tier 1 genes, three Tier 2 genes were defined as the closest protein-coding genes without eQTL association: FBXL4 (chr6q16.1), OLFM4 (chr13q14.3), and CCPG1 (chr15q21.3).

CHROMOSOME 6p
Chr6p contained seven Tier 1 genes.

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HFE (Tier 1)

• Protein: Homeostatic iron regulator protein. UniProt. GeneCards.
The allele that increases the risk of ME/CFS is associated with increasing HFE gene expression in the cortex and prostate.

• Molecular function: HFE protein regulates the interaction of the transferrin receptor with transferrin.

• Cellular function: HFE protein influences iron absorption by modulating the expression of hepcidin, the main controller of iron metabolism.

• Link to disease: Mutations in HFE can lead to hereditary haemochromatosis, an excessive absorption and accumulation of iron (41).

• Potential relevance to ME/CFS: Unclear.

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References
41 Barton JC, Edwards CQ, Acton RT. HFE gene: Structure, function, mutations, and associated iron abnormalities. Gene. 2015 Dec 15;574(2):179–92.

 

[Hutan]

This one got me a bit excited, as there are a number of references to iron issues and diagnoses related to iron control related to ME/CFS on the forum - papers and member experiences. And, we know that infections can result in a change in iron homeostasis. It seemed to me to be a mechanism that is worth considering as the perturbation that might help tip a body into ME/CFS.

I've tagged some of the possibly relevant threads with 'iron'.

Here's a couple:
Members Only - Could iron load impact ME?

Thread 'Iron dysregulation and inflammatory stress erythropoiesis associates with long-term outcome of COVID-19, 2024, Hanson et al'

Mar 4, 2024

Merged threads
Low ferritin levels for pwME has been a mystery. My levels were normal when I was tested by an Internist during the first year of illness, but rapidly started decreasing for no apparent reason for many years after. I took iron supplements regularly. No one could figure it out why.

I don't think it was from inflammation in my case b/c I had a c-reactive protein test and it was normal...

• Mij
• dendritic cells erythropoietic system iron long covid
• Replies: 58
• Forum: Long Covid research

• 

 

[Hutan]

More from the Iron dysregulation study. The 'Hanson' is not Maureen Hanson.

Getting back to the Hanson article, this is interesting:

Speculatively, the generally increased prevalence of iron deficiency in pre-menopausal women may contribute to the higher risk of PASC amongst this demographic7,9,10by enhancing the relative magnitude of infection-related iron redistribution against a baseline of lower iron stores.​

....​

It is unlikely that these observations are SARS-CoV-2 specific. Disruption of host iron homeostasis is a consequence of many viral infections, both through direct viral mechanisms of interference and as a consequence of the evoked inflammatory response50,84. Many infectious diseases—including Ebola85,86, influenza87 and SARS88—elicit broadly similar post-acute sequelae, suggesting similar iron-redistribution strategies may be considered. This study has implicated disrupted iron homeostasis and iron-deprived stress erythropoiesis that persisted for more than 2 weeks from symptom onset as potential drivers of PASC.​

I would like to go back in time, please. With an iron infusion.

Just a note on interpretation of the results for this study, since I explored this data in-depth as part of a validation for another LC study I was a part of.

Ferritin is a carrying molecule that is primarily present within cells in the body. Transferrin is the primary molecule that carries iron in the bloodstream (hemoglobin notwithstanding).

Some amount of ferritin leaks out of cells and is present in the blood plasma--because of this, free blood ferritin levels may often be used as a proxy for available iron stores in the body. The logic being that more ferritin in the blood = there's enough iron stored in ferritin in the cells to go around.

However, if there are differences in how greedily cells are holding onto that iron, levels of ferritin in the blood may not correlate that well to the actual presence of iron in the body.

The theoretical explanation based on these results is that there is an increased sequestration of iron in certain innate immune cells starting during infection and it continues beyond infection in individuals who experience LC. In simple terms, the rest of the body experiences "anemia" because certain innate immune cells are really active thieves.

This "iron theft" is often seen during acute infection and is induced as a response to certain cytokines. The main question in LC is why these cells don't return to normal behavior after infection is cleared. That question is somewhat beyond the scope of this paper.

Because they are still "thieving" iron, further iron supplementation may or may not help. It is hard to tell how much of that supplemented iron will actually end up where it is supposed to go vs. getting rounded up by those same greedy immune cells.

It's also hard to determine which LC symptoms are coming from the direct behavior of those immune cells vs. less iron availability for other cells. So even if you are able to get more iron to the rest of the body, that may only fix a portion of the problem.