Genetics: HFE

Hutan

Hutan

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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).
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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.
 
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?

Mij

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

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...
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More from the Iron dysregulation study. The 'Hanson' is not Maureen Hanson.
Evergreen said:
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.​
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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.
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jnmaciuch said:
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.
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I think iron metabolism per se would be hard to link to ME/CFS. However, transferrin receptor expression has been known as a marker of immune cell activation for some time and the AI summary on Google notes that transferrin receptor defects can produce immunodeficiency syndromes. So the molecule may be rather crucial for lymphocytes and maybe macrophages/microglia.

My guesses at relevance to ME/CFS would be:
1. Transferrin receptor usage by microglia might be relevant to neuron/microglia signalling in e.g. hypothalamus.
2. Transferrin receptor might be involved in innate immune signalling in response to 'daily junk' in the sort of context Jo, Jackie and I raised on Qeios.

One thought related to this is that processes like autophagy, immune cell priming with increased cytoplasmic size and shifts in respiration and mitochondrial content that occur in a peripheral immune response may be recapitulated within microglia and genetic shifts might affect both in such a way that the brain's microcosmal modelling of the body state might be subverted.
 
Utsikt said:
Can you elaborate on what this means?
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Not much, just that the brain's job is to model the world in one way or another and for microglia that might actually make use of some of the same signals that ae being modelled. Blocking cyclo-oxygenase in joints with ibuprofen helps flu myalgia but blocking cyclo-oxygenase in the brain also helps the fever. I am trying to think of a way to tie these things together that might lead to a light-bulb moment but I am not sure I have quite got there yet.
 
Jonathan Edwards said:
Not much, just that the brain's job is to model the world in one way or another and for microglia that might actually make use of some of the same signals that ae being modelled. Blocking cyclo-oxygenase in joints with ibuprofen helps flu myalgia but blocking cyclo-oxygenase in the brain also helps the fever. I am trying to think of a way to tie these things together that might lead to a light-bulb moment but I am not sure I have quite got there yet.
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It’s been evolutionarily beneficial across the body to repurpose the same pathways for a new function in a different context so long as the functions in different contexts don’t negatively interfere with eachother too much. We see that with the NOTCH pathway being involved in nearly everything, with metabolic pathways mediating nearly all immune effector functions, etc.

No “job fulfillment” needed to explain, though it is funny to think about the brain receiving a quarterly project assignment and self assessment questionnaire from evolution.
 
I have five measures of transferrin, all are below the normal range. Transferrin saturation has bounced around but has sometimes been high normal.

As I mentioned elsewhere, my son was found to have iron deficiency as part of the investigations after ME/CFS onset, and had to have iron tablets, despite having a normal non-vegetarian diet.
 
Seeing HFE pop up is intriguing. I’ve long wondered if my haemochromatosis and my ME are mutually reinforcing each other in some unhelpful way (beyond the fact that haemochromatosis treatment plus having to travel for it is a sure-fire way of ending up with PEM)

Clearly, simple iron levels by themselves can’t be a significant causative factor in ME. Most people with iron deficiency don’t have ME and neither do most people with iron overload

Though there might be an issue with misdiagnosis, especially for meat-eating males. It seems iron testing is anything but routine if you’re not part of a group considered at risk from anaemia, even if you present with fatigue. If that’s a big enough problem to skew research results I don’t know, maybe not, though it’s certainly a problem for the affected patients who’re missing out on effective treatment but that’s another story

More interesting, maybe, would be to consider the impact of the wrong amount of iron in the wrong place at the wrong time. This could conceivably cause some other cells to misbehave in some way

In this context it’s intriguing that, anecdotally, on the one hand we have pwME reporting low iron and unexpected difficulties with raising it and on the other hand pwME with iron overload and unexpected difficulties with lowering it. Do these seemingly opposite groups actually have something in common, maybe with respect to the way their bodies lock up iron? And can this tell us something about which cells might be misbehaving in what way as a result of something skewed in their iron supply?
 
Idly googling around for links between HFE and immunity and this review came up. Can’t say I understand much of it so obviously unable to judge the quality but it does seem clear that HFE’s role is very much not limited to iron homeostasis

“The hemochromatosis protein HFE 20 years later: An emerging role in antigen presentation and in the immune system” (2017)
The findings of all these studies present a strong and undeniable link between the immunity involving CD8+ T lymphocytes and HH with associated iron overload. A potential immunological function for HFE has been further implicated with the discovery of HFE and its striking homology with MHC I (Fig. 4A and B). Studies have demonstrated that mutated HFE has a direct impact on MHC I molecules and is associated with abnormal MHC I assembly and expression (Fig. 4C). Peripheral blood mononuclear cells (PBMCs) from HH patients carrying the HFEC282Y mutation were reported to have lower levels of MHC I expression due to an increased rate of MHC I endocytosis. This rapid turnover is caused by accelerated antigenic loading and premature MHC/peptide dissociation that coincides with greater expression of β2-m-unbound MHC I heavy chains at the cell surface 63. Further study revealed that misfolded HFEC282Y protein triggers the unfolded protein response (UPR), a mechanism that impacts intracellular trafficking, and gives rise to MHC I anomalies in HFEC282Y cells 99, including reduced cell surface expression. Importantly, despite its inability to present peptides, HFE can be recognized by a TCRαβ of mouse CD8+ T cells, particularly those expressing the variable AV6.1 and AV6.6 gene segments 65, further reinforcing a functional link between HFE and antigen presentation by MHC I. These reports have prompted investigations into the role of HFE on CD8+ T lymphocyte activation. One study evaluated how the presence of wild-type and mutated HFE molecules affected the ability of MHC I molecules, specifically HLA-A2, to present selected antigens and subsequently activate CD8+ T lymphocytes 62. Wild-type HFE, but not HFEC282Y, inhibited the secretion of T cell cytokines and the expression of lymphocyte activation markers, demonstrating the functional impact of HFE on CD8+ T lymphocytes. The inhibition of CD8+ T lymphocyte activation involved the α1–2 domains of wild-type HFE and was independent of MHC I expression level, β2-m competition, HFE-TfR1 interaction, or epitope origin and affinity 62. Considering its ubiquitous expression, these data suggest a new role for wild-type HFE in altering CD8+ T lymphocyte reactivity, which could modulate antigen immunogenicity.
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A quick search for more recent papers on HFE + immunity didn’t come up with much, but this super-technical paper may be of interest as a starting point if anyone wants to look further (I don’t have the capacity myself)

“Iron overload in HFE-related hemochromatosis severely impairs Vδ2+ γδ T-cell homeostasis” (2025)
Abstract

HFE-related hemochromatosis induces systemic iron overload. Although extensive studies indicate a pivotal role for iron homeostasis in αβ T-cell immunity, its effect on γδ T cells is unknown. Here, we found a reversal of the Vδ2+/Vδ2– ratio in the γδ T-cell compartment as a feature of hemochromatosis, which is associated with a Vδ2+ population that cannot be enriched by zoledronic acid (ZOL) stimulation, despite evidence of T-cell receptor (TCR)–ligand formation and strong proliferative behavior. In vivo, reactive oxygen species (ROS) production and exhaustion marker expression are significantly increased on Vδ2+ T cells in hemochromatosis compared with healthy individuals. Ex vivo, hemochromatosis donor–derived Vδ2+ cells are hyporesponsive to TCR stimulation in terms of ROS production but significantly increase their paramount expression of exhaustion markers. Fas-Fas ligand coexpression indicates their high susceptibility to activation-induced cell death. Consistent therewith, FeSO4 alone induces Vδ2+ subset-specific proliferation in healthy peripheral blood mononuclear cells comparable to stimulation by ZOL, and blocking experiments identify FeSO4-induced proliferation as BTN3A1/TCR mediated. Pyrophosphate is key for Vδ2+-TCR ligand formation. Iron, by suppressing pyrophosphatase alkaline phosphatase, promotes their stability. Therefore, our data suggest that the transcriptional repression of pyrophosphatases, as under the conditions of iron overload in hemochromatosis in vivo, leads to the constitutive availability of stress-signaling Vδ2+-TCR ligand and permanent TCR triggering in Vδ2+ T cells even under homeostatic conditions, which ultimately results in their subset-specific, activation-induced cell death. A similar phenotype was observed in patients with iron overload due to inborn hemoglobinopathies, suggesting an inverted Vδ2+/Vδ2– ratio in the γδ T-cell compartment as a hallmark of iron overload.
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