Genetics: OLFM4

[Hutan]

DecodeMe Candidate Gene

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 13
Chr13 contained no Tier 1 genes and one Tier 2 gene.

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OLFM4 (Tier 2)

• Protein: Olfactomedin-4. UniProt. GeneCards.

• Molecular function: OLFM4 facilitates cell adhesion, most probably through interaction with cell surface lectins and cadherin. It reduces neutrophil-dependent antibacterial and inflammatory responses by binding to neutrophil cationic proteins and neutralising their ability to kill bacteria and form immunogenic complexes with DNA (53).

• Cellular function: OLFM4 is a neutrophil-specific granule protein that is a biomarker for the severity of infectious diseases (54). It is expressed in gut epithelial cells and is stored in secondary granules of neutrophils.

• Link to disease: When cells are stimulated, OLFM4 is associated with neutrophil extracellular traps (NETs). NETs can be induced by reactive oxygen species produced by mitochondria (55). A cell death process called NETosis occurs after NET release, a form of antimicrobial innate immunity.

• Potential relevance to ME/CFS: OLFM4-positive neutrophils regulate microbial-induced damage of intestinal epithelial cells (56).

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References

53 Vandenberghe-Dürr S, Gilliet M, Di Domizio J. OLFM4 regulates the antimicrobial and DNA binding activity of neutrophil cationic proteins. Cell Rep. 2024 Oct 22;43(10):114863.

54 Liu W, Rodgers GP. Olfactomedin 4 Is a Biomarker for the Severity of Infectious Diseases. Open Forum Infect Dis. 2022 Apr;9(4)fac061.

55 Papayannopoulos V. Neutrophil extracellular traps in immunity and disease. Nat Rev Immunol. 2018 Feb;18(2):134–47.

56 Huber A, Jose S, Kassam A, Weghorn KN, Powers-Fletcher M, Sharma D, et al. Olfactomedin-4 + neutrophils exacerbate intestinal epithelial damage and worsen host survival after Clostridioides difficile infection. bioRxiv. 2023 Aug 22

 

[Jonathan Edwards]

Another hint of the anti-inflammatory?

It is almost as if the immune system is going around like the poison experts at the scene of the Novichok incident, all dressed up with anti-inflammatory gear, but it is a false alarm.

There may be some microglial activation in ME/CFS but there are no Neutrophil Extracellular Traps. NETS are visible on histology as bluish gunk, not easily missed. So these gene products may be found in the context of NETs but in ME/CFS they must just be expecting them.

 

[forestglip]

It is almost as if the immune system is going around like the poison experts at the scene of the Novichok incident, all dressed up with anti-inflammatory gear, but it is a false alarm.

Why do you refer to something like this as anti-inflammatory? You'd refer to something like TNF as inflammatory, right? In what way is this the opposite? It sounds like it's associated with neutrophils doing inflammation stuff. (Not that we know if the mutation increases or decreases whatever it does.)

 

[Alinda]

I'm in general just confused what anti-inflammatory is supposed to mean, but I suppose I"m understanding quite little of this..

 

[Jonathan Edwards]

In what way is this the opposite? It sounds like it's associated with neutrophils doing inflammation stuff.

The point is that in the case of ME/CFS the relevant inflammation isn't there. Complement is associated with inflammation but within the circulation it is anti-inflammatory because it mediates siloent clearance of immune complexes. You will often find policemen associated with criminals via handcuffs but that does not mean that policemen are criminal.

My experience is that the key to these diseases is finding the way in which the normal rules are broken, not in finding what is following the normal rules. We have done those diseases.

 

[Jonathan Edwards]

I'm in general just confused what anti-inflammatory is supposed to mean, but I suppose I"m understanding quite little of this..

It isn't a good word. I apologise. In a way I am making the mistake I complain about. Inflammation is a term for a whole lot of things that usually go together but in these diseases may not. Anti-inflammation then becomes a bit of a nonsense, but I have tried my best to explain what I am trying to get at.

 

[Kitty]

The point is that in the case of ME/CFS the relevant inflammation isn't there.

Tilting at windmills, mebbe.

Which won't grind our grain very well with damaged sails.

 

[Utsikt]

Complement is associated with inflammation but within the circulation it is anti-inflammatory because it mediates siloent clearance of immune complexes.

Does clearing of immune complexes mean to clear out antigens being bound to antibodies, but when it’s anti-inflammatory it does it without causing damage to the surrounding tissue?

More quietly escorting them out, and less full swat teams?

And it might be that the immune complexes its escorting is just junk that a less discriminating constable picked up, but it still requires the same resources and initiates the same processes as if it was dealing with something serious?

 

[Jonathan Edwards]

Does clearing of immune complexes mean to clear out antigens being bound to antibodies, but when it’s anti-inflammatory it does it without causing damage to the surrounding tissue?

Yes, it has been known about for many decades and is called red cell pitting.

Complement C1q engages the Fc portion of antibody in complexes in circulation. C1q activates the complement cascade down to C3b. Red cells are coated in complement receptor 1 (CR1, CD35) which binds C3b silently. The red cells are regularly passed through the spleen by recirculation and macrophages in the spleen 'carwash' the red cells free of complexes (for some reason called pitting) and let them back ito the circulation to do it again. The whole thing is completely silent and goes on in all of us every minute of the day.

In tissues, complement causes inflammation through the chemotactic action of the other half of C3, C3a (and some other bits). But if C3a is made in the circulation it cannot call white cells out into the tissues because it isn't in the tissues, it is with the white cells in the circulation.