Genetics: Chromosome 6 BTN2A2 and BTN3A3 (BTN2A1)

[Turtle]

Thanks. The more tempered statement is only relevant to the DecodeME GWAS result ("chr6p associated locus" containing several genes, including BTN2A1). The AstraZeneca result is specific to the gene: BTN2A1 has the significantly highest odds of disruptive rare DNA variants among pwME relative to people who do not have ME/CFS.
Yes, these genetic associations could be conferring risk mostly through increased susceptibility to infection (acute phase) rather than mechanisms acting subsequently.
What I find interesting about BTN2A1 is that it acts in innate immunity. Together with BTN3A1 it is a first-line sensor of bacterial presence, and it mediates the interaction with Vgamma9-Vdelta2 T-cells, which are "innate-like" lymphocytes.

Thanks for all your arduous work and taking the time to be part of s4me and explain all that complicated stuff.

Could that mean having EBV and pneumonia as the starting point of ME/CFS is a double whammy?
Obvious that I'm the opposite of a scientist.

 

[Verity]

I note that BTN2A1 variants confer risk for systemic lupus. That might be an important clue.

That's near the BTN2A1 locus for lupus and ME/CFS (not all genes shown). The ME/CFS locus is a little red hill on the left near the value 26.

It seems that for lupus, the main thing here is a gene farther to the right. Maybe an HLA gene. Though it's possible the BTN genes are also contributing to the significance towards the left

I don’t know enough to understand this image, but in case lupus is still potentially relevant at all, I just want to mention that a lot of people with SLE on the lupus subreddit report something that sounds very much like PEM, including symptoms you wouldn’t expect with regular exercise intolerance (e.g. iirc a significant delay and a sore throat). It seems like too many to be just chance overlap with ME.

I’ve done a little digging around on this because I have an “is it ME or is it something like lupus” situation going on myself.

If someone could explain if that image fully rules out a lupus connection with respect to the gene being discussed, I’d appreciate it!

 

[forestglip]

I note that BTN2A1 variants confer risk for systemic lupus. That might be an important clue.

Which study is this based on? I couldn't find it from a quick search.

 

[Jonathan Edwards]

Which study is this based on? I couldn't find it from a quick search.

Nor could I. AI is very unhelpful.
My impression is that the lupus linkage is so wide and complex that it is unlikely that the relatively local signal for ME/CFS is using the same risk mechanism.

 

[Nightsong]

I noticed that GeneCards had associated BTN2A1 with SLE (link). But if you follow the reference (ref 63), it comes from this page:

JensenLab - Literature associating BTN2A1 and systemic lupus erythematosus

The JensenLab tool is a database of gene/disease associations apparently based on automated text mining of papers. However, I'm not sure this is reliable - based on a few searches I don't see any SLE papers that report a specific association with BTN2A1, and the first few results from the database entry don't seem to make that specific link either, although many seem to mention BTN2A1 in other contexts.

 

[forestglip]

If someone could explain if that image fully rules out a lupus connection with respect to the gene being discussed, I’d appreciate it!

It certainly doesn't rule it out. It just doesn't provide good evidence for a connection.

 

[Jonathan Edwards]

Is there any possibility that BTN2A1 is binding to phospholipid in neurons or glia instead of bacterial phosphoantigens (which seem to be smaller sterols)?

As far as I can see BTN2A1 does not actually present the phosphoantigen to the T cell receptor but binds to the TCR if its cytoplasmic tail is bound by phosphoantigen.

 

[ScoutB]

If someone could explain if that image fully rules out a lupus connection with respect to the gene being discussed, I’d appreciate it!

No idea if it connects to this particular DecodeME locus, but that recent study comparing summary stats of DecodeMe to other GWAS said this:

Across adaptive and autoimmune traits, systemic lupus erythematosus (SLE) demonstrated the strongest association with ME/CFS (rg = 0.200, p = 1.15×10⁻¹⁰), with multiple sclerosis (MS) showing a smaller but consistent pattern.

Note that they only compared with 22 other traits (of which the adaptive and autoimmune ones were only a subset), so not sure how much weight to give this.

 

[Utsikt]

The findings of the present study extend knowledge of the role of BTN3A2 to a broader range of disorders. On the contrary, we found that BTN2A1 was associated with decreased risk of AD, anxiety, and SCZ, which is consistent with a report that BTN2A1 is involved in the immunomodulation of the activity of γδ T-cells and has significant anti-neuroinflammatory and neuroprotective effects51. Although BTN3A2 and BTN2A1 are known to interact52, given that BTN3A2 and BTN2A1 were separately identified as risk and protective factors for brain disorders in the present study, further studies are needed to elucidate the underlying mechanisms of how BTN3A2 and BTN2A1 proteins are oppositely involved in brain disorders.

BTN2A1 is protective for Alzheimer’s, anxiety and schizophrenia, according to this paper:

Atlas of proteomic signatures of brain structure and its links to brain disorders - Nature Communications

The connection between plasma proteomic and brain structure remains unclear. Here, the authors establish a comprehensive atlas of the patterns of associations between microscale proteome and brain structure, and demonstrate their potential value for studying brain disorders.

www.nature.com

51 is this:

Butyrophilins: γδ T Cell Receptor Ligands, Immunomodulators and More - PMC

Butyrophilins (BTN) are relatives of the B7 family (e.g., CD80, PD-L1). They fulfill a wide range of functions including immunomodulation and bind to various receptors such as the γδ T cell receptor (γδTCR) and small molecules. One intensively ...

pmc.ncbi.nlm.nih.gov

There also appears to be some ties to Coeliac disease:

BTN2A1 and BTN3A1 as Novel Coeliac Disease Risk Loci: An In Silico Analysis

Coeliac disease (CeD) is a gastrointestinal enteropathy triggered by the consumption of gluten in predisposed individuals. A recent study showed that individuals were at more than 10% risk of having CeD if a first-degree relative also had the disease. However, only around 50% of CeD genetic...

www.repository.cam.ac.uk

There might be some tissue data here, but I don’t have access:

https://academic.oup.com/jimmunol/article-abstract/179/6/3804/8022208