[nextos]

rs35044562. However, the effect is probably very small compared to environmental factors (e.g. disrupted innate immunity due to insulin resistance or obesity).

The highest genetic contribution to any common disease seems HLA-B27 ~ ankylosing spondylitis, closely followed by HLA II ~ type 1 diabetes. But in these cases, still, it just explains around 15% of the variance. After these big contributors, there's a long list of genes that contribute with exponentially diminishing effect sizes. And the overall contribution of genetics never exceeds 50%. It's good to understand some disease factors, but interventions are much simpler from the environmental side of things.

I'm surprised that COVID is not linked to HLA in any meaningful way. Probably the study from Pääbo is not accounting for HLA because of lack of imputed haplotypes. It's a bit of a statistics smell that there's no association whatsoever. Nothing shows up in his chr6 region in the Manhattan plot. All infectious agents have some correlation. That's the whole point of HLA, implementing different strategies against them.

For example, HLA-B57 and B27 tend to be super-responders against HIV. This haplotype seems to be trading more autoimmunity risk in exchange for better protection against rapidly mutating viruses. It expanded quite quickly around Northern Europe around 10000 years ago, probably due to another pandemic.

[takeda]

Apologies for my ignorance, but I still don't understand, does HLA-B27 makes covid symptoms worse or better?

[nextos]

We don't know, probably it doesn't. I was simply complaining about the lack of HLA correlations in the paper, which is suspicious. Probably they didn't type or impute HLA haplotypes.

My HLA-B27 example was actually a positive one. It gives you higher chances of a good outcome if infected by HIV.

Another paper, with a small sample size, claims HLA-B44 and C01 are susceptible [1].

I work with the Oxford vaccine group, and I am quite interested in this effect, including in vaccinated patients. It's pretty well known bad vaccine efficiency and side effects will correlate very strongly with HLA, and with thymic involution.

Sadly everything is quite chaotic at the minute and it's difficult to get samples and funding for these ideas. If we were more advanced, we would get be classifying vulnerable patients and asking them to shield according to HLA and immunoageing/dysfunction markers.

[1] https://www.mdpi.com/1422-0067/21/15/5205

[takeda]

Thank you.

So as I understand you are involved by the vaccine that AstraZeneca is also behind. So I kind of understand (well, as much as layman can understand, lol) the vaccine that Pfizer and Moderna works. I guess it is a bit better explained on Wikipedia. So their vaccines inject mRNA to our cells which start producing antibodies. While this is brand new kind of vaccine, it's hard to know long term effects of it, but there's a chance that it could cause an autoimmune disease.

When reading about vaccine created by Oxford, the biggest concern seems to be that people could have or develop antibodies for the adenovirus after first dose. I'm guessing someone with HLA-B27 has even a higher chance of doing that. I understand that, but I'm still not understanding how it works. Is it same as the mRNA vaccine, with the difference that the adenovirus is just used to deliver it?

[nextos]

I have collaborators in the vaccine group, but I'm not directly involved in the trial. In fact, I think the Oxford vaccine has 2 potential design issues, 1 of which is shared with all other vaccines.

The first issue is what you pointed out. Adenovirus delivery is potentially more risky. I'm incidentally also HLA-B27, and I will personally stay away from it.

The second issue, shared with all other vaccines, is that IMHO they should not have vaccinated us for the whole spike protein, but just for some fragment. The spike protein contains some mimotopes to confuse the immune system, and I'm worried that this might also be a source of autoimmunity in very rare cases. Naturally, because vaccines had to be rushed, this was not easy to account for.

Nonetheless, they all seem safe. Theoretically, mRNA ones might be safer, unless there's gene transfer/integration of mRNA into cells. But this is a very exotic issue unlikely to cause problems.