Preprint The alpha-2A-adrenergic receptor (ADRA2A) modulates susceptibility to Raynaud's syndrome 2023 Tervi et al

It's quite a collaboration - data from Finland, UK Biobank, Estonian Biobank, Mass General Brigham Biobank. Data from over 1 million people including 11,605 people with RS. Terrific to see that happening.

This is progress.

I think Raynaud's is quite common in people with ME/CFS? I wonder if having that tendency makes it easier to get ME/CFS? I think Systrom is part of Brigham Hospital, so he might be particularly aware of this research, which seems relevant to his work on oxygen extraction in capillaries.

Majority of RS patients are females (73%).

One of the genetic variants found to be associated with RS is associated with peripheral vascular disease (part of the HLA region), and another impacts on endothelial nitric oxide (NOS3). Also ACVR2A (activin receptor type 2A); one near IRX1; one near RAB6C; TMEM51 - a transmembrane protein; one near PCDH10.

The researchers particularly liked the ADRA2A variant, as it stood out as a significant association in each of the tested cohorts and so the rest of the paper is about the investigations they did of the significance of this variant.

 

Of course, I have no idea, but the picture does look exciting.

 

The researchers found a number of risk variants for ADRA2A. They suggest that the lead variant affects tibial arteries most, also prostate, brain, small intestine (See. Fig 2 b). They also say that it is expressed primarily in microvasculature.

The team applied their tools to work out specifically which cells in the vascular wall of a blood vessel express ADRA2A. They report that the ADRA2A cells are a relatively small proportion of all the cells.

It wasn't really clear to me how they knew that cells that express mature SMC genes and NOTCH3 must be microvascular cells. From Fig 3, they seem to have concluded that the cells involved are adventitial pericytes and some SMCs. I'm assuming that's due to pre-existing knowledge in the cell atlas.

And they say that they only found one cell line expressing ADRA2A "that was likely obtained from the pulmonary microvasculature". That sounded a bit vague. They went on to use this cell line in subsequent experiments.

Fig 3A-D



Fig 3G is levels of ADRA2A and NOTCH3 - smooth muscle cells of healthy controls on the left i.e. levels are set as the baseline, so 0. The fold changes (in pink) is very dramatic. (I'm not entirely sure what cells they were working with here.)

 

They next looked at the impact on the cells that were made to over-express ADRA2A - they concluded they were contracting more.

There's a picture of the theory, but, as far as I can work out, it's pretty simple. People with Raynaud's have more alpha 2a adrenergic receptors on the particular vascular cells. So, when there is cold or another stressor, the adrenergic receptor ligands (epinephrine, norepiphrine) have more sites to attach, and the contraction response is bigger.

They note that previous work in Raynaud's had focused on ADRA2C, but their study found that over expression of that gene didn't produce the cold-related contraction.

@EndME, I think that reference 42 is the paper you mentioned, still in preprint according to the reference list.

I haven't read the methods, which comes after the Discussion, but I think I'll just leave it at that for the moment, and feel happy that maybe this paper is progress.

 

I finally joined twitter today, just to like that tweet. I'm so impressed that this team wanted to understand Long Covid, ME/CFS and POTS and so undertook this large collaboration to look into Raynaud's. And the work was possible because of all the people who have worked on building biodata infrastructure.

This is the stuff that gives me hope. People who drill down into individual symptoms rather than not getting past 'fatigue'. (And, still I haven't read the methods section, and perhaps this study won't end up being part of the answer. But - there are people caring enough to try to answer useful questions and the tools are increasingly there to allow them to do that.)

 

Just as many of us are leaving Twitter!