Genetic and functional analysis of Raynaud’s syndrome implicates loci in vasculature and immunity 2024 Tervi et al

Highlights

• GWAS across four cohorts reveals eight loci for Raynaud’s syndrome
• ADRA2A shows temperature-dependent smooth muscle contraction
• Endothelial nitric oxide modulates the susceptibility to Raynaud’s syndrome
• ADRA2A, NOS3, and ACVR2A can be targeted by existing pharmaceuticals

Summary

Raynaud’s syndrome is a dysautonomia where exposure to cold causes vasoconstriction and hypoxia, particularly in the extremities. We performed meta-analysis in four cohorts and discovered eight loci (ADRA2A, IRX1, NOS3, ACVR2A, TMEM51, PCDH10-DT, HLA, and RAB6C) where ADRA2A, ACVR2A, NOS3, TMEM51, and IRX1 co-localized with expression quantitative trait loci (eQTLs), particularly in distal arteries.

CRISPR gene editing further showed that ADRA2A and NOS3 loci modified gene expression and in situ RNAscope clarified the specificity of ADRA2A in small vessels and IRX1 around small capillaries in the skin. A functional contraction assay in the cold showed lower contraction in ADRA2A-deficient and higher contraction in ADRA2A-overexpressing smooth muscle cells. Overall, our study highlights the power of genome-wide association testing with functional follow-up as a method to understand complex diseases.

The results indicate temperature-dependent adrenergic signaling through ADRA2A, effects at the microvasculature by IRX1, endothelial signaling by NOS3, and immune mechanisms by the HLA locus in Raynaud’s syndrome.

Open access, https://www.cell.com/cell-genomics/fulltext/S2666-979X(24)00234-9

 

Seems to be the published version of The alpha-2A-adrenergic receptor (ADRA2A) modulates susceptibility to Raynaud's syndrome?

They note that Raynauds is a common comorbidity in Long-Covid and ME/CFS (they cite https://www.tandfonline.com/doi/abs/10.1080/10852352.2014.973240). I've seen this commonly reported, amongst some patients and some doctors, but in my view it would be good if we'd have some better data on this, especially if all it would require would be adding an additional question to already existing questionnaires.

It's great that some of these authors are particularly interested in Long-Covid and ME/CFS and are collaborating on DecodeME.

 

It would probably need several questions, tbh. Reynaud's is so common that up to one in five women may have it or get it at some stage. Men get it too, but apparently less often.

Secondary Reynaud's is associated with so many things that even in one person it's not always obvious which might be the culprit. There's quite a list of drugs (my GP said it's possible it's associated with drugs that haven't even made the list yet), and also age-related stuff like mild arterial disease. I think mine's drug-related, but as stopping the med could result in a flare that'd be a lot more disabling than Reynaud's, it's not worth finding out. Same goes for my friend and her migraine meds.