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ADRA2A and IRX1 are putative risk genes for Raynaud’s phenomenon


Senior Member


Raynaud’s phenomenon (RP) is a common vasospastic disorder that causes severe pain and ulcers, but despite its high reported heritability, no causal genes have been robustly identified. We conducted a genome-wide association study including 5,147 RP cases and 439,294 controls, based on diagnoses from electronic health records, and identified three unreported genomic regions associated with the risk of RP (p < 5 × 10−8). We prioritized ADRA2A (rs7090046, odds ratio (OR) per allele: 1.26; 95%-CI: 1.20-1.31; p < 9.6 × 10−27) and IRX1 (rs12653958, OR: 1.17; 95%-CI: 1.12–1.22, p < 4.8 × 10−13) as candidate causal genes through integration of gene expression in disease relevant tissues. We further identified a likely causal detrimental effect of low fasting glucose levels on RP risk (rG = −0.21; p-value = 2.3 × 10−3), and systematically highlighted drug repurposing opportunities, like the antidepressant mirtazapine. Our results provide the first robust evidence for a strong genetic contribution to RP and highlight a so far underrated role of α2A-adrenoreceptor signalling, encoded at ADRA2A, as a possible mechanism for hypersensitivity to catecholamine-induced vasospasms.
Continue: https://www.nature.com/articles/s41467-023-41876-5


Senior Member
many genetic marker studies are like this

authors claim "strong" genetic contribution - but article goes on to detail odds ratios of low 1's

i.e. the chances of persons with this gene allele having the condition are only 1.17-1.31x higher than if they do not

so while humans are complex things - and every individual is different to the next - this being the case we would expect some small genetic contribution to ANY pathological condition - its hardly a smoking gun

for example - any genetic factor that tends to increase an inflammatory response would tend to raise disease risk across a broad spectrum of chronic diseases

but the rarer the condition - i.e. 99,990 out of every 100,000 people do not have the condition - and yet a good number of them do have the allele - the more there needs to be another (or several other) main causal mechanisms involved

this type of context is very often missing from such genetic studies - its left to the reader to unpick - which i find almost intentionally misleading.

or perhaps its a case of - "if you only have a hammer - everything looks like a nail" where our education and scientific institutions reward ultra specialism - rather than cross subject boundary expertise
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