ADRA2A and IRX1 are putative risk genes for Raynaud’s phenomenon (2023) Hartmann et al.

Milo · Oct 26, 2023

Abstract

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.

Published in Nature, here

Hutan · Oct 26, 2023

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

Interesting stuff. There's movement away from regarding Raynaud's as just a response to cold and emotional stress. Low blood sugar could be causing attacks. That makes sense, as in my family RP happens when the temperature is fine and there is no stress. I'll have to watch out to see if low blood sugar could explain the incidences.

Our results are in line with a vasoconstrictive role of α2A-adrenoreceptors under thermoneutral conditions17 and subsequent RP risk and further support findings of a quantitively stronger role of α2-adrenoreceptors compared to α1-adrenoreceptors during cold stress in RP patients38,39.
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Conversely, hypoglycaemia exerts profound changes on the vasculature, including vasoconstriction via increased adrenal catecholamine release to maintain blood flow to the brain51, which may, in turn, exaggerate hypersensitivity to catecholamines of arteriovenous anastomoses in fingers and toes. However, a drop in body temperature following hypoglycaemia is caused by cutaneous vasodilation, which might itself be a trigger for vasospastic effects in RP patients. Even a role of β-adrenergic receptors might be conceivable since beta-blockers can cause both, hypoglycaemia52 and RP4. A pragmatic consequence for people at RP risk, or even RP patients, might be to avoid episodes of low plasma glucose levels.
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We then extended the targeted analysis by computing genetic correlations with 185 medical concepts—‘phecodes’, to gain a more comprehensive view of possible diseases that share a genetic architecture with RP (see the “Methods” section; Supplementary Data 4). We observed 8 phecodes with significant, although moderate, genetic correlations with RP (Supplementary Data 4), of which only the significant genetic correlation with osteoporosis persisted when we restricted the analysis to patients with primary RP (rG = 0.35, p < 8.7 × 10−5). However, none of the phenotypes showed evidence of a direct causal link towards or from RP in latent causal variant analysis (see the “Methods” section; Supplementary Table 4).
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I checked for ME/CFS or CFS as 'phecodes' and didn't see them. 'fatigue and malaise' had a good rG (compare with the 0.35 of osteoporosis) but the p values aren't great. I'm not sure what that means, but I think it could mean the data is really noisy for 'malaise and fatigue', which certainly could be all sorts of things, but it doesn't rule out an association between ME/CFS and RP.

Malaise and fatigue - Primary RP - rG =0.31 p= 5.73E-01
Malaise and fatigue - All RP cases - rG = 0.29 p= 2.90E-01

You probably want to know what those top phecodes with significant moderate genetic correlations with RP were - here's the top ten P values from the Supplementary Data 4 sheet:
Osteoporosis NOS - All RP cases - 0.40 (P 1.36E-04)
Diaphragmatic hernia - All RP cases - 0.25 (P 1.49E-03)
Osteoporosis NOS - Primary RP - 0.35 (P 7.93E-03)
Nonspecific chest pain - All RP cases - 0.24 (P 1.21E-02)
Anal and rectal conditions - All RP cases - 0.47 (P 1.21E-02)
Urinary incontinence - All RP cases - 0.35 (P 1.21E-02)
Other headache syndromes - All RP cases - 0.32 (P 2.08E-02)
Other disorders of bladder - All RP cases -0.38 (P 2.22E-02)
Spondylosis and allied disorders - All RP cases - 0.31 (P 2.22E-02)
Dizziness and giddiness (Light-headedness and vertigo) - All RP cases 0.40 (P 6.32E-02)

Edit to add - Secondary RP is when there is another condition that might be causing it e.g. Lupus; Primary RP is when there isn't.

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ADRA2A and IRX1 are putative risk genes for Raynaud’s phenomenon (2023) Hartmann et al.

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ADRA2A and IRX1 are putative risk genes for Raynaud’s phenomenon (2023) Hartmann et al.

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