PubMed · 4485779
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J C Potier. 1972. [Raynaud's disease].. https://pubmed.ncbi.nlm.nih.gov/4485779/
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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.
Raynaud's phenomenon is characterised by episodic vasospasm of the fingers and toes typically precipitated by exposure to cold. Mild Raynaud's is common and is not usually a harbinger of clinically important disability; its onset, however, can be startling and uncomfortable for patients, and the well recognised association in some cases with systemic rheumatic conditions often precipitates aggressive assessments for underlying diseases. Advances in vascular physiology have shed light on the role of the endothelium as well as endothelium-independent mechanisms in the altered vasoregulation of Raynaud's. We review clinical aspects of the disorder and new insights with respect to pathophysiology, and we discuss potential new therapeutics based on the disease mechanism, such as prostacyclin analogues, serotonin antagonists, and calcitonin gene-related peptides.
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