The alpha-2A-adrenergic receptor (ADRA2A) modulates susceptibility to Raynaud's syndrome

Raynauds syndrome is a common dysautonomia where exposure to cold increases the vascular tone of distal arteries causing vasoconstriction and hypoxia, particularly in the extremities. Current treatment options are limited and unspecific. Biological mechanisms leading to the phenotype remain uncharacterized. Using genetic and electronic health record data from the UK Biobank, the Mass-General Brigham Biobank, the Estonian Biobank, and the FinnGen study, we identified 11,358 individuals with a diagnosis of Raynauds syndrome and 1,106,871 population controls. We found eight loci including endothelial nitric oxide synthase (NOS3), HLA, and a notable association at the 2A-adrenergic receptor (ADRA2A) locus (rs7090046, P = 3.93x10-47), implicating adrenergic signaling as a major risk factor with Raynauds syndrome. We further investigate the role of the variants and ADRA2A expression in functional and physiological models. In silico follow-up analysis revealed an expression quantitative trait locus (eQTL) that co-localized and increased ADRA2A gene expression in a tissue-specific manner in the distal arteries. Staining with RNA scope further clarified the specificity of ADRA2A expression in small vessels. We show by CRISPR gene editing that the SNP region modifies ADRA2A gene expression in pulmonary artery smooth muscle cells. Finally, we performed a functional contraction assay on smooth muscle cells in cold conditions and showed lower contraction in ADRA2A-deficient and higher contraction in ADRA2A-overexpressing smooth muscle cells. Our results indicate that Raynauds syndrome is related to vascular function mediated by adrenergic signaling through ADRA2A. Our study highlights the power of genome-wide association testing as a discovery tool for poorly understood clinical endpoints and further clarifies the role of adrenergic signaling in Raynauds syndrome by fine-mapping, using in vitro genomic manipulations and functional validation in distal smooth muscle cell populations located in arterioles