The α_2A-adrenergic receptor (ADRA2A) modulates susceptibility to Raynaud’s syndrome

Abstract

Raynaud’s 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 Raynaud’s syndrome and 1,106,871 population controls. We found eight loci including endothelial nitric oxide synthase (NOS3), HLA, and a notable association at the α2A-adrenergic receptor (ADRA2A)locus (rs7090046, P = 3.93×10-47), implicating adrenergic signaling as a major risk factor with Raynaud’s syndrome. We further investigate the role of the variants andADRA2Aexpression in functional and physiological models.In silicofollow-up analysis revealed an expression quantitative trait locus (eQTL) that co-localized and increasedADRA2Agene expression in a tissue-specific manner in the distal arteries. Staining with RNA scope further clarified the specificity ofADRA2Aexpression in small vessels. We show by CRISPR gene editing that the SNP region modifiesADRA2Agene 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 inADRA2A-deficient and higher contraction inADRA2A-overexpressing smooth muscle cells. Our results indicate that Raynaud’s syndrome is related to vascular function mediated by adrenergic signaling throughADRA2A. 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 Raynaud’s syndrome by fine-mapping, usingin vitrogenomic manipulations and functional validation in distal smooth muscle cell populations located in arterioles

Inhibiting Intracellular α2C-Adrenoceptor Surface Translocation Using Decoy Peptides: Identification of an Essential Role of the C-Terminus in Receptor Trafficking

“…Previous studies have reported α 2A -adrenoceptor single nucleotide polymorphism which contributes to increased receptor expression affecting insulin secretion and increasing type 2 diabetes risk [46]. Similarly, two recent genome-wide association studies (GWAS) have identified α 2 -adrenoceptor, particularly the α 2A -adrenoceptor subtype variant rs7090046 (which affects expression in microvascular smooth muscle cells in blood vessels), as a major risk factor in primary Raynaud's in a subset of patients having the clinical manifestation of Raynaud's phenomenon, suggesting that the α 2A -adrenoceptor modulates the susceptibility to Raynaud's [47,48]. The combined effect of α 2A -adrenoceptor variant rs7090046 and α 2C -adrenoceptors may therefore contribute to disease severity and clinical symptoms.…”

“…Additionally, Tervi et al also identified a variant rs3918226 of nitric oxide 3 (NOS3), which potentially affects gene transcription and is associated with essential hypertension [47,49]. NOS3 is predominantly expressed in endothelial cells which line blood vessels and regulates the production of vasodilator nitric oxide (NO).…”