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Genetic and functional analysis of Raynaud’s syndrome implicates loci in vasculature and immunity

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Aug 21, 2024 version files 266.66 MB

Abstract

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 discovering eight loci (ADRA2A, IRX1, NOS3, ACVR2A, TMEM51, PCDH10-DT, HLA, RAB6C) where ADRA2A, ACVR2A, NOS3, TMEM51 and IRX1 colocalized with eQTLs, particularly in distal arteries. CRISPR gene editing further showed that ADRA2A and NOS3 loci modified gene expression and in situ RNA scope clarified the specificity of ADRA2A in small vessels, and IRX1 around small capillaries in the skin. Functional contraction assay in 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.