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

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.