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

• Published in: Cell genomics 2024-09, Vol.4 (9), p.100630, Article 100630
• Main Authors: Tervi, Anniina, Ramste, Markus, Abner, Erik, Cheng, Paul, Lane, Jacqueline M., Maher, Matthew, Valliere, Jesse, Lammi, Vilma, Strausz, Satu, Riikonen, Juha, Nguyen, Trieu, Martyn, Gabriella E., Sheth, Maya U., Xia, Fan, Docampo, Mauro Lago, Gu, Wenduo, Esko, Tõnu, Saxena, Richa, Pirinen, Matti, Palotie, Aarno, Ripatti, Samuli, Sinnott-Armstrong, Nasa, Daly, Mark, Engreitz, Jesse M., Rabinovitch, Marlene, Heckman, Caroline A., Quertermous, Thomas, Jones, Samuel E., Ollila, Hanna M.
• Format: Article
• Language: English
• Subjects: Female; Genome-Wide Association Study; Humans; Male; Nitric Oxide Synthase Type III - genetics; Nitric Oxide Synthase Type III - metabolism; Quantitative Trait Loci; Raynaud Disease - genetics; Raynaud Disease - immunology
• ISSN: 2666-979X; 2666-979X
• DOI: 10.1016/j.xgen.2024.100630

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. [Display omitted] •GWAS across four cohorts reveals eight loci for Raynaud’s syndrome•ADRA2A shows temperature-dependent smooth muscle contraction•Endothelial nitric oxide modulates the susceptibility to Raynaud’s syndrome•ADRA2A, NOS3, and ACVR2A can be targeted by existing pharmaceuticals Raynaud’s syndrome (RS) manifests primarily as decreased blood flow in the fingers upon cold or stress exposure. Tervi, Ramste, et al. identified eight genes associated with RS. Follow-up studies validate causal genes important for temperature-dependent adrenergic signaling in microvasculature, endothelial signaling, and immunity, indicating a possible biological mechanism underlying RS.