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 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.
Authors
- Nasa Sinnott-Armstrong (ORCID: https://orcid.org/0000-0003-4490-0601)
- Juha Riikonen (ORCID: https://orcid.org/0009-0008-8101-0134)
- Trieu Nguyen (ORCID: https://orcid.org/0000-0001-5647-1301)
- Tōnu Esko (ORCID: https://orcid.org/0000-0003-1982-6569)
- Erik Abner (ORCID: https://orcid.org/0000-0002-6529-3161)
- Samuel E. Jones (ORCID: https://orcid.org/0000-0003-0153-922X)
- Maya U. Sheth (ORCID: https://orcid.org/0000-0003-1466-8899)
- Jacqueline M. Lane (ORCID: https://orcid.org/0000-0001-6101-2855)
- Richa Saxena (ORCID: https://orcid.org/0000-0003-2233-1065)
- Satu Strausz (ORCID: https://orcid.org/0000-0001-6778-4848)
- Marlene Rabinovitch (ORCID: https://orcid.org/0000-0001-7886-7104)
- Matthew Maher (ORCID: https://orcid.org/0000-0003-0034-1350)
- Hanna M. Ollila (ORCID: https://orcid.org/0000-0002-5302-6429)
- Mauro Lago‐Docampo (ORCID: https://orcid.org/0000-0002-8799-6079)
- Thomas Quertermous (ORCID: https://orcid.org/0000-0002-7645-9067)
- Caroline A. Heckman (ORCID: https://orcid.org/0000-0002-4324-8706)
- Wenduo Gu (ORCID: https://orcid.org/0000-0002-3859-3150)
- Anniina Tervi (ORCID: https://orcid.org/0000-0002-9857-2132)
- Fan Xia (ORCID: https://orcid.org/0009-0006-7113-7321)
- Gabriella E. Martyn (ORCID: https://orcid.org/0000-0001-5024-428X)
- Aarno V. Palotie (ORCID: https://orcid.org/0000-0002-2527-5874)
- Paul P. Cheng (ORCID: https://orcid.org/0000-0003-3429-2702)
- J Engreitz (ORCID: https://orcid.org/0000-0002-5754-1719)
- Vilma Lammi (ORCID: https://orcid.org/0000-0002-3256-5239)
- Mark J. Daly (ORCID: https://orcid.org/0000-0002-0949-8752)
- Samuli Ripatti
- Matti Pirinen
- Markus Ramste (ORCID: https://orcid.org/0000-0003-4048-4591)
- Jesse Tyler Valliere
Institutions
- Broad Institute (US)
- Massachusetts General Hospital (US)
- Fred Hutch Cancer Center (US)
- Stanford Health Care (US)
- Institute for Molecular Medicine Finland (FI)
- Stanford Medicine (US)
- University of Tartu (EE)
- Stanford University (US)
Publication Details
- Journal
- Cell Genomics
- Published
- 2024-08-13
- DOI
- https://doi.org/10.1016/j.xgen.2024.100630
- Citations
- 4
- Primary Topic
- Systemic Sclerosis and Related Diseases
- Type
- article
- Field-Weighted Citation Impact
- 1.70
Funders
- National Science Foundation
- Bristol-Myers Squibb
- Pfizer
- AstraZeneca
- Sanofi
- Maze Therapeutics
- European Commission
- Eesti Teadusagentuur
- Novo Nordisk
- Tartu Ülikool
- Novo Nordisk Fonden
- Business Finland
- National Institutes of Health
- Genentech
- Novartis Pharma
- European Regional Development Fund
- National Heart, Lung, and Blood Institute
- National Human Genome Research Institute
- Janssen Biotech