NEW YORK – A team from Finland, Estonia, and the US has linked both vascular and immune-related biological mechanisms to Raynaud's syndrome, a condition characterized by lower-than-usual blood flow to the fingers during bouts of stress or cold exposure that affects an estimated 3 percent to 5 percent of the population worldwide.
"This study sheds light on the genetic basis of [Raynaud's disease] and may be useful for further classification between primary and secondary forms of the disease," senior and co-corresponding author Hanna Ollila, FIMM-EMBL group leader with the Finnish Institute for Molecular Medicine, the University of Helsinki, Massachusetts General Hospital, and Harvard Medical School, said in an email.
Along with known Raynaud's syndrome-related mechanisms such as adrenergic signaling, she explained, the new work revealed additional mechanisms related to the immune system and nitric oxide signaling (NOS) processes.
As they reported in Cell Genomics on Tuesday, Ollila and her colleagues brought together genotyping profiles and electronic health record data for 11,358 individuals with Raynaud's syndrome and more than 1.1 million unaffected controls, enrolled through the FinnGen cohort, UK Biobank, Estonian Biobank, and Mass General Brigham Biobank for a genome-wide association study and GWAS meta-analysis.
Ollila called the study "a prime example of an approach where genetic GWAS-driven discovery is used to study disease pathomechanisms and identify several causal genes related to a disease."
The team's search led to eight Raynaud's syndrome-associated genetic loci, including sites in and around genes implicated in processes such as temperature-dependent smooth muscle contraction and signaling pathways with immune, endothelial, and microvasculature effects.
The authors noted that these genetic associations could help to "elucidate the more specific disease mechanisms or even provide insight into the heterogeneity of the symptomatology in [Raynaud's syndrome]."
While prior research had highlighted the importance of the alpha-adrenergic subtype 2C-coding gene ADRA2C, for example, findings from the GWAS also linked the ADRA2A gene to Raynaud's syndrome — a relationship that the researchers explored further in their subsequent gene editing and RNAscope in situ hybridization experiments, smooth muscle cell contraction assays, and expression quantitative trait locus analyses.
"Previous studies on its pathomechanisms have primarily focused on the alpha-2C adrenergic receptor," Ollila explained. "However, our data suggest that subtype 2A may be more important for the disease mechanism."
Those results lined up with a 2013 study in Nature by researchers from the UK, Germany, and the US who used UK Biobank data to identify ADRA2A and IRX1 as potential risk genes for the condition, she added, underscoring the apparent importance of alpha-adrenergic subtype 2A in Raynaud's syndrome-related vascular contraction processes.
Together, the authors explained, the results suggest Raynaud's syndrome features "can be mediated through multiple, possibly independent, mechanisms involving adrenergic signaling, immune mechanisms, and NOS."