Many people have Raynaud’s syndrome, which means that their fingers turn white because of decreased blood flow when they get cold. New research now elucidates the possible genetic background for this. A researcher says that the discovery could lead to treatment for people with Raynaud’s syndrome – especially if it is very painful.
Raynaud’s syndrome can also be associated with pain and discomfort when blood vessels spasm and close off the blood supply to the fingers and toes. Now researchers have identified a possible genetic cause.
The discovery could lead to developing new treatments – and especially for those who experience pain and discomfort.
“These results provide new knowledge about Raynaud’s syndrome and how we may be a step closer to treating it. This is of interest to people with Raynaud’s and in relation to several other diseases that are often comorbid with Raynaud’s,” explains a researcher behind the study, Anniina Tervi, Helsinki Institute of Life Science – HiLIFE, University of Helsinki, Finland.
The research has been published in Cell Genomics.
Raynaud’s syndrome associated with many diseases
Anniina Tervi and colleagues aim to understand the genetic background of myalgic encephalomyelitis/chronic fatigue syndrome and long COVID, which are often combined with Raynaud’s syndrome.
The researchers initially identified that chronic fatigue could be genetically linked to dysfunction in the autonomic nervous system. They investigated this more closely, and it turned out to be a genetic link with Raynaud’s syndrome.
The research found that the genetic link was associated with the norepinephrine system and the researchers wanted to better understand its role in Raynaud’s syndrome.
“This project involved close collaboration with researchers from the University of Helsinki, Stanford University and Harvard University. In particular, this was a close collaboration with Markus Ramste (affiliated with Stanford University and the University of Helsinki), who was responsible for conducting the functional studies in cell models. With this, we aimed to learn more about how genetic variation affects Raynaud’s syndrome and cell function,” says Anniina Tervi.
Searching for genetic clues
The researchers primarily found that ADRA2A gene variants and variants in seven other genes are involved when people develop Raynaud’s syndrome.
The ADRA2A gene codes for a receptor protein, a2A-adrenergic receptor, which is present in several cells and tissues, especially smooth muscle cells.
Adrenergic receptors communicate with norepinephrine, which constricts the blood vessels and cause the symptoms of Raynaud’s syndrome.
Noradrenaline is thus part of the body’s cold response by constricting the blood vessels, but people with Raynaud’s syndrome may lack fine-tuning.
“Therefore, it would make sense if a ADRA2A variant affects the corresponding receptors on the surface of the smooth muscle cells in the blood vessel walls and causes the vessels to contract more than desirable when exposed to cold,” explains Anniina Tervi.
Thorough investigation
The researchers performed many experiments to verify how the ADRA2A variants are associated with Raynaud’s syndrome.
They found that ADRA2A is expressed in smooth muscle cells from arteries in the microvascular system, which sends blood to the extremities.
They thereby confirmed that ADRA2A is expressed in a tissue in which the gene may be instrumental in turning the fingers white.
The researchers also manipulated the genetic variants discovered to be related to Raynaud’s syndrome to determine how they affect the expression of ADRA2A and found that they regulate the expression of ADRA2A.
Finally, the researchers exposed cells to both cold and heat and found that the extent of contraction depended on the expression of ADRA2A.
All this indicated that ADRA2A variants may be one reason why some people have Raynaud’s syndrome.
According to Anniina Tervi, ADRA2A variants could increase the communication between norepinephrine and the adrenergic receptors on the surface of the cells in capillaries, causing the cells to contract unnecessarily when exposed to cold.
Could lead to new treatments
Anniina Tervi says that the discovery could be useful in treating Raynaud’s syndrome and can provide insight into the mechanisms underlying other similar diseases.
Treatment targeting the adrenergic system may also be relevant for symptoms more severe than white fingers.
For some people with Raynaud’s syndrome, exposure to cold can be very painful if the symptoms last long or are frequent, and Anniina Tervi envisions that creams or gels could be developed that could relax the cells locally in the capillaries.
“These medicines could reduce the effect of norepinephrine through the adrenergic receptors in response to cold. However, further research is required to examine the role of the adrenergic system and other possible mechanisms associated with Raynaud’s syndrome,” concludes Anniina Tervi.
