Researchers have discovered a genetic cause of Raynaud's syndrome, a disorder that affects blood circulation in small blood vessels. Raynaud's syndrome is a disease that affects blood circulation in small blood vessels, and researchers have discovered that two genes - ADRA2A and IRX1 - predispose people to the disease, which could help develop effective treatments.
Researchers from the Precision Medicine University Research Institute (PHURI) at Queen Mary University of London and the Berlin Institute for Health Research (BIH) at Charité University in Berlin have identified the genetic cause of Raynaud's phenomenon (also known as Raynaud's syndrome and Raynaud's disease). Their research, published today (October 12) in Nature Communications, may lead to the first effective treatments for Raynaud's patients.
Understanding Raynaud's Phenomenon
Raynaud's phenomenon (RP) is a genetic disorder that affects blood circulation. It is a vasospastic disorder, which means that small blood vessels near the surface of the skin spasm, restricting blood flow. People with Raynaud's disease who develop attacks when they are cold or stressed often experience pain in their fingers and toes, along with changes in skin color. More severe cases may cause severe pain or ulcers.
About 2-5% of people have Raynaud's disease. Although Raynaud's disease is a common condition, it has been poorly studied and little is known about its genetic causes.
ADRA2A and IRX1 are putative risk genes for Raynaud's phenomenon" study illustration. Source: Maik Pietzner, Department of Computational Medicine, Charité-Universitätsmedizin Berlin, Germany, and Precision Healthcare University Institute, Queen Mary University of London, UK.
Current treatments for RP are limited. Doctors often advise patients to use "self-management" strategies, such as keeping warm and avoiding triggers. Severe cases may be given medications, which are "repurposed medications" and are typically medications used to lower high blood pressure. These drugs often cause serious side effects for patients. To develop safe and effective treatments, a better understanding of the underlying genetic mechanisms leading to RD is necessary.
research methods
Researchers led by Professors Claudia Langenberg and Maik Pietzner, in collaboration with PHURI and BIH, conducted the largest genetic study of Raynaud's phenomenon. The team identified more than 5,000 people with Raynaud's disease using electronic health records from UK Biobank, a large biomedical database and research resource containing genetic and health information on 500,000 UK participants. The research team also used electronic health records from the Queen Mary Hospital Genetics and Health Study.
Research results
The researchers identified two genetic variants that predispose to Raynaud's phenomenon: one is the alpha-2A-adrenergic receptor ADRA2A for epinephrine, a classic stress receptor that causes small blood vessels to constrict.
Maik Pietzner, professor of health data modeling at PHURI and leader of the BIH group, explains: "In times of cold or danger, this makes sense because the body has to supply blood to the inside of the body."
"In people with Raynaud's disease, this receptor appears to be particularly active, which could explain the cause of vasospasm, especially when combined with the second gene we discovered: this gene is the transcription factor IRX1, which regulates the ability of blood vessels to dilate. If IRX1 production is increased, it may activate genes that prevent constricted blood vessels from relaxing normally. Combined with overactive adrenergic receptors, this may cause the blood vessels to fail to supply enough blood for an extended period of time, leading to the whitening of the fingers and toes observed."
The researchers replicated some of their findings using data from British Bangladeshi and Pakistani participants in the Genes and Health Study at Queen Mary.
Potential Impact and Future Research
The researchers' findings are the first to help understand why patients' small blood vessels react so strongly, even when there is seemingly no external stimulus, such as exposure to cold.
Dr Emma Bramond, head of research at Scleroderma and Raynaud's UK (SRUK), said: "Raynaud's disease is a painful, chronic condition that affects around one in six people in the UK. We know that certain triggers, such as cold and stress, can cause Raynaud's to flare up, but even less is known about why some people develop Raynaud's and others don't. For the millions of people living with Raynaud's, simple everyday tasks "Everything is a challenge, so studies like this are vital and can greatly advance our understanding of Raynaud's disease and the role that genetics may play in causing Raynaud's disease. The next step is to confirm these important findings in a more diverse population and validate the results through functional studies. If successful, these findings will help us open up more new treatment avenues for Raynaud's disease, leading to better, more targeted and more friendly treatments."
These findings could provide patients with suggestions to help them manage their condition or symptoms. For example, researchers found that people with a genetic predisposition to hypoglycemia are at increased risk for Raynaud's phenomenon, suggesting that patients should avoid longer episodes of hypoglycemia.
For Claudia Langenberg, director of PHURI and professor of computational medicine at BIH, this study shows that integrating genomic and electronic health record data can quickly help people better understand diseases with unknown causes. She said:
"Of course, we ultimately hope that our findings will provide us with new treatment options. Drugs that more or less specifically inhibit ADRA2A function (such as the antidepressant mirtazapine) are already approved, and our findings suggest that these drugs may provide alternative treatment options for patients with Raynaud's disease."