Researchers from the Precision Healthcare University Research Institute (PHURI) at Queen Mary University of London and the Berlin Institute of Health (BIH) at Charité – Universitätsmedizin Berlin have identified the genetic causes of Raynaud’s phenomenon. Their findings, published today (October 12) in Nature Communicationscould lead to the first effective treatments for people with Raynaud’s disease.
Raynaud’s phenomenon (RP) is an inherited condition that affects blood circulation. It is a Vasospastic condition, which means that small blood vessels near the surface of the skin go into spasms that can limit blood flow. People with Raynaud’s disease often experience pain in their fingers and toes, often along with changes in skin color, due to a lack of blood flow during attacks, when they are cold or emotionally stressed. In more serious cases, it can cause severe pain or ulcers.
About 2-5% of the population is affected by Raynaud’s disease. Despite being a common disease, it is little investigated and little is known about the genetic cause of the disease.
There are limited treatments available for RP. Doctors often advise patients to use “self-management” strategies such as staying warm and avoiding attack triggers. In severe cases, medications may be prescribed, which are “repurposed medications,” usually medications to lower high blood pressure. These often cause serious side effects in patients. A better understanding of the underlying genetic mechanisms that cause DR is needed to develop safe and effective treatments.
Researchers led by Professor Claudia Langenberg and Professor Maik Pietzner, working at PHURI and BIH, have carried out the largest genetic study of Raynaud’s phenomenon. The team used electronic health records from the UK Biobank, a large-scale biomedical database and research resource containing genetic and health information from half a million UK participants, to identify more than 5,000 people affected by Raynaud’s disease. The team also used electronic health records from the Queen Mary Genes & Health study.
The researchers discovered variations in two genes that predisposed participants to Raynaud’s phenomenon: one was the alpha-2A-adrenergic receptor for adrenaline, ADRA2Aa classic stress receptor that causes small blood vessels to constrict.
“This makes sense when it is cold or dangerous, because the body has to supply blood to the inside of the body,” explains Maik Pietzner, professor of health data modeling at PHURI and group leader at BIH.
“In Raynaud’s patients, this receptor seemed to be particularly active, which could explain the vasospasms, especially in combination with the second gene we found: this gene is the transcription factor IRX1which can regulate the ability of blood vessels to dilate.
“If its production is increased, it can activate genes that prevent constricted vessels from relaxing as they normally would. Together with the overactive adrenaline receptor, this can cause the vessels to not supply enough blood for a long period of time, which leads to the white fingers and toes seen.
The researchers replicated some of their findings using data from British-origin Bangladeshi and Pakistani participants from the Queen Mary Genes & Health study.
The researchers’ findings help to understand, for the first time, why small vessels react so strongly in patients, even apparently without external stimuli, such as exposure to cold.
Dr Emma Blamont, Head of Research for Scleroderma and Raynaud’s UK (SRUK), said:
“Raynaud’s disease is a chronic and painful condition that affects around one in six people in the UK. We know that attacks can be triggered by certain triggers, such as cold and stress, but relatively little is known about why some people get Raynaud’s and others don’t. t. For the millions of people living with this condition, simple everyday tasks can be a challenge, so research like this, which significantly advances our understanding of Raynaud’s disease and the role genetics may play in causing it, are crucial.
“The next step is to confirm these important findings in more diverse population groups and validate the results through functional studies. If successful, these discoveries could help us unlock more new therapeutic avenues for Raynaud’s, leading to better, more targeted and kinder treatments.”
The findings could lead to recommendations for patients to help manage the disease or its symptoms. For example, researchers have shown that people with a genetic predisposition to low blood sugar have an increased risk of Raynaud’s phenomenon, suggesting that patients should avoid longer episodes of low blood sugar.
For Claudia Langenberg, Director of PHURI and Professor of Computational Medicine at BIH, this study exemplifies that the integration of genomic data and electronic health records can quickly help to better understand diseases whose etiology remains unknown. She said:
“Of course, we hope that our findings point to new treatment options. There are already approved medications that more or less specifically inhibit the function of ADRA2A, such as the antidepressant mirtazapine, and our results suggest that these may present alternative treatment options for patients suffering from the symptoms of Raynaud’s disease.”
ADRA2A and IRX1 are putative risk genes for Raynaud’s phenomenon
Article publication date
October 12, 2023
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