Researchers at Queen Mary University of London’s Precision Healthcare Research Institute (PHURI) and the Berlin Institute of Health (BIH) at Charité – Universitätsmedizin Berlin have identified the genetic causes of Raynaud’s phenomenon. Their findings, published today in Nature Communications, could lead on to the primary effective treatments for individuals with Raynaud’s.

Raynaud’s phenomenon (RP) is a heritable condition that affects blood circulation. It is a vasopastic condition, which suggests that small blood vessels near the surface of the skin have spasms that may limit blood flow. Individuals with Raynaud’s often experience pain of their fingers and toes, often alongside changes of color of their skin, due an absence of blood flow during attacks after they’re cold or emotionally stressed. In additional serious cases, it might cause severe pain or ulcers.

Around 2-5% of the population are affected by Raynaud’s. Despite it being a standard condition, it’s under-investigated and little is known concerning the genetic reason behind the condition.

There are limited treatments available for RP. Doctors often advise that the patient use ‘self-management’ strategies reminiscent of keeping warm and avoiding triggers of attacks. In severe cases medications could be prescribed, these are ‘repurposed drugs’, often medicines to lower hypertension. These often cause severe negative effects in patients. A greater understanding of the underlying genetic mechanisms that cause RD is required to develop secure and effective treatments.

Researchers led by Professor Claudia Langenberg and Professor Maik Pietzner, working across PHURI and the BIH, carried out the biggest genome-wide association study (GWAS) for 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 1,000,000 UK participants, to discover greater than 9,000 people affected by Raynaud’s. The team also used electronic health records from Queen Mary’s Genes & Health study.

The findings

The researchers discovered variation in two genes that predisposed participants to Raynaud’s phenomenon: One was the alpha-2A-adrenergic receptor for adrenaline, ADRA2A, a classic stress receptor that causes the small blood vessels to contract.

“This is sensible when it’s cold or dangerous, since the body has to produce the inside the body with blood,” explains Maik Pietzner, Health Data Chair of PHURI and co-lead of the Computational Medicine Group at BIH.

“In Raynaud’s patients, nonetheless, this receptor appeared to be particularly energetic, which could explain the vasospasms, especially together with the second gene that we found: This gene is the transcription factor IRX1, which can regulate the flexibility of blood vessels to dilate.

If its production is increased, it might activate genes that prevent constricted vessels from relaxing as they’d normally do. Along with the overactive adrenaline receptor, this may increasingly then result in the vessels not suppling enough blood for an extended time frame, which results in the observed white fingers and toes.”

The researchers were also in a position to replicate parts of their findings using data from participants of British Bangladeshi and Pakistani origin from Queen Mary’s Genes & Health study.

The researchers’ findings also help to know for the primary time why the small vessels react so strongly in patients, even apparently without external stimuli, reminiscent of exposure to cold.

Raynaud’s is a painful, chronic condition that affects around one in ten people within the UK. We all know that attacks could be brought on by certain triggers like cold and stress, but relatively little is thought about why some people experience Raynaud’s and others don’t. For the hundreds of thousands of individuals living with this condition, easy on a regular basis tasks generally is a challenge, so research like this, which significantly advances our understanding of Raynaud’s and the role that genetics may play in causing it, is crucial.”

Dr Emma Blamont, Head of Research for Scleroderma and Raynaud’s UK, Queen Mary University of London

“The following step is to verify these vital findings in additional diverse population groups and validate the outcomes through functional studies. If successful, these findings could help us unlock more latest therapeutic avenues for Raynaud’s leading to higher, more targeted and kinder treatments.”

The findings could lead on to recommendations for patients to assist manage the condition. For instance, the researchers showed that individuals with a genetic predisposition to low blood sugar levels have an increased risk of Raynaud’s phenomenon and subsequently patients should possibly avoid longer episodes of low blood sugar. Their findings may even point to novel treatment options as Claudia Langenberg explained “For instance, already approved drugs that roughly specifically inhibit the function of ADRA2A may very well be another, reminiscent of the antidepressant mirtazapine.

“I’m convinced that our findings provide a path to novel effective medications.”

Source:

Queen Mary University of London