And What triggers Raynaud’s phenomenon attacks?

Scientists at Queen Mary University of London’s Precision Healthcare Research Institute (PHURI) and the Berlin Institute of Health (BIH) at Charité – Universitätsmedizin Berlin have discovered the genetic origins of Raynaud’s phenomenon, a painful, chronic condition that can be triggered by cold and stress.

This breakthrough, announced today in Nature Communications, might pave the way for the development of the first truly efficient treatments for individuals affected by Raynaud’s.

Raynaud’s phenomenon

Raynaud’s phenomenon (RP) is an inheritable disorder that interferes with blood circulation, characterized by spasms in small blood vessels near the skin’s surface, restricting blood flow.

Raynaud’s symptoms: Those with Raynaud’s frequently experience discomfort in their fingers and toes, often accompanied by skin color changes due to decreased blood flow during episodes triggered by cold or emotional stress. In more severe instances, it can result in intense pain or ulcers.

Raynaud’s impacts approximately 2-5% of the population. However, despite its prevalence, it is under-researched, and the genetic roots of the condition remain largely unknown.

Treatment options for Raynaud’s disease

The options for treating RP are currently limited. Patients are typically guided towards ‘self-management’ approaches, such as maintaining warmth and steering clear of triggers.

In extreme cases, medications, often repurposed drugs for hypertension, can be prescribed, although they frequently lead to severe side effects. Therefore, a comprehensive understanding of the genetic mechanisms underlying RD is crucial for the creation of safe and efficient treatments.

The research, helmed by Professor Claudia Langenberg and Professor Maik Pietzner, spanning both PHURI and BIH, executed the most extensive genome-wide association study (GWAS) for Raynaud’s phenomenon to date.

The team utilized electronic health records from the UK Biobank, a comprehensive biomedical database and research resource that houses genetic and health data from half a million UK participants. This helped identify over 9,000 individuals suffering from Raynaud’s. Electronic health records from Queen Mary’s Genes & Health study were also employed by the team.

Who is most affected by Raynaud’s phenomenon?

The team found variations in two genes that make individuals susceptible to Raynaud’s phenomenon: The first is the alpha-2A-adrenergic receptor for adrenaline, ADRA2A, a conventional stress receptor that causes small blood vessels to constrict.

According to Maik Pietzner, Health Data Chair of PHURI and co-lead of the Computational Medicine Group at BIH, this behavior is logical during cold or dangerous situations as the body needs to direct blood to its interior.

However, in Raynaud’s patients, this receptor appears to be unusually active, potentially accounting for the vasospasms, particularly when coupled with the second gene discovered: This gene is the transcription factor IRX1, which might control blood vessels’ ability to dilate.

Increased production of this transcription factor may trigger genes that stop constricted vessels from relaxing as they usually would. In conjunction with the overactive adrenaline receptor, this could lead to prolonged inadequate blood supply, resulting in noticeable white fingers and toes.

Parts of these findings were validated using data from British Bangladeshi and Pakistani participants from Queen Mary’s Genes & Health study.

These findings also illuminate why small vessels in patients react so intensely, even seemingly without external triggers such as cold exposure.

For the millions struggling with this condition, even mundane daily activities can be daunting.

And “We know relatively little about why some people are afflicted with Raynaud’s and others aren’t,” comments Dr. Emma Blamont, Head of Research for Scleroderma and Raynaud’s UK (SRUK).

Understanding “Raynaud’s and the role that genetics may play in causing it “is 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 findings could help us unlock more new therapeutic avenues for Raynaud’s leading to better, more targeted and kinder treatments.”

These findings might inform recommendations for patients to better manage their condition. For instance, the research demonstrated that individuals genetically predisposed to low blood sugar levels are at a higher risk for Raynaud’s phenomenon.

Therefore, patients might be advised to avoid extended periods of low blood sugar. Furthermore, their findings could potentially point towards new treatment options, as Claudia Langenberg elaborated

“For example, already approved drugs that more or less specifically inhibit the function of ADRA2A could be an alternative, such as the antidepressant mirtazapine.

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

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