Genetic Etiology of Raynaud’s Phenomenon Revealed

The genetic causes of Raynaud’s phenomenon have been uncovered by researchers at Queen Mary University of London’s Precision Healthcare Research Institute (PHURI) and Charité – Universitätsmedizin Berlin’s Berlin Institute of Health (BIH).

Raynaud’s phenomenon (RP) is a heritable blood circulation disorder. It’s a vasospastic disorder, which implies that small blood vessels near the skin’s surface spasm, limiting blood flow. People with Raynaud’s syndrome frequently experience discomfort in their fingers and toes, as well as changes in skin color, as a result of a lack of blood flow during attacks when they are cold or emotionally upset. In more extreme cases, it might result in severe pain or ulceration.

Raynaud’s disease affects around 2-5% of the population. Despite the fact that it is a prevalent ailment, it is understudied, and nothing is known about the genetic etiology of the condition.

There are few RP therapies available. Doctors frequently urge patients to use’self-management’ techniques such as staying warm and avoiding attack triggers. In severe circumstances, pharmaceuticals can be provided; these are’repurposed drugs,’ mainly blood pressure medications. These frequently result in serious negative effects in people. To create safe and effective treatments, a greater knowledge of the underlying genetic processes that underlie RD is required.

The largest genetic investigation of Raynaud’s phenomenon was conducted by researchers led by Professor Claudia Langenberg and Professor Maik Pietzner from PHURI and the BIH. The researchers identified over 5,000 Raynaud’s patients using electronic health records from the UK Biobank, a large-scale scientific database and research resource including genetic and clinical information from half a million UK individuals. The researchers also consulted computerized health information from Queen Mary University’s Genes & Health program.

The results
The researchers detected genetic variations in two genes that predispose people to Raynaud’s phenomenon: ADRA2A, a classic stress receptor that induces tiny blood vessels to contract, was one of them.

“This makes sense when it’s cold or dangerous, because the body has to supply the inside of the body with blood,” explains Maik Pietzner, PHURI Professor of Health Data Modeling and BIH group leader.

“This receptor appeared to be more active in Raynaud’s patients, which could explain the vasospasms, especially in combination with the second gene that we discovered: This gene encodes the transcription factor IRX1, which may influence blood vessel dilation.

“Increasing its production may activate genes that prevent constricted vessels from relaxing normally.” Together with the overactive adrenaline receptor, this may result in the veins not supplying enough blood for a longer period of time, resulting in the white fingers and toes observed.”

Some of the findings were repeated using data from Queen Mary’s Genes & Health study participants of British Bangladeshi and Pakistani descent.

The findings of the researchers serve to explain, for the first time, why tiny vessels react so strongly in patients, even when no external stimuli, such as cold exposure, are present.

According to Dr. Emma Blamont, Head of Research at Scleroderma and Raynaud’s UK (SRUK),

“Raynaud’s is a painful, chronic condition that affects approximately one in every six people in the United Kingdom.” We know that certain triggers, such as cold and stress, can cause episodes, but little is known about why some people get Raynaud’s and others don’t. Simple everyday tasks can be difficult for the millions of individuals living with this condition, therefore research like this, which considerably enhances our understanding of Raynaud’s and the role that genetics may play in producing it, is critical.

The next step is to confirm these significant findings in a broader range of population groups and validate the findings through functional studies.” If successful, these results may lead to additional novel therapeutic pathways for Raynaud’s disease, resulting in better, more targeted, and gentler treatments.

The findings could result in patient recommendations to assist manage the disease or its symptoms. For example, the researchers discovered that persons who have a hereditary tendency to low blood sugar levels are more likely to develop Raynaud’s phenomenon, implying that patients should avoid extended periods of low blood sugar.

This work shows, according to Claudia Langenberg, Director of PHURI and Professor of Computational Medicine at BIH, how merging genomic and electronic health record data might quickly help to better understand diseases whose aetiology is unknown. She stated:

“Of course, we hope that our findings will eventually lead to new treatment options.” There are already approved medications that more or less specifically suppress the action of ADRA2A, such as the antidepressant mirtazapine, and our findings imply that these may present additional therapy choices for people suffering from Raynaud’s symptoms.”

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