̽��ֱ�� of Cambridge - Steven Bell

Genetics study points to potential treatments for restless leg syndrome

cjb250 — Wed, 05 Jun 2024 09:00:25 +0000

Restless leg syndrome can cause an unpleasant crawling sensation in the legs and an overwhelming urge to move them. Some people experience the symptoms only occasionally, while others get symptoms every day. Symptoms are usually worse in the evening or at night-time and can severely impair sleep.

Despite the condition being relatively common – up to one in 10 older adults experience symptoms, while 2-3% are severely affected and seek medical help – little is known about its causes. People with restless leg syndrome often have other conditions, such as depression or anxiety, cardiovascular disorders, hypertension, and diabetes, but the reason why is not known.

Previous studies had identified 22 genetic risk loci – that is, regions of our genome that contain changes associated with increased risk of developing the condition. But there are still no known ‘biomarkers’ – such as genetic signatures – that could be used to objectively diagnose the condition.

To explore the condition further, an international team led by researchers at the Helmholtz Munich Institute of Neurogenomics, Institute of Human Genetics of the Technical ̽��ֱ�� of Munich (TUM) and the ̽��ֱ�� of Cambridge pooled and analysed data from three genome-wide association studies. These studies compared the DNA of patients and healthy controls to look for differences more commonly found in those with restless leg syndrome. By combining the data, the team was able to create a powerful dataset with more than 100,000 patients and over 1.5 million unaffected controls.

̽��ֱ��results of the study are published today in Nature Genetics.

Co-author Dr Steven Bell from the ̽��ֱ�� of Cambridge said: “This study is the largest of its kind into this common – but poorly understood – condition. By understanding the genetic basis of restless leg syndrome, we hope to find better ways to manage and treat it, potentially improving the lives of many millions of people affected worldwide.”

̽��ֱ��team identified over 140 new genetic risk loci, increasing the number known eight-fold to 164, including three on the X chromosome. ̽��ֱ��researchers found no strong genetic differences between men and women, despite the condition being twice as common in women as it is men – this suggests that a complex interaction of genetics and the environment (including hormones) may explain the gender differences we observe in real life.

Two of the genetic differences identified by the team involve genes known as glutamate receptors 1 and 4 respectively, which are important for nerve and brain function. These could potentially be targeted by existing drugs, such as anticonvulsants like perampanel and lamotrigine, or used to develop new drugs. Early trials have already shown positive responses to these drugs in patients with restless leg syndrome.

̽��ֱ��researchers say it would be possible to use basic information like age, sex, and genetic markers to accurately rank who is more likely to have severe restless leg syndrome in nine cases out of ten.

To understand how restless leg syndrome might affect overall health, the researchers used a technique called Mendelian randomisation. This uses genetic information to examine cause-and-effect relationships. It revealed that the syndrome increases the risk of developing diabetes.

Although low levels of iron in the blood are thought to trigger restless leg syndrome – because they can lead to a fall in the neurotransmitter dopamine – the researchers did not find strong genetic links to iron metabolism. However, they say they cannot completely rule it out as a risk factor.

Professor Juliane Winkelmann from TUM, one of senior authors of the study, said: “For the first time, we have achieved the ability to predict restless leg syndrome risk. It has been a long journey, but now we are empowered to not only treat but even prevent the onset of this condition in our patients.”

Professor Emanuele Di Angelantonio, a co-author of the study and Director of the NIHR and NHS Blood and Transplant-funded Research Unit in Blood Donor Health and Behaviour, added: "Given that low iron levels are thought to trigger restless leg syndrome, we were surprised to find no strong genetic links to iron metabolism in our study. It may be that the relationship is more complex than we initially thought, and further work is required."

̽��ֱ��dataset included the INTERVAL study of England’s blood donors in collaboration with NHS Blood and Transplant.

A full list of funders can be found in the study paper.

Reference
Schormair et al. Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology, and risk prediction. Nature Genetics; 5 June 2024; DOI: 10.1038/s41588-024-01763-1

Scientists have discovered genetic clues to the cause of restless leg syndrome, a condition common among older adults. ̽��ֱ��discovery could help identify those individuals at greatest risk of the condition and point to potential ways to treat it.

By understanding the genetic basis of restless leg syndrome, we hope to find better ways to manage and treat it, potentially improving the lives of many millions of people affected worldwide

Steven Bell

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Restless legs syndrome study identifies 13 new genetic risk variants

cjb250 — Thu, 12 Oct 2017 23:01:27 +0000

As many as one in ten people of European ancestry is affected by restless legs syndrome, in which sufferers feel an overwhelming urge to move, often in conjunction with unpleasant sensations, usually in the legs. Rest and inactivity provoke the symptoms, whereas movement can lead to temporary relief. ̽��ֱ��condition is chronic and can get progressively worse, with long-lasting effects on patients’ mental and physical health. People with restless legs syndrome have substantially impaired sleep, reduced overall quality of life, and increased risk of depression, anxiety disorders, hypertension, and, possibly, cardiovascular disease.

For around one in 50 people, the condition can be severe enough to require chronic medication, which may in turn have potentially serious side effects.

Studies of families and twins have shown that there is a strong genetic component to the disorder and led to the discovery of six genetic variants that increased the risk of developing the condition.

“We have studied the genetics of restless legs syndrome for more than 10 years and the current study is the largest conducted so far,” says Dr Barbara Schormair from the Institute of Neurogenomics at the Helmholtz Zentrum München, first author of the study. “We are convinced that the newly discovered risk loci will contribute substantially to our understanding of the causal biology of the disease.”

Now, an international team of researchers has compared the genetic data from over 15,000 patients with more than 95,000 controls, and identified a further 13 genetic risk variants. ̽��ֱ��findings were then replicated in a sample of 31,000 patients and 287,000 controls. ̽��ֱ��results are published today in Lancet Neurology.

“Restless legs syndrome is surprisingly common, but despite this, we know little about what causes it – and hence how to treat it,” says Dr Steven Bell from the Department of Public Health and Primary Care at the ̽��ֱ�� of Cambridge, also one of the first authors on the study. “We already know that it has a strong genetic link, and this was something we wanted to explore in more detail.”

Several of the genetic variants have previously been linked to the growth and development of nerve cells – a process known as neurogenesis – and to changes in the formation of neuronal circuits. These findings strengthen the case for restless legs syndrome being a neurodevelopmental disorder whose origins may go back to development in the womb as well as impaired nerve cell growth in later life.

“ ̽��ֱ��genetic risk variants that we’ve discovered add more weight to the idea that this condition is related to the development of our nervous system,” says Dr Emanuele Di Angelantonio, also from the Department of Public Health and Primary Care. “It also gives us some clues to how we may treat patients affected by the condition.”

Prof Juliane Winkelmann, who heads the Institute of Neurogenomics at the Helmholtz Zentrum as well as a restless legs syndrome outpatient clinic at the Klinikum Rechts der Isar in Munich, adds: “Our genetic findings are an important step towards developing new and improved treatment options for our patients.”

One particular biological pathway implicated by the findings is known to be a target for the drug thalidomide. While the drug has a controversial reputation due to its previous use when treating pregnant women that led to serious birth defects in their offspring, it is now used to treat some cancers. ̽��ֱ��researchers suggest that thalidomide or similar drugs may offer potential treatment options for male patients with restless leg syndrome and female patients beyond reproductive age, but they stress the necessity of rigorous clinical testing for efficacy and side-effects before any such use.

̽��ֱ��study was largely funded by NHS Blood and Transplant, National Institute for Health Research, British Heart Foundation, European Commission, European Research Council, National Institute for Health Research Cambridge Biomedical Research Centre, UK Medical Research Council, Deutsche Forschungsgemeinschaft (DFG) and Helmholtz Zentrum München.

Reference
Schormair, B., Zhao, C., Bell, S. et al. Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis. Lancet Neurology; 10th October 2017; DOI: 10.1016/S1474-4422(17)30327-7

A new study into the genetics underlying restless legs syndrome has identified 13 previously-unknown genetic risk variants, while helping inform potential new treatment options for the condition.

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Moderate drinking linked to lower risk of some – but not all – heart conditions

cjb250 — Wed, 22 Mar 2017 23:30:27 +0000

̽��ֱ��finding that moderate drinking is not universally associated with a lower risk of all cardiovascular conditions suggests a more nuanced approach to the role of alcohol in prevention of cardiovascular disease is necessary, say the researchers.

Moderate drinking is thought to be associated with a lower risk of developing cardiovascular disease compared with abstinence or heavy drinking.

In the UK, moderate drinking is defined as no more than 14 units of alcohol a week, the equivalent of 7 pints of ordinary strength beer or just over one and a half bottles of ordinary strength wine.

There is, however, a growing scepticism around this observation, with some experts pointing out several shortcomings in the evidence, for example grouping non-drinkers with former drinkers, who may have stopped drinking due to poor health.

Researchers at the ̽��ֱ�� of Cambridge and ̽��ֱ�� College London set out to investigate the association between alcohol consumption and 12 cardiovascular diseases by analysing electronic health records for 1.93 million healthy UK adults as part of the CALIBER (ClinicAl research using LInked Bespoke studies and Electronic health Records) data resource.

All participants were free from cardiovascular disease at the start of the study, and non-drinkers were separated from former and occasional drinkers to provide additional clarity in this debate.

̽��ֱ��researchers looked at the effect of different levels of drinking on the risk of ‘first presenting’ to a doctor with a number of cardiovascular diseases; for example, did moderate drinking make it more or less likely that an individual’s first diagnosis of cardiovascular disease was a heart attack.

After several influential factors were accounted for, moderate drinking was associated with a lower risk of several, but not all, cardiovascular conditions, including angina, heart failure and ischaemic stroke (the most common type of stroke, when a blood clot blocks the flow of blood and oxygen to the brain), compared with abstaining from alcohol.

“This doesn’t mean that it is advisable for individuals to take up drinking as a means of lowering their cardiovascular risk,” says Dr Steven Bell from the Department of Public Health and Primary Care at the ̽��ֱ�� of Cambridge. “Alcohol consumption is associated with other diseases, such as liver disease and certain types of cancer. There are other, safer and more effective ways, such as being more physically active, maintaining a healthy diet and stopping smoking.

“Ultimately an individual’s decision to drink, and at what level, should not be considered in isolation of other health behaviours or risk factors and instead be motivated by their own personal circumstances.”

Heavy drinking (exceeding recommended limits) conferred an increased risk of a range of cardiovascular diseases, including heart failure, cardiac arrest (when the heart malfunctions and stops beating suddenly) and ischaemic stroke compared with moderate drinking. However, it carried a lower risk of heart attack (when blood flow to the heart is blocked) and angina.

Again, the authors explain that this does not mean that heavy drinkers will not go on to experience a heart attack in the future, just this was less likely to be their first diagnosis compared with moderate drinkers.

This is an observational study, so no firm conclusions can be drawn about cause and effect. Added to which, the authors point to some study limitations that could have introduced bias.

Nevertheless, they say it is the first time this association has been investigated on such a large scale and their findings have implications for patient counselling, public health communication, and disease prediction tools.

In a linked editorial, researchers at Harvard Medical School and Johns Hopkins School of Public Health in the US say this study “sets the stage for ever larger and more sophisticated studies that will attempt to harness the flood of big data into a stream of useful, reliable, and unbiased findings that can inform public health, clinical care, and the direction of future research”.

Reference
Bell, S et al. Association between clinically recorded alcohol consumption and initial presentation of 12 cardiovascular diseases: population based cohort study using linked health records. BMJ; 23 Mar 2017; DOI: 10.1136/bmj.j909

Adapted from a press release from ̽��ֱ��BMJ.

Moderate drinking is associated with a lower risk of several, but not all, cardiovascular diseases, according to a large study of UK adults led by researchers at the ̽��ֱ�� of Cambridge and ̽��ֱ�� College London published today in ̽��ֱ��BMJ.

This doesn’t mean that it is advisable for individuals to take up drinking as a means of lowering their cardiovascular risk. There are other, safer and more effective ways, such as being more physically active, maintaining a healthy diet and stopping smoking

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