Gene genie

[Jo Bowyer]

Genetics Link Sleep Disturbances With Restless Leg Syndrome, Schizophrenia and Obesity

http://neurosciencenews.com/sleep-ge...ophrenia-5776/

The study looked at the biological controllers of sleep duration, insomnia and excessive daytime sleepiness and how they linked to the health and life histories of more than 112,000 people taking part in the world-leading UK Biobank study. Study participants reported their sleep duration, the degree of insomnia and daytime sleepiness, and then had their genes mapped. Other information about them, such as their weight and any diseases they suffered from, was also collected.

The researchers identified for the first time areas of the genome that are associated with sleep disturbance – including insomnia and excessive daytime sleepiness – and also discovered novel genetic links with several medical conditions, including restless legs syndrome, schizophrenia and obesity. The strongest genetic association for insomnia symptoms fell within a gene previously linked to restless legs syndrome – a nervous system disorder affecting around 1 in 20 people that leads to a strong urge to move one’s legs, which is often worse at night. Other gene regions were important for insomnia, but selectively in either men or women.

The team also identified genetic links between longer sleep duration and schizophrenia risk and between increased levels of excessive daytime sleepiness and measures of obesity (body mass index and waist circumference). The research also suggested that insomnia has shared underlying biology with major depression and abnormal glucose metabolism.

Insomnia not purely psychological condition: Insomnia genes found

https://www.sciencedaily.com/release...0612115358.htm

In a sample of 113,006 individuals, the researchers found 7 genes for insomnia. These genes play a role in the regulation of transcription, the process where DNA is read in order to make an RNA copy of it, and exocytosis, the release of molecules by cells in order to communicate with their environment. One of the identified genes, MEIS1, has previously been related to two other sleep disorders: Periodic Limb Movements of Sleep (PLMS) and Restless Legs Syndrome (RLS). By collaborating with Konrad Oexle and colleagues from the Institute of Neurogenomics at the Helmholtz Zentrum, München, Germany, the researchers could conclude that the genetic variants in the gene seem to contribute to all three disorders. Strikingly, PLMS and RLS are characterized by restless movement and sensation, respectively, whereas insomnia is characterized mainly by a restless stream of consciousness.

Genetic overlap with other characteristics

The researchers also found a strong genetic overlap with other traits, such as anxiety disorders, depression and neuroticism, and low subjective wellbeing. "This is an interesting finding, because these characteristics tend to go hand in hand with insomnia. We now know that this is partly due to the shared genetic basis," says neuroscientist Anke Hammerschlag (VU), PhD student and first author of the study.

Different genes for men and women

The researchers also studied whether the same genetic variants were important for men and women. "Part of the genetic variants turned out to be different. This suggests that, for some part, different biological mechanisms may lead to insomnia in men and women," says professor Posthuma. "We also found a difference between men and women in terms of prevalence: in the sample we studied, including mainly people older than fifty years, 33% of the women reported to suffer from insomnia. For men this was 24%."

The risk genes could be tracked down in cohorts with the DNA and diagnoses of many thousands of people. The UK Biobank -- a large cohort from England that has DNA available -- did not have information as such about the diagnosis of insomnia, but they had asked their participants whether they found it difficult to fall asleep or to have an uninterrupted sleep. By making good use of information from slaapregister.nl (the Dutch Sleep Registry), the UK Biobank was able, for the first time, to determine which of them met the insomnia profile. Linking the knowledge from these two cohorts is what made the difference.

Update 14/06/2017

[Jo Bowyer]

MicroRNAs Associated with Shoulder Tendon Matrisome Disorganization in Glenohumeral Arthritis

http://journals.plos.org/plosone/art...l.pone.0168077

Abstract

The extracellular matrix (ECM) provides core support which is essential for the cell and tissue architectural development. The role of ECM in many pathological conditions has been well established and ECM-related abnormalities leading to serious consequences have been identified. Though much has been explored in regards to the role of ECM in soft tissue associated pathologies, very little is known about its role in inflammatory disorders in tendon. In this study, we performed microRNA (miRNA) expression analysis in the long head of the human shoulder biceps tendon to identify key genes whose expression was altered during inflammation in patients with glenohumeral arthritis. We identified differential regulation of matrix metalloproteinases (MMPs) that could be critical in collagen type replacement during tendinopathy. The miRNA profiling showed consistent results between the groups and revealed significant changes in the expression of seven different miRNAs in the inflamed tendons. Interestingly, all of these seven miRNAs were previously reported to have either a direct or indirect role in regulating the ECM organization in other pathological disorders. In addition, these miRNAs were also found to alter the expression levels of MMPs, which are the key matrix degrading enzymes associated with ECM-related abnormalities and pathologies. To our knowledge, this is the first report which identifies specific miRNAs associated with inflammation and the matrix reorganization in the tendons. Furthermore, the findings also support the potential role of these miRNAs in altering the collagen type ratio in the tendons during inflammation which is accompanied with differential expression of MMPs.

[Jo Bowyer]

Individual Cell Clocks and Immunity

http://jonlieffmd.com/blog/individua...9c0c4-90589721

Each cell has oscillating gene networks that somehow help organize, synchronize, and anticipate activity of the tissues and the entire organism. Energy from the sun is transformed into energy and material for the cell to use in sync to these rhythms. The rhythms also are related to how the cell develops in particular organs and responses to damage and distress. It is not yet clear how these individual unique 24 hour clocks in each cell translates to the rhythms of the entire animal. In evolution, the development of these clocks appears to be vital to provide the needed resources for DNA repair at the proper time of day. Also, it provides machinery at the right time to make oxygen and a way to avoid expending energy for little gain.

The two previous posts have described the discovery of individual clocks in each cell and the way individual cells interact with tissues and the brain clocks to regulate metabolism in the most efficient manner. This post describes the unique clocks in immune cells and how vital this is the response to infection and trauma. The next post will describe the central brain clocks that synchronize some of the circadian rhythms.

[marcel]

http://phys.org/news/2016-12-cogniti...orms.html#nRlv

New study shows cognitive decline may be influenced by interaction of genetics and...
30 dec. 2016

,.....The goal of this study, Trumble explains, was to reexamine the potentially detrimental effects of the globally-present ApoE4 allele in environmental conditions more typical of those experienced throughout our species' existence—in this case, a community of Amazonian forager-horticulturalists called the Tsimane.

"For 99% of human evolution, we lived as hunter gatherers in small bands and the last 5,000-10,000 years—with plant and animal domestication and sedentary urban industrial life—is completely novel,"

Due to the tropical environment and a lack of sanitation, running water, or electricity, remote populations like the Tsimane face high exposure to parasites and pathogens, which cause their own damage to cognitive abilities when untreated.

As a result, one might expect Tsimane ApoE4 carriers who also have a high parasite burden to experience faster and more severe mental decline in the presence of both these genetic and environmental risk factors.

But when the Tsimane Health and Life History Project tested these individuals using a seven-part cognitive assessment and a medical exam, they discovered the exact opposite.

In fact, Tsimane who both carried ApoE4 and had a high parasitic burden displayed steadier or even improved cognitive function in the assessment versus non-carriers with a similar level of parasitic exposure. The researchers controlled for other potential confounders like age and schooling, but the effect still remained strong. This indicated that the allele potentially played a role in maintaining cognitive function even when exposed to environmental-based health threats.

For Tsimane ApoE4 carriers without high parasite burdens, the rates of cognitive decline were more similar to those seen in industrialized societies, where ApoE4 reduces cognitive performance.

[marcel]

http://phys.org/news/2016-12-junk-rn...-key-role.html

'Junk RNA' molecule found to play key role in cellular response to stress
December 15, 2016

A study from Massachusetts General Hospital (MGH) investigators has found a surprising role for what had been considered a nonfunctional "junk" RNA molecule: controlling the cellular response to stress. In their report in the Dec. 15 issue of Cell, the researchers describe finding that a highly specific interaction between two elements previously known to repress gene transcription—B2 RNA and EZH2, an enzyme previously known only to silence genes—actually induces the expression of stress-response genes in mouse cells.

"EZH2 is part of a structure called the Polycomb Repressive Complex 2, which silences target genes," says Jeannie T. Lee, MD, PhD,of the MGH Department of Molecular Biology, senior author of the report. "But a big paradox in the field has been that EZH2 is found at the sites of both active and inactive genes. We have shown, for the first time, that EZH2 can act outside of the PRC2 complex to activate genes through another mechanism—in this case by cleaving the B2 RNA molecule, which then activates stress response genes."

[marcel]

A few words from sapolsky, in the part before this he explains the "misunderstandings" (in plain english) of how genes work

https://aeon.co/essays/dead-or-alive...e-selfish-gene

It makes no sense to ask what a particular gene does
Robert Sapolsky

,....The environment can be the local cellular environment. Suppose oxygen radicals are accumulating in a cell, not a good thing. Scattered throughout the cell are copies of a class of sentinel transcription factors that are activated by oxygen radicals. Once activated, they head off to the DNA. There are a number of genes that code for antioxidants that mop up oxygen radicals, and just before the start of each is a promoter regulated by that transcription factor. So in this scenario, the genome inside this cell mobilises antioxidant defences in response to signals from the cellular environment.

The environment can be the environment of the body. Suppose a woman is secreting oestrogen from her ovaries during the latter half of her reproductive cycle. After coursing through the bloodstream, oestrogen will enter the uterine cells and bind to an oestrogen receptor. And this activated receptor now acts as… yes, a transcription factor. It binds to promoters ‘upstream’ of genes related to cell division. And as a result, new cells proliferate, the uterus thickens, preparing it for implantation of a fertilised egg. In this scenario, the genome inside this cell causes it to divide in response to a signal from a distant organ.

And the environment can be environment with a capital ‘E’, the outside world. Suppose a male antelope smells the pheromones of a threatening competitor. Through steps leading from the nose to the testes, he secretes testosterone. Which makes its way to a muscle cell, binds to a testosterone receptor, which acts as a transcription factor and activates genes related to cell growth, contributing to increased muscle mass. And thus in this scenario, the much-vaunted genome inside that cell is being regulated by some other guy’s pee.

It ultimately makes no sense to ask what a gene does, only what it does in a particular environment; remember what turns grasshoppers into locusts. It is the triumph of context.

[Jo Bowyer]

Laboratory and clinical genomic data sharing is crucial to improving genetic health care: a position statement of the American College of Medical Genetics and Genomics

Abstract

Keywords: genomic data sharing; genomic databases; gene variant databases; genotypehenotype correlations
There exist 5,000–7,000 rare genetic diseases, each of which harbors considerable clinical variability. None are common individually. In addition, more common diseases with genetic influences may have rare variants associated with them. Vast allelic heterogeneity lies at the foundation of most genetic diseases, the effects of which are compounded by background genomic variation that may further affect clinical presentation.

The considerable variation in clinical presentation and molecular etiology of genetic disorders, coupled with their relative individual rarity, makes it clear that no single provider, laboratory, medical center, state, or even individual country will typically possess sufficient knowledge to deliver the best care for patients in need of care. Even in the relatively rare situation in which pathogenic variants are few (e.g., sickle cell anemia), variants in other alleles may contribute to the genomic variation and clinical manifestations of disease. For more genetically complex conditions such as cystic fibrosis, in spite of decades of study, as many as 10% of cases have a CFTR variant so rare that it is represented in only one or two people in current databases, a situation paralleled in many genetic diseases.1,2

To ensure that our patients receive the most informed care possible, the American College of Medical Genetics and Genomics advocates for extensive sharing of laboratory and clinical data from individuals who have undergone genomic testing. Information that underpins health-care service delivery should be treated neither as intellectual property nor as a trade secret when other patients may benefit from the knowledge being widely available. It is similarly important for understanding the risks associated with genetic test results that place asymptomatic/presymptomatic individuals at high risk of developing a genetic disease. Sharing data in this precompetitive space will provide both a resource for clinical laboratories interpreting test results and clinical validity data that can benefit device manufacturers developing new tests and testing platforms. Contributing to public clinical databases in the precompetitive space recognizes that information about genetic diseases is dense and accumulating rapidly, and that information science is empowering the use of “big data.” Further, the shift to public databases being populated by de-identified case-level information from electronic health records will speed the time to “publication” of what are essentially case reports in real time. This process can also reduce the time period during which one might be able to protect trade secrets. Recognizing the importance of data sharing for both research and clinical care, the National Institutes of Health has established a genomic data-sharing policy for its funded investigators.3

Responsible sharing of genomic variant and phenotype data will provide the robust information necessary to improve clinical care and empower device and drug manufacturers that are developing tests and treatments for patients.

Broad data sharing is necessary and will improve care by making available the best data possible by which:

○ Key clinical attributes of the phenotype of those with genetic diseases can be described

○The qualitative strength of the association between genetic diseases and the underlying causative genes can be established

○ The classification of genomic variants across the range of benign to pathogenic can be established

○ Differences in variant interpretation among laboratories can be reconciled

○ The appropriate classification of variants of uncertain significance can be made
○ Standards used in variant classification can be improved


Data sharing will provide the scientific community, health-care providers, and industry with the best data on which:

○ Web-based systems for integrated clinical decision support are based

○ Secondary studies using these data are powered
Data sharing will offer significant financial benefits by which:

○ More standardized approaches to coverage and reimbursement policies can be made

○ The expensive duplication of previously resolved, but unpublished, research efforts currently occurring among pharmaceutical companies can be reduced
The analytical challenges of migrating and integrating clinical and laboratory data across the genome are daunting. Standardization of laboratory and clinical information will enable:


Data compatibility
Interoperability between information systems
Importantly, broad data sharing is compatible with the critical imperative of protecting the privacy of individual health-care information and the security of data systems holding that information. For data to be shared safely for patients and providers, systems are required that:

Ensure the security of databases, whether centralized or federated
Ensure the privacy of patient and family medical information
Provide transparency in the documentation of data-sharing transactions
Clinical-grade standards by which claims about gene/disease associations and the clinical significance of variants are made (e.g., data provenance, database versioning, and expert information curation) are central to a shared genomics data system. However, the need to deliver safe and effective care for those with or at risk for rare diseases, despite weak data for most variants and inevitable conflicts in data interpretation, requires balancing regulatory oversight with the need to provide services regardless of how well a rare disease is understood.

Due to the vast amount of data now being generated by genomic testing, genetic diseases will offer the opportunity to develop the framework for a national learning health-care system because the shared experiences of those caring for these patients continually contribute to improvements in delivering services to this population. A learning health-care system that facilitates access to diagnostic, treatment, and outcomes data to inform the care of today’s patients requires a paradigm shift in how we share data to be used in research and clinical practice. Academic medical centers have already begun to address how providers within their systems can use information about their patients to benefit other patients. This approach could be made national in scope to the benefit of patients everywhere. The National Institutes of Health has already made such data sharing a priority in the research that it funds. However, to accomplish these goals, and to ensure that the tremendous amounts of information now being generated are not wasted, our community must both demonstrate the will to share data broadly and develop the mechanisms to do so easily. These efforts will require support and participation from clinical laboratories, clinicians, regulatory agencies, researchers, and patients to ensure success in improving patient care through genomic medicine.

[marcel]

The dark side of the human genome
Kelly Rae Chi
Nature aug. 2016

Fifteen years ago, scientists celebrated the first draft of the sequenced human genome. At the time, they predicted that humans had between 25,000 and 40,000 genes that code for proteins. That estimate has continued to fall. Humans actually seem to have as few as 19,000 such genes1 — a mere 1–2% of the genome. The key to our complexity lies in how these genes are regulated by the remaining 99% of our DNA, known as the genome's 'dark matter'.

So far, the data suggest that there are hundreds of thousands of functional regions in the human genome whose task is to control gene expression: it turns out that much more space in the human genome is devoted to regulating genes than to the genes themselves. Scientists are now trying to validate each predicted element experimentally to ascertain its function — a mammoth task, but one for which they now have a powerful new tool.

Since the gene-editing technique CRISPR–Cas9 entered the scientific arena, the speed at which researchers can test functional elements in the non-coding regions has ramped up. But it is still a daunting endeavour: more than 3 million regulatory DNA regions, thought to contain some 15 million binding sites for regulatory proteins called transcription factors, control gene expression in the human cell types studied thus far. About 150,000 may be active in any given cell type.

http://www.nature.com/nature/journal...l/538275a.html

[marcel]

A simpler twist of fate

Ways to directly convert one mature cell type into another may eventually offer a safer, faster strategy for regenerative medicine.
Nature 2016

Until the day it dies, a cell that has become a skin cell remains a skin cell — or so scientists used to think. Over the past decade, it has become clear that cellular identity is not written in stone but can be rewritten by activating specific genetic programs. Today, the field of regenerative medicine faces a question: should this rewriting take the conventional route, in which mature cells are first converted back into stem cells, or, where feasible, a more direct approach?

'Terminally differentiated' is a term that sums up the old way of thinking — that skin, muscle or other mature cells cannot be coaxed to adopt a drastically different fate. That idea began to falter a decade ago, when cell biologist Shinya Yamanaka of Kyoto University in Japan showed that a handful of genes could transform adult fibroblast (connective tissue) cells into induced pluripotent stem (iPS) cells1. Like embryonic stem cells, iPS cells can develop into any cell type, a property called pluripotency. They can also be produced in unlimited quantities, unlike embryonic stem cells, which must be harvested from human embryos and therefore come with considerable political baggage.

http://www.nature.com/nature/journal...l/534421a.html

[marcel]

Let the structural symphony begin
Nature 2016

Like other structural biologists, Eva Nogales works in extraordinary times. The University of California, Berkeley, faculty member now has the tools to tackle important questions about cells' molecular machinery that would have been impossible to answer just a few years ago.

A recent project with Berkeley colleague Jennifer Doudna, the molecular biologist who co-pioneered the CRISPR–Cas9 gene-editing method, is a case in point. Both were intensely interested in the R-loop, a structure made of nucleic acids that forms in cells in many situations, but also just before DNA is snipped by CRISPR–Cas9. Nogales and her team revealed an R-loop in Streptococcus pyogenes bacteria, and from the near-atomic-resolution images, deduced how the Cas9 enzyme opens up the DNA conformation at specific sites and makes them accessible to CRISPR's molecular scissors1.

http://www.nature.com/nature/journal...l/536361a.html

The details of the enzyme RNA polymerase

[marcel]

Nature | Outlook: Precision medicine

In this Supplement
Outlook
Related articles

Health care that is tailored on the basis of an individual’s genes, lifestyle and environment is not a uniquely modern concept. But advances in genetics and the growing availability of health data for researchers and physicians promise to make this new era of medicine more personalized than ever before.
Free full access =>

http://www.nature.com/nature/outlook...html#editorial

From:Nature Supplements archive (many free access papers)

http://www.nature.com/nature/archive/supplements.html

[Jo Bowyer]

Cellular Stress Response Gene Expression During Upper and Lower Body High Intensity Exercises

http://journals.plos.org/plosone/art...l.pone.0171247

Introduction

High intensity exercise causes metabolic changes on many levels of human body altering the production of interleukins and heat shock protein [1–3], the availability of substrates, activation of metabolic enzymes [4], and others. All these changes start at the level of gene transcription. It is now understood that changes in genes expression caused by exercises occur primarily in genes associates with apoptosis and inflammation [1]. Considerable evidence demonstrates the influence of various types of exercise on inflammation [5, 6] and the expression of genes encoding heat shock protein [7, 8], thereby mediating the health benefits of episodic and prolonged exercise. The health promoting effects of exercise are associated with production of interleukins, elicited anti-inflammatory response trough inflammation [1], and increased stress tolerance.

[Jo Bowyer]

Low back pain and FokI (rs2228570) polymorphism of vitamin D receptor in athletes

http://bmcsportsscimedrehabil.biomed...102-017-0069-x

Abstract

Background
Low back pain (LBP) is common in athletes. LBP can be detrimental to athletic performance and health. Factors predisposing to LBP in athletes remain elusive and require further studies. We investigated whether carriage of a specific genotype and/or allele of vitamin D receptor gene (VDR) FokI polymorphism (rs2228570) was a risk factor for LBP in athletes of different sports disciplines.

Methods
This genotype/phenotype association case-control study included 60 Italian athletes (25 females and 35 males; mean age 33.9 ± 13.3 years; body-mass-index 23.5 ± 3.5 kg/m2) of which 16.7% were swimmers, 11.7% soccer players, 11.7% volleyball players, 10.0% rugby players and other disciplines. VDR-FokI polymorphism was measured by PCR-RFLP in 24 athletes with LBP and 36 athletes without LBP episodes. Absence or presence of the FokI restriction site was denoted “F” and “f”, respectively. Other risk factors were evaluated by a questionnaire.

Results
The homozygous FF genotype was found in 58.3% (14/24) of athletes with LBP versus 27.8% (10/36) of athletes without LBP, adjusted OR = 5.78, 95% CI 1.41–23.8, P = 0.015. The F allele was a 2-fold risk factor to develop LBP, adjusted OR = 2.55, 95% CI 1.02–6.43, P = 0.046, while f allele was protective. Exposure to vehicle vibrations ≥2 h daily, and family history of lumbar spine pathology were significant risk factors for LBP with OR = 3.54, and OR = 9.21, respectively.

Conclusions
This is the first study in which an association between VDR-FokI polymorphism and LBP in athletes was found. Further research is needed to extend our results, and to clarify the biochemical pathways associated with how vitamin D modulates LBP in athletes. The VDR-FokI polymorphism should be considered when developing genetic focused studies of precision medicine on health in athletes.

Keywords

Lumbar pain Exercise Vitamin D receptor Vitamin D receptor gene Vitamin D receptor polymorphism FokI polymorphism Exposure to vibrations Smoking and low back pain Discopathies

[Jo Bowyer]

Genetic contributions to self-reported tiredness

http://www.nature.com/mp/journal/vao.../mp20175a.html

Abstract

Self-reported tiredness and low energy, often called fatigue, are associated with poorer physical and mental health. Twin studies have indicated that this has a heritability between 6 and 50%. In the UK Biobank sample (N=108 976), we carried out a genome-wide association study (GWAS) of responses to the question, ‘Over the last two weeks, how often have you felt tired or had little energy?’ Univariate GCTA-GREML found that the proportion of variance explained by all common single-nucleotide polymorphisms for this tiredness question was 8.4% (s.e.=0.6%). GWAS identified one genome-wide significant hit (Affymetrix id 1:64178756_C_T; P=1.36 × 10−11). Linkage disequilibrium score regression and polygenic profile score analyses were used to test for shared genetic aetiology between tiredness and up to 29 physical and mental health traits from GWAS consortia. Significant genetic correlations were identified between tiredness and body mass index (BMI), C-reactive protein, high-density lipoprotein (HDL) cholesterol, forced expiratory volume, grip strength, HbA1c, longevity, obesity, self-rated health, smoking status, triglycerides, type 2 diabetes, waist–hip ratio, attention deficit hyperactivity disorder, bipolar disorder, major depressive disorder, neuroticism, schizophrenia and verbal-numerical reasoning (absolute rg effect sizes between 0.02 and 0.78). Significant associations were identified between tiredness phenotypic scores and polygenic profile scores for BMI, HDL cholesterol, low-density lipoprotein cholesterol, coronary artery disease, C-reactive protein, HbA1c, height, obesity, smoking status, triglycerides, type 2 diabetes, waist–hip ratio, childhood cognitive ability, neuroticism, bipolar disorder, major depressive disorder and schizophrenia (standardised β’s had absolute values<0.03). These results suggest that tiredness is a partly heritable, heterogeneous and complex phenomenon that is phenotypically and genetically associated with affective, cognitive, personality and physiological processes.

[Jo Bowyer]

Prevalence and associated comorbidities of restless legs syndrome (RLS): Data from a large population-based door-to-door survey on 19176 adults in Tehran, Iran

http://journals.plos.org/plosone/art...l.pone.0172593

Abstract

Background

Discrepancies have been reported in the prevalence rate of restless legs syndrome (RLS) among different ethnic groups and geographic populations. Furthermore, there are disagreements on determinant factors and associated comorbidities of RLS. We aimed to estimate prevalence of RLS and investigate its associated comorbid conditions and risk factors in a large population-based door-to-door survey.

Methods

Following a multistage random sampling from the households lived in 22 urban districts of Tehran, Iran, 19176 participants with ≥30 years of age were recruited. Trained surveyors filled study checklist consisting of baseline characteristics, risk factors and comorbidity profile and the International RLS Study Group (IRLSSG) diagnostic criteria through face-to-face interviews.

Results

In total, 1580 individuals were positively screened for RLS resulting in a standardized prevalence rate of 60.0/1000. There was a gradual increase in RLS prevalence by advancing age, however, sex difference disappeared after adjustment. Parkinsonism [adjusted odds’ ratio (adj-OR) = 7.4 (95% CI: 5.3–10.4)], peripheral neuropathy [adj-OR = 3.7 (95% CI: 3.3–4.1)], subjective cognitive impairment (SCI) [adj-OR = 3.1 (95% CI: 2.7–3.4)], acting out dreams [adj-OR = 2.8 (95% CI: 2.5–3.2)], hyposmia [adj-OR = 2.5 (95% CI: 2.2–2.9)], active smoking [adj-OR = 1.5 (95% CI: 1.3–1.9)] and additional number of cardiometabolic diseases associated with higher risk of RLS [adj-OR = 1.6 (95% CI: 1.2–2.3)].

Conclusion

Our findings showed that neuro-cognitive co-morbidities such as parkinsonism, peripheral neuropathy, SCI, acting out dreams and hyposmia as well as cardio-metabolic risk factors and diseases were independent determinants of RLS. It is recommended to screen individuals with either these comorbid conditions for RLS or the ones with RLS for the accompanying diseases.

Restless legs syndrome and cardiovascular diseases: A case-control study

http://journals.plos.org/plosone/art...l.pone.0176552

Abstract

Objective

The association between restless legs syndrome (RLS), cardiovascular diseases (CVD) and hypertension is inconsistent. This case-control study examined i) the association between primary RLS, CVD and hypertension by taking into account many potential confounders and ii) the influence of RLS duration, severity and treatment, sleep and depressive symptoms on CVD and hypertension in primary RLS.

Methods

A standardized questionnaire to assess the RLS phenotype, history of CVD and hypertension, sleep and depressive symptoms, drug intake and demographic/clinical features was sent to the France-Ekbom Patients Association members. A CVD event was defined as a self-reported history of coronary heart disease, heart failure, arrhythmia or stroke. Hypertension was also self-assessed. Current treatment for hypertension and arrhythmia also defined underlying hypertension and arrhythmia. Controls without RLS and without consanguinity were chosen by the patients.

Results

487 patients with primary RLS (median age 71 years; 67.4% women) and 354 controls (68 years, 47.7% women) were included. Most of the patients (91.7%) were treated for RLS, especially with dopaminergic agonists. The median age of RLS onset was 45 years. CVD and hypertension were associated with RLS in unadjusted association, but not after adjustment for age, sex and body mass index. Patients with RLS and with CVD and/or hypertension were significantly older, with hypercholesterolemia, sleep apnea and older age at RLS and at daily RLS onset compared with patients without CVD and/or hypertension. No significant difference was found for other RLS features, ferritin levels, daytime sleepiness, insomnia and depressive symptoms.

Conclusion

Despite some limitations in the design of this study, we found that most of the treated patients for primary RLS had no association with CVD and hypertension after controlling for key potential confounders. Comorbid CVD or hypertension was associated with cardiovascular risk factors, but not with RLS features except for older age at onset.

Update 27/04/2017




Restless Legs Syndrome: From Pathophysiology to Clinical Diagnosis and Management

http://journal.frontiersin.org/artic...017.00171/full

Restless legs syndrome (RLS), a common neurological sensorimotor disorder in western countries, has gained more and more attention in Asian countries. The prevalence of RLS is higher in older people and females. RLS is most commonly related to iron deficiency, pregnancy and uremia. The RLS symptoms show a significant circadian rhythm and a close relationship to periodic limb movements (PLMs) in clinical observations, while the pathophysiological pathways are still unknown. The diagnostic criteria have been revised in 2012 to improve the validity of RLS diagnosis. Recent studies have suggested an important role of iron decrease of brain in RLS pathophysiology. Dopaminergic (DA) system dysfunction in A11 cell groups has been recognized long ago from clinical treatment and autopsy. Nowadays, it is believed that iron dysfunction can affect DA system from different pathways and opioids have a protective effect on DA system. Several susceptible single nucleotide polymorphisms such as BTBD9 and MEIS1, which are thought to be involved in embryonic neuronal development, have been reported to be associated with RLS. Several pharmacological and non-pharmacological treatment are discussed in this review. First-line treatments of RLS include DA agents and α2δ agonists. Augmentation is very common in long-term treatment of RLS which makes prevention and management of augmentation very important for RLS patients. A combination of different types of medication is effective in preventing and treating augmentation. The knowledge on RLS is still limited, the pathophysiology and better management of RLS remain to be discovered.

Background
The symptoms of the RLS were first described by Willis (1685) and then published by Ekbom (1960). Despite being introduced hundreds of years ago, it’s still a poorly recognized disorder because of the unclear pathophysiology and relatively low morbidity, resulting in limited recognition by primary care physicians and common misdiagnosis and under-diagnosis. RLS is considered as a common neurological sensorimotor disorder that manifests as an irresistible urge to move the body to relieve the uncomfortable sensations. There’s a significant circadian rhythm of the RLS, as it commonly worsens at night.

Update 05/06/2017




Nerve decompression and Restless Legs Syndrome: A retrospective analysis

http://journal.frontiersin.org/artic...00287/abstract

Restless Legs Syndrome (RLS) is a prevalent sleep disorder affecting quality of life, and is often comorbid with other neurological diseases, including peripheral neuropathy. The mechanisms related to RLS symptoms remain unclear, and treatment options are often aimed at symptom relief rather than etiology. RLS may present in distinct phenotypes often described as “primary” vs. “secondary” RLS. Secondary RLS is often associated with peripheral neuropathy.

Nerve decompression surgery of the common and superficial fibular nerves is used to treat peripheral neuropathy. Anecdotally, surgeons sometimes report improved RLS symptoms following nerve decompression for peripheral neuropathy. The purpose of this retrospective analysis was to quantify the change in symptoms commonly associated with RLS using visual analog scales (VAS).

Methods: Forty-two patients completed VAS scales (0-10) for pain, burning, numbness, tingling, weakness, balance, tightness, aching, pulling, cramping, twitchy/jumpy, uneasy, creepy/crawly, and throbbing, both before and 15 weeks after surgical decompression.

Results: Subjects reported significant improvement among all VAS categories except for “pulling” (P = 0.14). The change in VAS following surgery was negatively correlated with the pre-surgery VAS for both the summed VAS (r = -0.58, P < 0.001) and the individual VAS scores (all P < 0.01), such that patients who reported the worst symptoms before surgery exhibited relatively greater reductions in symptoms after surgery.

Conclusion: This is the first study to suggest improvement in RLS symptoms following surgical decompression of the common and superficial fibular nerves. Further investigation is needed to quantify improvement using RLS-specific metrics and sleep quality assessments.

Keywords: Common fibular nerve, Common peroneal nerve, peripheral neuropathy, Willis-Ekbom disease, Nerve entrapment, Surgical Decompression

Hmmm, seems a bit drastic

Update 05/06/2017




Restless Legs Syndrome and Sleep-Wake Disturbances in Pregnancy

http://www.aasmnet.org/jcsm/ViewAbstract.aspx?pid=31045

Study Objectives

To estimate the association of restless legs syndrome (RLS) and its frequency with sleep-wake disturbances in pregnancy.

Methods
A cohort of 1,563 women in their third trimester of pregnancy were recruited from prenatal clinics between March 2007 and December 2010. Demographic, pregnancy, and delivery data were extracted from medical records and sleep information was collected with questionnaires. To diagnose RLS, we used standardized criteria of RLS symptoms and frequency that were developed by the International Restless Legs Study Group. Logistic regression models were constructed to investigate the association of RLS and its frequency with sleep-wake disturbances (poor sleep quality, daytime sleepiness, poor daytime function) and delivery outcomes.

Results
Overall 36% of the pregnant women had RLS, and half had moderate to severe symptoms. Compared to women without RLS, those with RLS were more likely to have poor sleep quality (odds ratio [OR] 2.2, 95% confidence interval [CI] 1.7–2.9), poor daytime function (OR 1.9, 95% CI 1.4–2.4), and excessive daytime sleepiness (OR 1.6, 95% CI 1.3–2.0). A dose-response relationship also was evident between RLS frequency and each of the sleep-wake disturbances. There was no evidence for any association between RLS and delivery outcomes.

Conclusions
RLS is a significant contributor to poor sleep quality, daytime sleepiness, and poor daytime function, all common and often debilitating conditions in pregnancy. Obstetric health care providers should be aware of these associations and screen women for RLS.
Commentary
A commentary on this article appears in this issue on page 857.
Citation

INTRODUCTION

Restless legs syndrome (RLS), also known as Willis-Ekbom disease, is a sensorimotor disorder composed of an urge to move, with or without associated discomfort that occurs with inactivity and improves with movement. It follows a circadian pattern, with a predilection for the evening and night.1 RLS is a common, underdiagnosed condition that affects up to 5% of the population worldwide,2–4 with up to 15% prevalence in Caucasians.5 The prevalence of RLS is positively correlated with age and body mass index (BMI) among both men and women.6,7 Although RLS has a genetic predisposition, it is also associated with other conditions such as end-stage renal disease, neuropathy, and pregnancy.8
RLS affects up to one-third of pregnant women9,10 peaks in the third trimester,9–11 and usually subsides after delivery.11 Multiparous women are affected up to three times more often than nulliparous women.10 The high prevalence of RLS during pregnancy has been attributed to hemodynamic and hormonal changes, iron and folate metabolism, and psychomotor behaviors.12 Although RLS is related to reduced quality of life and poor sleep in the general population13,14 data on RLS-associated maternal sleep-wake disturbances are lacking. Prior reports have linked sleep-wake disturbances to adverse pregnancy and delivery outcomes (eg, preterm delivery, prolonged labor, cesarean section deliveries, and postpartum depression).15–17 Therefore, the goal of this study was twofold: (1) to examine the frequency of RLS in a large, heterogeneous sample of pregnant women using standardized diagnostic criteria for RLS; and (2) to investigate the role of RLS in sleep-wake disturbances (ie, poor sleep quality, excessive daytime sleepiness, and poor daytime function) in addition to key delivery outcomes.

Update 16/07/2017