Researchers at Case Western Reserve University School of Medicine have uncovered the first molecular evidence linking the body’s natural circadian rhythms to sudden cardiac death.
Mukesh K. Jain, MD, Darwin Jeyaraj, MD, and colleagues discovered a genetic factor called Kruppel-like Factor 15—or KLF15—that links the body’s natural clock to the heart’s electrical activity system. Too much or too little KLF15 causes a disruption in the heart’s electrical activity, greatly increasing susceptibility to arrhythmias.
These abnormal heart rhythms, which are the most common cause of sudden cardiac death, occur most frequently in the morning and evening. While scientists have been aware of these patterns in the heart’s electrical stability for years, this discovery provides insight into the biological mechanism behind the variations and suggests therapies that modulate the biological clock could be beneficial in preventing sudden cardiac death. Case Western Reserve University

High blood cholesterol, a serious hereditary disease, is far more common than previously recognised and not treated sufficiently. This is shown in new research from the University of Copenhagen and Herlev Hospital.
A group of scientists from the University of Copenhagen has recently shown that far more Danes than expected suffer from high blood cholesterol. The study also shows that the serious hereditary disease is not treated effectively.
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Dr Børge Nordestgaard, clinical professor at the Faculty of Health and Medical Sciences, University of Copenhagen, and senior physician at Herlev Hospital is surprised at the findings.

‘We have now investigated 69,000 Danes to see how many have hereditary high blood cholesterol and have undergone sufficient treatment for the disease. We can see that out of 137 people in Denmark 1 has hereditary high blood cholesterol. That corresponds to 40,000 people with the disease in the Danish population of 5.5 million,’ states Børge Nordestgaard.
The study also shows that very few families and individuals with this serious disease have been identified and treated effectively with statins, a type of drug for treating high cholesterol. In Holland, by comparison, early detection of patients and their families has almost eliminated the increased risk of coronary disease, because effective treatment to reduce cholesterol levels was implemented quickly.
‘Never before anywhere in the world has the ordinary population been studied to see how many people and families with hereditary high blood cholesterol there actually are. It was previously assumed that only 1 out of every 500 people had it, so it was quite a surprise for us suddenly to find 3 ½ times as many people with this serious disease. At the same time, it was also startling to discover that a disease that can easily be prevented by treatment to reduce blood cholesterol has not been treated sufficiently,’ says Dr. Marianne Benn, senior physician, also from the University of Copenhagen.
Of those Danes shown to have hereditary high blood cholesterol, one-third already had coronary disease, and only half were being treated with statins. People with hereditary high blood cholesterol not undergoing treatment with statins have a 1,200 per cent higher risk of developing coronary disease. Even more surprising: people with hereditary high blood cholesterol who are being treated with statins still have a 900 per cent higher risk of incurring coronary disease. In total, the study documents massive underdiagnosis and undertreatment of these high-risk individuals and their families in Denmark.
Researchers used the internationally recognised Dutch criteria for hereditary high blood cholesterol based on very high blood cholesterol level and early-onset coronary disease in the test person and his/her family, and on the finding of mutations that directly lead to hereditary high blood cholesterol. The increased risks appear even when figures are adjusted for several other factors that also contribute to coronary disease. Researchers use this method to eliminate biased results.
These new figures mean that there are about 50 million people worldwide with hereditary high blood cholesterol. Today most of these people are undiagnosed, untreated and therefore at serious risk of dying early from coronary disease. According to the World Health Organization (WHO), coronary disease is the most common cause of death in adults worldwide. WHO estimates that at least 17 million people die from coronary disease annually. A considerable number of these deaths are due to hereditary high blood cholesterol.
‘We have known for decades about high blood cholesterol and how to prevent it. Nonetheless the disease is massively underdiagnosed and undertreated. This means that many people unnecessarily develop early-onset coronary disease and die far earlier than normal,’ says Børge Nordestgaard. University of Copenhagen

The study, led by King’s College London’s Institute of Psychiatry (IoP) provides the most detailed understanding yet of the brain processes involved in teenage alcohol abuse.
Alcohol and other addictive drugs activate the dopamine system in the brain which is responsible for feelings of pleasure and reward. Recent studies from King’s IoP found that the RASGRF2 gene is a risk gene for alcohol abuse, however, the exact mechanism involved in this process has, until now, remained unknown.
Professor Gunter Schumann, from the Department of Social, Genetic and Developmental Psychiatry (SGDP) at King’s Institute of Psychiatry and lead author of the study says: ‘People seek out situations which fulfill their sense of reward and make them happy, so if your brain is wired to find alcohol rewarding, you will seek it out. We now understand the chain of action: how our genes shape this function in our brains and how that, in turn, leads to human behaviour. We found that the RASGRF-2 gene plays a crucial role in controlling how alcohol stimulates the brain to release dopamine, and hence trigger the feeling of reward. So, if people have a genetic variation of the RASGRF-2 gene, alcohol gives them a stronger sense of reward, making them more likely to be heavy drinkers.’
Approximately 6 out of 10 young people aged 11-15 in England report drinking, a figure which has remained relatively stable over the past 20 years. However, binge drinking has become more common, with teenagers reportedly drinking an average of 6 units per week in 1994 and 13 units per week in 2007. In the UK, around 5,000 teenagers are admitted to hospital every year for alcohol-related reasons. Teenage alcohol abuse is also linked to poor brain development, health problems in later life, risk taking behaviour (drunk driving, unsafe sex) and antisocial behaviour.
The study initially looked at mouse models without the RASGRF2 gene to see how they reacted to alcohol. They found that the absence of the RASGRF-2 gene was linked to a significant reduction in alcohol-seeking activity. Upon intake of alcohol, the absence of the RASGRF-2 impaired the activity of dopamine-releasing neurons in a region of the brain called the ventral tegmental area (VTA) and prevented the brain from releasing dopamine, and hence any sense of reward.
The research team then analysed the brain scans of 663 14 year old boys – who at that age had not been exposed to significant amounts of alcohol. They found that individuals with genetic variations to the RASGRF2 gene had higher activation of the ventral striatum area of the brain (closely linked to the VTA and involved in dopamine release) when anticipating reward in a cognitive task. This suggests that individuals with a genetic variation on the RASGRF-2 gene release more dopamine when anticipating a reward, and hence derive more pleasure from the experience.
To confirm these findings, the researchers analysed drinking behaviour from the same group of boys at 16 years old, when many had already begun drinking frequently. They found that individuals with the variation on the RASGRF-2 gene drank more frequently at the age of 16 than those with no variation on the gene.
Professor Schumann concludes: ‘Identifying risk factors for early alcohol abuse is important in designing prevention and treatment interventions for alcohol addiction.’ King’s College London

Researchers have identified 38 new genetic regions that are associated with glucose and insulin levels in the blood. This brings the total number of genetic regions associated with glucose and insulin levels to 53, over half of which are associated with type 2 diabetes.
The researchers used a technology that is 100 times more powerful than previous techniques used to follow-up on genome-wide association results. This technology, Metabochip, was designed as a cost-effective way to find and map genomic regions for a range of cardiovascular and metabolic characteristics on a large scale. Previous approaches were not cost effective and tested only 30-40 DNA sequence variations, but this chip allowed researchers to look at up to 200,000 DNA sequence variations for many different traits at one time. The team hoped to find new variants influencing blood glucose and insulin traits and to identify pathways involved in the regulation of insulin and glucose levels.
‘We wanted to use this improved Metabochip technology to see whether we could find additional genomic associations that may have been previously missed,’ says Dr Claudia Langenberg, co-lead author from the Medical Research Council Epidemiology Unit, Cambridge. ‘Our earlier work identified 23 genetic regions associated with blood glucose levels, highlighting important biological pathways involved in the regulation of glucose. At that stage, and before the design of the Metabochip, we were still limited by our capacity to quickly follow-up and afford parallel genotyping of promising, but unconfirmed genetic regions associated with glucose levels in many different studies across the world.’
The team combined data from new samples typed on the Metabochip with data from a previous study to discover genetic regions associated with blood glucose and insulin levels. They identified 38 previously unknown regions for three different quantitative traits associated with blood glucose levels; fasting glucose concentrations, fasting insulin concentrations and post-challenge glucose concentrations.
.’ Further analysis such as genetic mapping or ‘fine-mapping’ and functional analysis will expand and improve our understanding of the control of glucose and insulin levels in healthy persons and what goes wrong in type 2 diabetes patients. ‘
…’Our research is beginning to allow us to look at the overlap between genomic regions that influence insulin levels and other metabolic traits,’ says Dr Inga Prokopenko, co-lead author from the University of Oxford. ‘We observed some overlap between the regions we identified and genetic regions associated with abdominal obesity and various lipid levels, which are a hallmark of insulin resistance. We hope that these studies will help to find gene networks with potential key modifiers for important metabolic processes and related diseases, such as type 2 diabetes.’
The team also found many more, less significant, genetic regions that may be associated with blood glucose and insulin levels but currently don’t have the available data to definitively establish them as genome-wide significant. This supports previous evidence that there is a long tail of many other genetic regions that add up to quite small genetic effects but may increase the risk of such diseases as diabetes. Collectively, these less significant associations may represent important blood glucose and insulin level associations.
‘In addition to these top signals there is statistical evidence that many other regions that appear to be biologically plausible also influence these traits, but what’s limiting is that we don’t have large enough sample sizes to have the power to validate them,’ explains Dr Inês Barroso, co-lead author from the Wellcome Trust Sanger Institute. ‘Nevertheless, studying these functionally would be extremely beneficial if we want to fully understand the biology of blood glucose levels and the origin of diabetes.’
‘What we’ve found in this study is a number of genomic regions that influence blood glucose and insulin traits. Further analysis such as genetic mapping or ‘fine-mapping’ and functional analysis will expand and improve our understanding of the control of glucose and insulin levels in healthy persons and what goes wrong in type 2 diabetes patients.’ Wellcome Trust Sanger Institute

Neuroscientists studying the link between poor sleep and schizophrenia have found that irregular sleep patterns and desynchronised brain activity during sleep could trigger some of the disease’s symptoms. The findings suggest that these prolonged disturbances might be a cause and not just a consequence of the disorder’s debilitating effects.
The possible link between poor sleep and schizophrenia prompted the research team, led by scientists from the University of Bristol, the Lilly Centre for Cognitive Neuroscience and funded by the Medical Research Council (MRC), to explore the impact of irregular sleep patterns on the brain by recording electrical brain activity in multiple brain regions during sleep.
For many people, sleep deprivation can affect mood, concentration and stress levels. In extreme cases, prolonged sleep deprivation can induce hallucinations, memory loss and confusion all of which are also symptoms associated with schizophrenia.
Dr Ullrich Bartsch, one of the study’s researchers, said: ‘Sleep disturbances are well-documented in the disease, though often regarded as side effects and poorly understood in terms of their potential to actually trigger its symptoms.’
Using a rat model of the disease, the team’s recordings showed de-synchronisation of the waves of activity which normally travel from the front to the back of the brain during deep sleep. In particular the information flow between the hippocampus — involved in memory formation, and the frontal cortex — involved in decision-making, appeared to be disrupted. The team’s findings reported distinct irregular sleep patterns very similar to those observed in schizophrenia patients.
Dr Matt Jones, the lead researcher from the University’s School of Physiology and Pharmacology, added: ‘Decoupling of brain regions involved in memory formation and decision-making during wakefulness are already implicated in schizophrenia, but de-coupling during sleep provides a new mechanistic explanation for the cognitive deficits observed in both the animal model and patients: sleep disturbances might be a cause, not just a consequence of schizophrenia. In fact, abnormal sleep patterns may trigger abnormal brain activity in a range of conditions.’
Cognitive deficits — reduced short term memory and attention span, are typically resistant to medication in patients. The findings from this study provide new angles for neurocognitive therapy in schizophrenia and related psychiatric diseases. Bristol University