Researchers at King’s College London have identified a genetic variant associated with an increased risk of stroke and heart attack.

Stroke and heart attack are caused when arteries, already clogged up by fatty substances (a condition known as atherosclerosis), become completely blocked by the formation of a blood clot. Risk factors for this include smoking, high blood pressure and high cholesterol.

The findings suggest a new genetic link caused by a variation in a protein known as ‘glycoprotein IIIa’. This genetic variant is found in platelets, a type of blood cell involved in the formation of blood clots.

These findings may, in future, allow clinicians to identify patients who are at particularly high risk of stroke or heart attack by looking for the genetic variant. This would represent advancement on current practice, which mainly addresses risk factors such as smoking and high blood pressure.

Previous findings surrounding this genetic variant have been inconsistent and the study at King’s represents the first large-scale meta-analysis of the literature, including over 50,000 participants from a combined total of 82 studies.

In the UK over 150,000 people have a stroke every year. Stroke is the third largest cause of death after heart disease and cancer. A stroke occurs when blood supply to part of the brain is cut off, leading to damage of brain cells. There are around 103,000 heart attacks in the UK each year, caused by blockage of a coronary artery that supplies blood to the heart and resulting in damage to heart muscles.

In the first research paper, which examined stroke patients, researchers found that carrying the PlA2 genetic variant of glycoprotein IIIa was associated with an increased risk of thrombotic stroke – that is, stroke caused by a blood clot. This equated to a higher risk of around 10-15 per cent, which was even stronger (amounting to a 70 per cent increase in risk) in people who carried two copies of this gene variant. The variant was not associated with haemorrhagic stroke, which is caused by bleeding into the brain.

The second research paper found that the same genetic variant was also associated with an increased risk of heart attack. This link was stronger in younger than in older patients, which is likely to reflect the greater influence of other cardiovascular risk factors in older patients (such as smoking and high cholesterol), according to the researchers.

Albert Ferro, Professor of Cardiovascular Clinical Pharmacology at King’s College London, said: ‘The genetic risk found in stroke and heart attack patients is likely to be caused by over-active platelets. Under normal circumstances, platelets help your body form clots to stop bleeding, but in these patients platelet activation has the undesired effect of causing their narrowed arteries to be blocked off completely. In future it may be possible to reduce the chances of this happening by examining patients for this variant on a blood test, so that if they carry the PlA2 form – and especially if they carry two copies of it – such patients could be identified for a more determined reduction of risk factors such as smoking, high blood pressure or high cholesterol.’ King’s College London

Researchers from Dana-Farber Cancer Institute, the Broad Institute of MIT and Harvard, and other centres have identified novel mutations in a well-known cancer-causing pathway in lung adenocarcinoma, the most common subtype of lung cancer. Knowledge of these mutations could potentially identify a greater number of patients with treatable mutations because many potent cancer drugs that target these mutations already exist. In addition, these findings may expand the number of possible new therapeutic targets for this disease.

In this new study researchers from the Cancer Genome Atlas (TCGA) Research Network, led by Dana-Farber scientist Matthew Meyerson, MD, PhD, examined the genomes, RNA, and some protein from 230 lung adenocarcinoma samples. In three-quarters of the samples, the scientists ultimately identified mutations that put a cell-signalling pathway known as the RTK/RAS/RAF pathway into overdrive.

“Lung adenocarcinoma is the leading cause of human cancer death. This is because there are so many ways to develop the disease, and many different pathways are altered in this cancer,” said Meyerson, who is also a Broad senior associate member. “In recent years, we have made enormous progress in lung adenocarcinoma treatment by targeting EGFR, ALK, and other mutated proteins. Through this study, we are able to add to the range of such alterations and therefore gain potential new therapeutic targets.”

Mutations affecting the RTK/RAS/RAF pathway can cause it to become stuck in the “on” state. As a result, signals that promote cancer cell proliferation and survival are produced continuously. However, drugs are currently available that curb aberrant activity of this pathway and prompt therapeutic responses in patients.

“About 10% of patients have tumours with EGFR mutations, and these patients uniquely benefit from anti-EGFR therapy,” said Alice Berger, a post-doctoral fellow in the Meyerson lab and co-author of the study. “We were motivated to find genetic aberrations in patients that lack EGFR mutations and that might be similarly suitable for therapeutic targeting. Ultimately, we want to be able to provide every patient with an effective drug for their specific cancer.”

In the group’s initial scan of the tumour samples, researchers identified gene mutations that would increase RTK/RAS/RAF pathway activity in 62 percent of the samples. The affected genes are oncogenes, or genes that have the potential to cause cancer when mutated or expressed at high levels. Consequently, these tumour samples were classified as oncogene-positive. To identify additional alterations, the investigators looked at DNA copy number changes, or changes in gene number resulting from the deletion or amplification (multiplication) of sections of DNA in the genome. In doing so, they detected amplification of two oncogenes, ERBB2 and MET, which are part of the RTK/RAS/RAF pathway in the “oncogene negative” cancers. Gene amplification usually leads to increased expression of the encoded protein in cells.

Now that these amplifications have been identified in cancers without other activity of the RTK/RAS/RAF pathway, clinicians may be able to treat patients whose tumours have specific gene changes with drugs that are either currently available or under development.

“It is quite striking that we have now identified an actionable mutation in over 75 percent of patients with lung adenocarcinoma, a significant improvement from a decade ago,” said Meyerson.

Additional analysis identified other genes that may play important roles in lung cancer development. Mutations in one of these genes, NF1 — a known tumour suppressor gene that regulates the RTK/RAS/RAF pathway — had previously been reported in lung cancer. Mutations of NF1 also put that pathway into overdrive. Another mutated gene, RIT1, is also part of the RTK/RAS/RAF pathway, and this is the first study to associate mutation of this gene with lung cancer. Dana-Farber Institute

Genetics could be the key to explaining nation’s levels of happiness, according to research from the University of Warwick.

Economists at the University’s Centre for Competitive Advantage in the Global Economy (CAGE) have looked at why certain countries top the world happiness rankings. In particular they have found the closer a nation is to the genetic makeup of Denmark, the happier that country is. The research could help to solve the puzzle of why a country like Denmark so regularly tops the world happiness rankings.

Dr Eugenio Proto and Professor Andrew Oswald found three forms of evidence for a link between genetic makeup and a nation’s happiness.

Firstly they used data on 131 countries from a number of international surveys including the Gallup World Poll, World Value Survey and the European Quality of Life Surveys. The researchers linked cross-national data on genetic distance and well-being.

Dr Proto said: “The results were surprising, we found that the greater a nation’s genetic distance from Denmark, the lower the reported wellbeing of that nation. Our research adjusts for many other influences including Gross Domestic Product, culture, religion and the strength of the welfare state and geography.

The second form of evidence looked at existing research suggesting an association between mental wellbeing and a mutation of the gene that influences the reuptake of serotonin, which is believed to be linked to human mood.

Dr Proto added: “We looked at existing research which suggested that the long and short variants of this gene are correlated with different probabilities of clinical depression, although this link is still highly debated. The short version has been associated with higher scores on neuroticism and lower life satisfaction. Intriguingly, among the 30 nations included in the study, it is Denmark and the Netherlands that appear to have the lowest percentage of people with this short version.”

The final form of evidence looked at whether the link between genetics and happiness also held true across generations, continents and the Atlantic Ocean.

Professor Oswald said: “We used data on the reported wellbeing of Americans and then looked at which part of the world their ancestors had come from. The evidence revealed that there is an unexplained positive correlation between the happiness today of some nations and the observed happiness of Americans whose ancestors came from these nations, even after controlling for personal income and religion.” University of Warwick

University of Delaware researchers have identified a protein, hiding in plain sight, that acts like a bodyguard to help protect and stabilize another key protein, that when unstable, is involved in Crohn’s disease. The fundamental research points to a possible pathway for developing an effective therapy for the inflammatory bowel disease.

The research was conducted by Catherine Leimkuhler Grimes, assistant professor of chemistry and biochemistry at UD, and Vishnu Mohanan, doctoral student in biological sciences,

As the scientists point out, our immune system provides the first line of defence against invading pathogens, a task even more challenging in the human gut, where over a trillion commensal bacteria live — resident microorganisms that help convert food into protein, vitamins and minerals.

To distinguish “bad” versus “good” bacteria, our bodies rely on a complex network of receptors that can sense patterns that are unique to bacteria, such as small fragments of bacterial cell wall. The receptors recognize and bind to these fragments, triggering an immune response to take out the “bad guys” or control the growth of the “good guys.”

However, when one of these receptors breaks down, or mutates, an abnormal immune response can occur, causing the body to mount an immune response against the “good” bacteria. Chronic inflammatory disorders, such as Crohn’s disease, are hypothesized to arise as a result.

The UD team focused on a protein called NOD2 — nucleotide-binding oligomerisation domain containing protein 2. More than 58 mutations in the NOD2 gene have been linked with various diseases, and 80 percent of these mutations are connected specifically to Crohn’s disease, according to Grimes.

In experiments to unveil NOD2’s signalling mechanisms and where they break down, “we stumbled on this chaperone molecule,” says Mohanan, who was the lead author of the scientific article.

The chaperone molecule was HSP70, which stands for “heat shock protein 70.” It assists with the folding of proteins into their correct three-dimensional shapes, even when cells are under stress from elevated body temperatures, such as a fever.

Grimes said she was a little sceptical at first about pursuing studies with HSP70 because it is a commonly known protein, but she found Mohanan’s initial data intriguing.

“Vishnu found that if we increased the expression level of HSP70, the NOD2 Crohn’s mutants were able to respond to bacterial cell wall fragments. A hallmark of the NOD2 mutations is inability to respond to these fragments. Essentially, Vishnu found a fix for NOD2, and we wanted to determine how we were fixing it.”

In further experiments, Mohanan created a tagged-wild-type NOD2 cell line in which NOD2 levels nearly matched the levels found in nature (versus “super” levels that might stimulate an artificial response) and found that NOD2 became more stabilized and degraded more slowly when treated with HSP70. In fact, HSP70 increased the half-life of NOD2 by more than four hours.

“Basically, HSP70 keeps the protein around — it kind of watches over and protects NOD2, and keeps it from going in the cellular trash can,” Grimes explains.

The researchers tested three human cell lines in their study: kidney cells, colon cells and white blood cells. In the next phase of the study, patient tissue will be examined through a collaboration with Nemours/A.I. duPont Hospital for Children to determine if NOD2 levels can be controlled via HSP70 expression.

“We want to figure out why the mutation in NOD2 results in an increase in inflammation,” says Mohanan. “Right now, we have limited knowledge. Once the signalling mechanism is figured out, we will have the keystone.” University of Delaware

Dysfunction in dopamine signalling profoundly changes the activity level of about 2,000 genes in the brain’s prefrontal cortex and may be an underlying cause of certain complex neuropsychiatric disorders, such as schizophrenia, according to UC Irvine scientists.

This epigenetic alteration of gene activity in brain cells that receive this neurotransmitter showed for the first time that dopamine deficiencies can affect a variety of behavioural and physiological functions regulated in the prefrontal cortex.

The study was led by Emiliana Borrelli, a UCI professor of microbiology & molecular genetics.

“Our work presents new leads to understanding neuropsychiatric disorders,” Borrelli said. “Genes previously linked to schizophrenia seem to be dependent on the controlled release of dopamine at specific locations in the brain. Interestingly, this study shows that altered dopamine levels can modify gene activity through epigenetic mechanisms despite the absence of genetic mutations of the DNA.”

Dopamine is a neurotransmitter that acts within certain brain circuitries to help manage functions ranging from movement to emotion. Changes in the dopaminergic system are correlated with cognitive, motor, hormonal and emotional impairment. Excesses in dopamine signalling, for example, have been identified as a trigger for neuropsychiatric disorder symptoms.

Borrelli and her team wanted to understand what would happen if dopamine signalling was hindered. To do this, they used mice that lacked dopamine receptors in midbrain neurons, which radically affected regulated dopamine synthesis and release.

The researchers discovered that this receptor mutation profoundly altered gene expression in neurons receiving dopamine at distal sites in the brain, specifically in the prefrontal cortex. Borrelli said they observed a remarkable decrease in expression levels of some 2,000 genes in this area, coupled with a widespread increase in modifications of basic DNA proteins called histones – particularly those associated with reduced gene activity.

Borrelli further noted that the dopamine receptor-induced reprogramming led to psychotic-like behaviours in the mutant mice and that prolonged treatment with a dopamine activator restored regular signalling, pointing to one possible therapeutic approach. University of California, Irvine