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

Influenza infection can enhance the ability of the bacterium Streptococcus pneumoniae to cause ear and throat infections, according to new research

 In the study, the investigators infected mice with either influenza alone, pneumococci alone, or both at once, and then monitored the populations of bacteria and virus over time. They also monitored the mice for development of middle ear infection.

Influenza infection enhanced the bacterium’s ability to colonize the nasopharynx, and to infect the normally sterile middle ear.

 “We learned that once influenza virus is introduced, all of the “rules” regarding phase variants are out the window,” says corresponding author W. Edward Swords of Wake Forest University, Winston-Salem, NC. Phase variation refers to the fact that the colonizing bacteria have transparent cell surfaces, while those that spread within the host have opaque surfaces.

 “However, in the presence of influenza, opaque variants can readily colonize the nasopharynx, and transparent variants can persist in the ear,” says Swords. “This indicates that the host environs are more permissive for infection by the entire bacterial population.”

 Furthermore, recent research had shown that influenza interferes with innate immunity in a way that enables pneumococci to flourish. In this research, Swords shows that that interference manifests as increased inflammatory responses at the mucosal surface in the influenza-infected mice, such as within the middle ear, and in the nasopharynx.

“As with most pneumococcal infections, it should be appreciated that localized nonlethal infections are much more common than the rapidly lethal presentations,” says Swords. “For example, influenza is a contributing factor in otitis media (middle ear infections) in children.”

 “If we can understand why and how viral infection causes bacteria to colonize privileged sites like the middle ear, we will better know what aspects of disease to focus on with preventive or therapeutic treatments,” says Swords. American Society for Microbiology

An Ottawa-led team of researchers describe the role of a specific gene, called Snf2h, in the development of the cerebellum. Snf2h is required for the proper development of a healthy cerebellum, a master control centre in the brain for balance, fine motor control and complex physical movements.

Athletes and artists perform their extraordinary feats relying on the cerebellum. As well, the cerebellum is critical for the everyday tasks and activities that we perform, such as walking, eating and driving a car. By removing Snf2h, researchers found that the cerebellum was smaller than normal, and balance and refined movements were compromised.

Led by Dr. David Picketts, a senior scientist at the Ottawa Hospital Research Institute and professor in the Faculty of Medicine at the University of Ottawa, the team describes the Snf2h gene, which is found in our brain’s neural stem cells and functions as a master regulator. When they removed this gene early on in a mouse’s development, its cerebellum only grew to one-third the normal size. It also had difficulty walking, balancing and coordinating its movements, something called cerebellar ataxia that is a component of many neurodegenerative diseases.

‘As these cerebellar stem cells divide, on their journey toward becoming specialized neurons, this master gene is responsible for deciding which genes are turned on and which genes are packed tightly away,’ said Dr. Picketts. ‘Without Snf2h there to keep things organized, genes that should be packed away are left turned on, while other genes are not properly activated. This disorganization within the cell’s nucleus results in a neuron that doesn’t perform very well—like a car running on five cylinders instead of six.’

The cerebellum contains roughly half the neurons found in the brain. It also develops in response to external stimuli. So, as we practice tasks, certain genes or groups of genes are turned on and off, which strengthens these circuits and helps to stabilize or perfect the task being undertaken. The researchers found that the Snf2h gene orchestrates this complex and ongoing process. These master genes, which adapt to external cues to adjust the genes they turn on and off, are known as epigenetic regulators.

‘These epigenetic regulators are known to affect memory, behaviour and learning,’ said Dr. Picketts. ‘Without Snf2h, not enough cerebellar neurons are produced, and the ones that are produced do not respond and adapt as well to external signals. They also show a progressively disorganized gene expression profile that results in cerebellar ataxia and the premature death of the animal.’

There are no studies showing a direct link between Snf2h mutations and diseases with cerebellar ataxia, but Dr. Picketts added that it ‘is certainly possible and an interesting avenue to explore.’

In 2012, Developmental Cell published a paper by Dr. Picketts’ team showing that mice lacking the sister gene Snf2l were completely normal, but had larger brains, more cells in all areas of the brain and more actively dividing brain stem cells. The balance between Snf2l and Snf2h gene activity is necessary for controlling brain size and for establishing the proper gene expression profiles that underlie the function of neurons in different regions, including the cerebellum. Ottawa Hospital Research Institute

Two new potential therapeutic targets for the treatment of pulmonary arterial hypertension, a deadly disease marked by high blood pressure in the lungs, have been identified by researchers at the University of Illinois at Chicago.

Early symptoms of pulmonary arterial hypertension include shortness of breath and exercise intolerance. As the disease progresses, patients may require oxygen supplementation and lung transplantation. Heart failure can develop and is a major cause of death in the disease.

Most cases of pulmonary hypertension are of unknown cause, though the condition often occurs in association with other diseases, including scleroderma, congenital heart disease and liver disease. One of the underlying factors driving the increased blood pressure in the lungs is a narrowing of the pulmonary blood vessels. This narrowing can be due to an abnormal proliferation of cells within the walls of the blood vessels, particularly in the smooth muscle cells of the pulmonary artery.

Jiwang Chen, research assistant professor of critical care medicine, sleep and allergy in the UIC College of Medicine, and his colleagues investigated the molecular mechanisms behind the abnormal proliferation of smooth muscle cells in the pulmonary artery and discovered two ways that the proliferation could be suppressed.

They knew that an enzyme, sphingosine kinase 1, that produces a signalling molecule called sphingosine-1-phosphate (S1P), had been linked to the abnormal growth of cells in cancer, including lung cancer.
“The characteristic proliferation of cells that line the blood vessels in pulmonary hypertension is similar to the abnormal growth and reproduction of cells that form cancerous tumours,” says Chen. “We wanted to see if sphingosine kinase 1 and S1P were involved in the development of pulmonary arterial hypertension.”
Looking at samples of lung tissue from patients, Chen and colleagues found that patients with pulmonary arterial hypertension had significantly elevated levels of both the enzyme and the signalling molecule it produces. They found similarly elevated levels of both molecules in mouse and rat models of pulmonary hypertension.

Knockout mice lacking the gene for sphingosine kinase 1 were less likely than normal mice to develop pulmonary hypertension when exposed to the low-oxygen conditions used to induce the disease in the laboratory.

Drugs that either suppress production of sphingosine kinase 1 or block the signalling of S1P through its receptors on smooth muscle cells prevented mice from developing pulmonary hypertension in low-oxygen conditions.

The researchers also showed in mice that over-production of sphingosine kinase 1 and S1P promote the proliferation of pulmonary artery smooth muscle cells.
“Our results yield two new potential targets for the development of drugs to treat or prevent the progression of pulmonary arterial hypertension,” Chen said.
“By blocking the binding site for S1P or suppressing the production of S1P, like we did in our experimental rodent model, we can reduce the proliferation of pulmonary artery smooth muscle cells, which is a major contributor to pulmonary hypertension.” University of Illinois at Chicago