Category: Genetics

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New Gene Variants Significantly Increase the Risk of Blood Clots

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Thrombophilia. Credit: Scientific Animations CC4.0.

Though blood clots can form in both arteries and veins, the reasons behind them differ, as do the consequences and the chances of preventing blood clots. In Sweden, almost half of all cases of venous thrombosis have a genetic explanation. A team of researchers from Lund University in Sweden has now discovered three gene variants that increase the risk of blood clots in the leg by up to 180%.

There is a difference between arterial and venous blood clots. Blood clots in the arteries form when plaque in calcified vessels bursts and the body perceives it as an injury. This activates the platelets, which clump together and form a clot. In the worst case, it can lead to a stroke or heart attack. A venous thrombus, on the other hand, usually forms in the leg when the blood stagnates for too long. This can activate the body’s coagulation system, allowing the clotting system to be activated and the blood to clot, blocking blood flow. If the clot breaks loose and travels with the blood to the lungs, it can lead to pulmonary embolism, a life-threatening condition.

“Venous thrombosis is in fact one of the most common causes of death in the world. It is a common disease that has always been somewhat overshadowed by arterial blood clots,” says Bengt Zöller, a specialist in general medicine at Skåne University Hospital and professor of general medicine at Lund University.

In Sweden, more than 10 000 people suffer from venous thromboembolism each year and that number appears to be increasing. Several factors are contributing to this increase. One of the strongest risk factors is age, and as the number of older people in Sweden grows, the number of clots is also increasing. Ten per cent of 80-year-olds experience a blood clot at some point. The risk also increases if you are overweight or tall.

“The muscles control the blood flow in the veins and the legs become like columns of fluid where the force of gravity is strong. Too much sedentary and inactive behaviour, then, is harmful. Only the valves of the veins prevent backflow and if these are damaged, the risk of blood clots can increase. Therefore, tall people are more prone to blood clots, as their larger veins provide less blood flow, combined with the fact that blood must travel a greater distance back to the heart.”

Because the heart pumps blood out into the arteries, there is much higher blood pressure in the arteries than in the veins, which can contribute to atherosclerosis. High blood pressure, high levels of blood lipids and smoking are all risk factors for atherosclerosis of the arteries. But because the veins are a low-pressure system, the vessels do not become atherosclerotic. Therefore, neither high blood pressure nor blood lipids are associated with venous clots and smoking is considered only a weak to moderate risk factor. Being overweight, on the other hand, is a very significant culprit. Obesity has a negative impact on venous circulation, especially when combined with the fact that overweight people are often less active. Some clotting factors are also affected by obesity.

“In terms of diet, there are fewer studies, but ultra-processed foods have been associated with a slightly increased risk of blood clots, and plant-based, healthy foods with a reduced risk. In our studies, we have also seen that commercial fishermen have a lower risk, which may be due to a higher omega-3 content in their diet.”

There are also specific situations in which the risk of venous blood clots is particularly high. The risk of blood clots increases when blood flow is reduced, such as when travelling by air for long periods of time or when lying in bed for several days. Surgery or inflammation that damages the vessel wall can also lead to an increased tendency to clot. Particularly during pregnancy, blood clotting factors increase and levels of some protective proteins may decrease.

“In these risk situations, prophylaxis in the form of blood thinners may be particularly important if other risk factors are also present.”

Other risk factors are the genetic variants that affect different parts of the blood’s clotting ability. In Sweden, we have a high prevalence of APC (activated protein C) resistance due to an inherited mutation in the gene for coagulation factor V, called Factor V Leiden. About 10 per cent of Swedes have this mutation, which is considered the most common coagulation mutation among Indo-Europeans.

“Evolutionarily, bleeding less has been an advantage, but in our modern, sedentary society, APC resistance is becoming a risk factor.”

Bengt Zöller and his fellow researchers have now identified the strongest genetic risk factor since Factor V Leiden was discovered. They used data from the population-based Malmö Kost Cancer study, involving 30,000 Malmö residents. By selecting 27 genes previously associated with clotting disorders, they found three variants that, when taken together, were as significant a risk factor for venous blood clots as Factor V Leiden: ABO, F8, and VWF each increased the risk of venous blood clots by 10 to 30 percent.

“And the more of these variants a person has – the higher the risk. An individual with five of these gene variants has a 180 per cent higher risk of venous thrombosis. Unlike Factor V Leiden, which is only found in Indo-Europeans, these three different mutations are found in between five and fifty per cent of various populations around the globe.”

As these genetic variants are present in all populations, the next step is to investigate how the number of risk genes affects the duration of treatment with anticoagulants after a blood clot.

“I think tailoring treatment based on risk assessment will become increasingly important,” concludes Bengt Zöller.

The study results were published in Research and Practice in Thrombosis and Haemostasis.

Source: Lund University

Categories : GeneticsTags : Leave a comment

Massive US Study Finds that ‘Race’ is a Poor Proxy for Genetic Ancestry

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Genetic ancestry is much more complicated than how people report their race and ethnicity. New research, using data from the National Institutes of Health’s (NIH) All of Us Research Program, finds that people who identify as being from the same race or ethnic group can have a wide range of genetic differences. The findings are reported June 5 in the American Journal of Human Genetics.

As doctors and researchers learn more about how genetic variants influence the incidence and course of human diseases, the study of genetic ancestry has become increasingly important. This research is driving the field of precision medicine, which aims to develop individualized healthcare.

People whose ancestors came from the same part of the world are likely to have inherited the same genetic variants, but self-identified race and ethnicity don’t tell the whole story about a person’s ancestors. NIH’s All of Us Research Program was created in part to address this puzzle and to learn more about how genetic ancestry influences human health.

In the current study, the investigators looked at the DNA of more than 230 000 people who have volunteered to share their health information for All of Us. They compared it to other large DNA projects from around the world using a technique called principal component analysis (PCA) to visualise population structure and help identify genetic similarity between individuals and groups of people. This analysis showed that people in the US have very mixed ancestry, and their DNA doesn’t always match the race or ethnicity they write on forms. Instead of falling into clear groups based on race or ethnicity, people’s genetic backgrounds show gradients of variation across different US regions and states.

This is especially significant for people who identify as being of Hispanic or Latino origin. These people have a wide-ranging blend of ancestries from European, Native American, and African groups. Importantly, genetic ancestry among these people varies across the US in part because of historic migration patterns. For example, Hispanics/Latinos in the Northeast are more likely to have Caribbean (and thus African) ancestry, and those in the Southwest are more likely to have Mexican and Central American (and thus Native American) ancestry.

One specific discovery was that ancestry was significantly associated with body mass index (BMI) and height, even after adjusting for socio-economic differences. For example, West and Central African ancestries were associated with higher BMI, whereas East Africa ancestry was associated with lower BMI. There were similar findings showing that people with ancestral origins from different parts of Europe have different body measurements including height, with northern European ancestry associated with greater height and southern European ancestry associated with shorter height. This suggests that subcontinental differences in ancestry can have opposite effects on biological traits and diseases.

This finding suggests that the subcontinental differences in ancestry between individuals can have opposite effects on biological traits, diseases, and health outcomes, emphasising the importance of not classifying individuals into broad ancestry groups such as African, European, or Asian. Doing this will help to make this research more accurate and will help to improve the field of precision medicine.

Source: Cell Press via EurekAlert!

Categories : Genetics Neurodegenerative DiseasesTags :

Common Gene Variant Doubles Dementia Risk for Men

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New research has found that men who carry a common genetic variant are twice as likely to develop dementia in their lifetime compared to women. The research, published in Neurology, used data from the ASPirin in Reducing Events in the Elderly (ASPREE) trial to investigate whether people who had variants in the haemochromatosis (HFE) gene, which is critical for regulating iron levels in the body, might be at increased risk of dementia.

Co-author Professor John Olynyk, from the Curtin Medical School, said one in three people carry one copy of the variant, known as H63D, while one in 36 carry two copies.

“Having just one copy of this gene variant does not impact someone’s health or increase their risk of dementia. However, having two copies of the variant more than doubled the risk of dementia in men, but not women,” Professor Olynyk said.

“While the genetic variant itself cannot be changed, the brain pathways which it affects – leading to the damage that causes dementia – could potentially be treated if we understood more about it.”

Professor Olynyk said further research was needed to investigate why this genetic variant increased the risk of dementia for males but not females.

“The HFE gene is routinely tested for in most Western countries including Australia when assessing people for haemochromatosis – a disorder that causes the body to absorb too much iron. Our findings suggest that perhaps this testing could be offered to men more broadly,” Professor Olynyk said.

“While the HFE gene is critical for controlling iron levels in the body, we found no direct link between iron levels in the blood and increased dementia risk in affected men.

“This points to other mechanisms at play, possibly involving the increased risk of brain injury from inflammation and cell damage in the body.”

The ASPREE trial was a double-blind, randomised, placebo-controlled trial of daily low-aspirin in 19 114 healthy older people in Australia and the USA. Primarily undertaken to evaluate the risks versus benefits of daily low-dose aspirin in this cohort, it created a treasure trove of healthy ageing data that has underpinned a wealth of research studies.

Source: Curtin University

Categories : Diseases, Syndromes and Conditions GeneticsTags :

Baby with Rare, Incurable Disease is First to Receive Personalised Gene Therapy

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NIH-supported gene-editing platform lays groundwork to rapidly develop treatments for other rare genetic diseases.

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A research team supported by the National Institutes of Health (NIH) has developed and safely delivered a personalised gene editing therapy to treat an infant with a life-threatening, incurable genetic disease. The infant, who was diagnosed with the rare condition carbamoyl phosphate synthetase 1 (CPS1) deficiency shortly after birth, has responded positively to the treatment.

The process, from diagnosis to treatment, took only six months and marks the first time the technology has been successfully deployed to treat a human patient. The technology used in this study was developed using a platform that could be tweaked to treat a wide range of genetic disorders and opens the possibility of creating personalised treatments in other parts of the body.

A team of researchers at the Children’s Hospital of Philadelphia (CHOP) and the Perelman School of Medicine at the University of Pennsylvania (Penn) developed the customised therapy using the gene-editing platform CRISPR. They corrected a specific gene mutation in the baby’s liver cells that led to the disorder. CRISPR is an advanced gene editing technology that enables precise changes to DNA inside living cells. This is the first known case of a personalised CRISPR-based medicine administered to a single patient and was carefully designed to target non-reproductive cells so changes would only affect the patient.

“As a platform, gene editing – built on reusable components and rapid customisation – promises a new era of precision medicine for hundreds of rare diseases, bringing life-changing therapies to patients when timing matters most: Early, fast, and tailored to the individual,” said Joni L. Rutter, Ph.D., director of NIH’s National Center for Advancing Translational Sciences (NCATS).

CPS1 deficiency is characterized by an inability to fully break down byproducts from protein metabolism in the liver, causing ammonia to build up to toxic levels in the body. It can cause severe damage to the brain and liver. Treatment includes a low protein diet until the child is old enough for a liver transplant. However, in this waiting period there is a risk of rapid organ failure due to stressors such as infection, trauma, or dehydration. High levels of ammonia can cause coma, brain swelling, and may be fatal or cause permanent brain damage.

The child initially received a very low dose of the therapy at six months of age, then a higher dose later. The research team saw signs that the therapy was effective almost from the start. The six-month old began taking in more protein in the diet, and the care team could reduce the medicine needed to keep ammonia levels low in the body. Another telling sign of the child’s improvement to date came after the child caught a cold, and later, had to deal with a gastrointestinal illness. Normally, such infections for a child in this condition could be extremely dangerous, especially with the possibility of ammonia reaching dangerous levels in the brain.

“We knew the method used to deliver the gene-editing machinery to the baby’s liver cells allowed us to give the treatment repeatedly. That meant we could start with a low dose that we were sure was safe,” said CHOP pediatrician Rebecca Ahrens-Nicklas, MD, PhD.

“We were very concerned when the baby got sick, but the baby just shrugged the illness off,” said Penn geneticist and first author Kiran Musunuru, MD, PhD. For now, much work remains, but the researchers are cautiously optimistic about the baby’s progress.

The scientists announced their work at the American Society of Gene & Cell Therapy Meeting on May 15th and described the study in The New England Journal of Medicine.

Source: NIH/Office of the Director

Categories : Genetics HIVTags :

Researchers Map 7000-year-old Genetic Mutation that Protects Against HIV

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Modern HIV medicine is based on a common genetic mutation. Now, researchers have traced where and when the mutation arose – and how it protected our ancestors from ancient diseases.

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What do a millennia-old human from the Black Sea region and modern HIV medicine have in common? Quite a lot, it turns out, according to new research from the University of Copenhagen.

18–25% of the Danish population carries a genetic mutation that can make them resistant or even immune to HIV. This knowledge is used to develop modern treatments for the virus.

Until now, it was unknown where, when, or why the mutation occurred. But by using advanced DNA technology, researchers have now solved this genetic mystery.

“It turns out that the variant arose in one individual who lived in an area near the Black Sea between 6700 and 9000 years ago,” says Professor Simon Rasmussen from the Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR) at the University of Copenhagen, corresponding author of a new study mapping the mutation. He adds:

“HIV is a relatively new disease – less than 100 years old – so it’s almost coincidental and very fascinating that a genetic variation that arose thousands of years ago also protects against a modern virus like HIV.”

Analyzed 900 skeletons

To determine where and when the mutation arose, researchers first mapped it by analysing the genetic material of 2000 living people worldwide. They then developed a new AI-based method to identify the mutation in ancient DNA from old bones.

The researchers examined data from over 900 skeletons dating from the early Stone Age to the Viking Age.

“By looking at this large dataset, we can determine where and when the mutation arose. For a period, the mutation is completely absent, but then it suddenly appears and spreads incredibly quickly. When we combine this with our knowledge of human migration at the time, we can also pinpoint the region where the mutation originated,” explains first author Kirstine Ravn, senior researcher at CBMR.

Thus, the researchers were able to locate the mutation in a person from the Black Sea region up to 9000 years ago – an individual from whom all carriers of the mutation descend.

Immune weakening was beneficial back then

But why do so many Danes carry a millennia-old genetic mutation that protects against a disease that didn’t exist back then?

The researchers believe the mutation arose and spread rapidly because it gave our ancestors an advantage:

“People with this mutation were better at surviving, likely because it dampened the immune system during a time when humans were exposed to new pathogens,” explains Leonardo Cobuccio, co-first author and postdoc at CBMR. He and Kirstine Ravn elaborate:

“What’s fascinating is that the variation disrupts an immune gene. It sounds negative, but it was likely beneficial. An overly aggressive immune system can be deadly – think of allergic reactions or severe cases of viral infections like COVID-19, where the immune system often causes the damage that kills patients. As humans transitioned from hunter-gatherers to living closely together in agricultural societies, the pressure from infectious diseases increased, and a more balanced immune system may have been advantageous.”

Source: University of Copenhagen – The Faculty of Health and Medical Sciences

Categories : Cancer GeneticsTags :

Research Challenges the Understanding of Cancer Predisposition Gene NF-1

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Despite what was previously thought, new research has shown that genetic changes alone cannot explain why and where tumours grow in those with genetic condition neurofibromatosis type 1 (NF-1). Understanding more about the factors involved could, in the future, facilitate early cancer detection in NF-1 patients and even point towards new treatments.

Researchers from the Wellcome Sanger Institute and collaborating institutions, focused on NF-1, a genetic condition that causes specific types of tumours, and investigated how and why these developed.

The study, published in Nature Genetics, reports that the genetic changes thought to cause tumours can be found in normal tissues throughout the body, suggesting that other factors are also necessary for tumour development.

They also uncovered a pattern of changes in the affected gene, NF1, that may explain why the nervous system in particular is a common site for these tumours to develop.

Understanding what other factors are involved in developing these tumours could help inform monitoring programmes for patients with NF-1, who require regular screening to detect tumours early on and could potentially require multiple surgeries and chemotherapy.

In the future, refining our knowledge of why tumours grow in some places and not others may help us identify the patients most likely to need early medical intervention.

This model of tumour development is not unique to NF-1, raising the possibility that similar events occur in related genetic conditions, meaning many more could benefit from tailored management.

NF-1 is a genetic condition that causes brown skin patches, similar to birthmarks, and tumours1. While the tumours are often benign, they can become cancerous over time and may cause a range of symptoms depending on where they are1. For example, NF-1 can cause soft tissue and brain tumours that may restrict movement and vision.

The symptoms and impact of NF-1 can vary greatly from person to person. It is one of the most common inherited genetic conditions, impacting around one in 2500 people. Those with NF-1 have a genetic change that means one copy of the gene encoding the neurofibromin protein, NF1, does not work. It was previously thought that tumours and brown skin patches occurred when the second copy of the gene was lost.

In a new study, researchers from the Sanger Institute, UCL Great Ormond Street Institute of Child Health, Great Ormond Street Hospital, Cambridge University Hospitals NHS Foundation Trust, and their collaborators, studied nearly 500 tissue samples from a child with NF-1 and compared them to tissues from children without the condition.

They found that changes causing a loss of NF1 gene function were not limited to tumours and skin changes but instead can be found throughout other tissues of the child with NF-1 as well. This suggests, whilst advantageous to the affected cells, the mutation is insufficient to cause tumour formation.

For this research, the team applied a new sequencing technology that allowed them to look at genetic changes at a higher resolution than was previously possible and studied additional tissue samples from nine adults with NF-1, showing similar findings.

The team found a pattern of mutations across all patients that showed these were particularly common in tissues of the nervous system. This is a common place for tumours to form in those with NF-1, which can help explain why these tissues are specifically impacted.

“We were astonished to see such extensive genetic changes in the normal tissues of patients with NF-1, seemingly without consequence. This is contrary to our understanding of tumour development in the condition and other related conditions. Additional factors must clearly play a role, perhaps including the cell type and anatomical location affected. Whilst further investigation is needed, I hope this work represents the first step towards developing more personalised care for these patients, such as better identifying who is at greater risk of developing tumours, and adjusting screening to intervene early on and minimise complications.”

Dr Thomas Oliver,co-first author from the Wellcome Sanger Institute and Cambridge University Hospitals NHS Foundation Trust

“NF-1 can have many different impacts on a person’s life. In order to better treat and support those with NF-1, we have to understand more about what is going on at a biological and genetic level, especially in the parts of the body that are most affected, such as the brain and nervous system. Our study showed that these areas of the body have a different pattern of DNA changes, suggesting that if we look further, there could be a potential target for new therapies to help treat or stop tumour development.”

Professor Thomas Jacques,co-senior author from UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital

“Loss of the second NF1 gene had always been thought to cause tumours in individuals with NF-1. Our findings fundamentally question this decade-old paradigm and force us to rethink how tumours arise, to pave the way for better screening, prevention, and treatment of cancers.”

Professor Sam Behjati,co-senior author from the Wellcome Sanger Institute and Cambridge University Hospitals NHS Foundation Trust

Source: Wellcome Trust Sanger Institute

Categories : GeneticsTags :

Genes Associated with Plague Survival Linked to Alopecia Risk

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In a new JAMA Dermatology study, scientists at King’s found that changes in two parts of the genome work together to influence alopecia risk.

Frontal fibrosing alopecia (FFA) is a highly distressing dermatological disorder which is associated with inflammation, scarring and irreversible hair loss. The disease affects an increasing number of patients worldwide and is caused by genetic and environmental factors.

The study authors conducted a meta-analysis of four cohorts of women with FFA across the UK and Europe. When looking into a cluster of immune genes known as the major histocompatibility complex, which help immune systems recognise foreign substances, they identified specific genetic differences that interact with ERAP1 and increase the risk of developing FFA.

This gene-gene interaction is a rare phenomenon in human genetics, known as “epistasis”. This means that the risk associated with one gene is modified by another gene. Different versions of the two genes involved in this interaction have been observed in some other autoimmune diseases, including psoriasis and ankylosing spondylitis.

Previous research has identified that genetic variants in the ERAP1 and ERAP2 genes were associated with survival of the Black Death, a bubonic plague which swept through Europe in the mid-1300s. Such genetic variants, which are associated with protection from infection, may also make people more prone to certain immune conditions. This new study demonstrates that this is the case for FFA.

“Our study is the largest ever genome-wide association study into frontal fibrosing alopecia (FFA), an inflammatory and scarring condition affecting almost exclusively women,” said Dr Christos Tziotzios, Senior Lecturer of the St John’s Institute of Dermatology at King’s and Consultant Dermatologist at Guy’s and St Thomas’ NHS Foundation Trust

He added: “Since the disease was described in 1994, the number of people affected has increased dramatically. Our newest finding sheds more light into the autoimmune basis of the condition and provides direction for further research into drug development.”

As well as improving our understanding of the genetic factors that drive FFA, the authors hope that these findings can be applied to predict risk of its development while paving the way for new treatments.

The team of scientists are now investigating the prospect of predictive genetic test for FFA risk, while exploring the potential of targeting ERAP1 with highly specific drugs as a new way of treating this condition.

Source: King’s College London

Categories : GeneticsTags :

Review of Research Finds No Link between Sickle Cell Trait and Sudden Death

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Expert panel’s findings refute attribution of sudden death to sickle cell trait

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A systematic literature review found no evidence to support that physical exertion without rhabdomyolysis (muscle breakdown) or heat injury can cause sudden death for individuals with sickle cell trait (SCT), nor is there any high-level evidence that SCT causes acute pain crises. These results were published in the American Society of Hematology’s flagship journal, Blood, and informed the Society’s updated position statement on SCT.

“SCT has long been misunderstood, fuelling widespread misinformation and medically inaccurate claims that it can lead to sudden death. This misconception has been especially prominent in cases of Black men with SCT,” said Belinda Avalos, MD, ASH president. “In light of the pervasive, widely publicized, and harmful nature of this myth, the Society aims to further promote accurate information to protect and empower affected communities.”

Individuals with SCT have one copy of the gene associated with sickle cell disease (SCD). SCD is a blood disorder characterised by misshapen blood cells that can cause blockages, leading to infections and episodes of severe pain, often referred to as acute pain crises. Unlike SCD, SCT – which affects over 100 million people worldwide, including 8 to 10% of Black Americans – is not a disease. Individuals with SCT do not go on to develop SCD and generally do not experience any related health complications.  

“To date, this is the most authoritative and definitive systematic review on this subject,” said study author Michael R. DeBaun, MD, MPH, professor of pediatrics and medicine at Vanderbilt University School of Medicine and founder and director of the Vanderbilt-Meharry Sickle Cell Disease Center of Excellence. “This review shows that any primary, secondary, or tertiary cause of death attributable to SCT is not a diagnosis substantiated by the medical evidence.”

ASH convened an expert panel of hematologists and forensic pathologists to systematically review all existing available research to answer two primary questions: 1) Do uncomplicated acute pain crises occur in people with SCT? and 2) Can physical activity above baseline result in sudden death among those individuals?

The experts conducted a multi-database search for English-language studies on SCT and pain crises or mortality, identifying 1474 such citations. Only seven of those studies reported original data, included laboratory testing for SCT in individuals, and addressed the two primary research questions.

Of these studies, none assessed acute pain crises in individuals with SCT compared to those with SCD and only one described death in individuals reported to have SCT. This study of active-duty U.S. soldiers found only that SCT was associated with a higher risk of heat-related-exertional rhabdomyolysis, or muscle breakdown, but not a higher risk of death from any cause. After the implementation of precautions to prevent heat and environmental-related injury in military personnel, the race-adjusted risk of death was no different in individuals with SCT compared to individuals without SCT.

“In the absence of two medical conditions that we are all at risk for, exertional rhabdomyolysis or crush injuries leading to rhabdomyolysis, individuals with SCT are not susceptible to sudden death. Even under these extreme environmental conditions, unexplained sudden death cannot be attributed to SCT,” said Dr. DeBaun. Taken together, these findings demonstrate that “in individuals with SCT, the likelihood of SCT alone or pain crises being the root cause of sudden death is medically impossible,” he added.

While conducting this systematic review, the experts found several studies in which the presence of sickled blood cells at autopsy was cited as evidence of death by acute pain crisis in individuals with SCT. However, the experts did not find any studies that had human data to support this hypothesis, nor any clinical descriptions sufficient to make a diagnosis of an acute pain crisis immediately preceding death.

“Medicine, even in the post-mortem setting, is science,” said corresponding study author Lachelle D. Weeks, MD, PhD, assistant professor of medicine at Harvard Medical School and physician-scientist in the division of population sciences at Dana-Farber Cancer Institute. “Our diagnoses have to make sense and be backed by medical evidence. Given the findings of this study, we owe it to individuals with SCT to ensure that post-mortem examinations check for evidence of rhabdomyolysis and other medical or traumatic causes of death.”

The review had some limitations, most notably a lack of high quality, peer-reviewed direct evidence. To help mitigate this challenge, panel members were encouraged to consider indirect evidence when reviewing abstracts and judged evidence certainty following the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) framework. However, given this paucity of data, the experts hope this review prompts additional SCT research.

Following the results of this study, ASH revised its position statement on SCT, which states that listing “sickle cell crisis” or “sickle cell trait” as a cause of death on an autopsy report for an individual with sickle cell trait is medically inaccurate and without medical evidence of causation. To read the updated statement and learn more about ASH’s advocacy efforts in this area, visit https://hematology.org/advocacy.

Source: American Society of Hematology

Categories : GeneticsTags :

DNA Damage can Stay Unrepaired for Years

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The findings are set to change our understanding of genetic mutation

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In a paradigm shift in how we view mutations, researchers uncover forms of DNA damage in healthy cells – most particularly in blood stem cells – that can persist unrepaired for years.

While most known types of DNA damage are fixed by our cells’ in-house repair mechanisms, some forms of DNA damage evade repair and can persist for many years, new research shows. This means that the damage has multiple chances to generate harmful mutations, which can lead to cancer.

Scientists from the Wellcome Sanger Institute and their collaborators analysed family trees of hundreds of single cells from several individuals. The team pieced together these family trees from patterns of shared mutations between the cells, indicating common ancestors.

Researchers uncovered unexpected patterns of mutation inheritance in the trees, revealing that some DNA damage persists unrepaired. In the case of blood stem cells, this can be for two to three years.

The research, published in Nature, changes the way we think about mutations, and has implications for understanding the development of various cancers.

Throughout our life, all of the cells in our body accumulate genetic errors in the genome, known as somatic mutations. These can be caused by damaging environmental exposures, such as smoking, as well as the everyday chemistry occurring in our cells.

DNA damage is distinct from a mutation. While a mutation is one of the standard four DNA bases (A, G, T or C) in the wrong place, similar to a spelling mistake, DNA damage is chemical alteration of the DNA, like a smudged unrecognisable letter. DNA damage can result in the genetic sequence being misread and copied incorrectly during cell division, in a process known as DNA replication. This introduces permanent mutations that can contribute to the development of cancers. However, the DNA damage itself is usually recognised and mended quickly by repair mechanisms in our cells.

If researchers can better understand the causes and mechanisms of mutations, they may be able to intervene and slow or remove them.

In a new study, Sanger Institute scientists and their collaborators analysed data in the form of family trees of hundreds of single cells from individuals. The family trees are constructed from patterns of mutations across the genome that are shared between cells – for example, cells with many shared mutations have a recent common ancestor cell and are closely related.

The researchers collated seven published sets of these family trees, known as somatic phylogenies. The data set included 103 phylogenies from 89 individuals,1 spanning blood stem cells, bronchial epithelial cells and liver cells

The team found unexpected patterns of mutation inheritance in the family trees, revealing that some DNA damage can persist unrepaired through multiple rounds of cell division. This was particularly evident in blood stem cells, where between 15 to 20 per cent of the mutations resulted from a specific type of DNA damage that persists for two to three years on average, and in some cases longer.

This means that during cell division, each time the cell attempts to copy the damaged DNA it can make a different mistake, leading to multiple different mutations from a single source of DNA damage. Importantly, this creates multiple chances of harmful mutations that could contribute to cancer. Researchers suggest that although these types of DNA damage occur rarely, their persistence over years means they can cause as many mutations as more common DNA damage.

Overall, these findings change the way researchers think about mutations, and have implications for understanding the development of cancer.

Source: Wellcome Trust Sanger Institute

Categories : Genetics Neurodegenerative DiseasesTags :

Brain Changes in Huntington’s Disease Seen Decades ahead of Symptoms

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Subtle changes in the brain, detectable through advanced imaging, blood and spinal fluid analysis, happen approximately twenty years before a clinical motor diagnosis in people with Huntington’s disease, finds a new study led by UCL researchers which appears in Nature Medicine.

The team found that although functions such as movement, thinking or behaviour remained normal for a long time before the onset of symptoms in Huntington’s disease, subtle changes to the brain were taking place up to two decades earlier. These findings pave the way for future preventative clinical trials, offer hope for earlier interventions that could preserve brain function and improve outcomes for individuals at risk of Huntington’s disease.

Huntington’s disease is a devastating neurodegenerative condition affecting movement, thinking and behaviour. It is a genetic disease and people with an affected parent have a 50% chance of inheriting the Huntington’s disease mutation, meaning they will develop disease symptoms – typically in mid-adulthood.

The disease is caused by repetitive expansions of three DNA blocks (C, A and G) in the huntingtin gene. This sequence tends to continually expand in certain cells over a person’s life, in a process known as somatic CAG expansion. This ongoing expansion accelerates neurodegeneration, making brain cells more vulnerable over time.

For the new study, the researchers studied 57 people with the Huntington’s disease gene expansion, who were calculated as being on average 23.2 years from a predicted clinical motor diagnosis.  

They were examined at two time points over approximately five years to see how their bodies and brains changed over time. Their results were compared to 46 control participants, matched closely for age, sex and educational level.

As part of the study, all participants volunteered to undergo comprehensive assessments of their thinking, movement and behaviour, alongside brain scans and blood and spinal fluid sampling.

Importantly, the group with Huntington’s disease gene expansion showed no decline in any clinical function (thinking, movement or behaviour) during the study period, compared to the closely matched control group.

However, compared to the control group, subtle changes were detected in brain scans and spinal fluid biomarkers of those with Huntington’s disease gene expansion. This indicates that the neurodegenerative process begins long before symptoms are evident and before a clinical motor diagnosis.

Specifically, the researchers identified elevated levels of neurofilament light chain (NfL), a protein released into the spinal fluid when neurons are injured, and reduced levels of proenkephalin (PENK), a neuropeptide marker of healthy neuron state that could reflect changes in the brain’s response to neurodegeneration.

Lead author, Professor Sarah Tabrizi (UCL Huntington’s Disease Research Centre, UCL Queen Square Institute of Neurology, and UK Dementia Research Institute at UCL), said: “Our study underpins the importance of somatic CAG repeat expansion driving the earliest neuropathological changes of the disease in living humans with the Huntington’s disease gene expansion. I want to thank the participants in our young adult study as their dedication and commitment over the last five years mean we hope that clinical trials aimed at preventing Huntington’s disease will become a reality in the next few years.”

The findings suggest that there is a treatment window, potentially decades before symptoms are present, where those at risk of developing Huntington’s disease are functioning normally despite having detectable measures of subtle, early neurodegeneration. Identifying these early markers of disease is essential for future clinical trials in order to determine whether a treatment is having any effect.

Co-first author of the study, Dr Rachael Scahill (UCL Huntington’s Disease Research Centre and UCL Queen Square Institute of Neurology) said: “This unique cohort of individuals with the Huntington’s disease gene expansion and control participants provides us with unprecedented insights into the very earliest disease processes prior to the appearance of clinical symptoms, which has implications not only for Huntington’s disease but for other neurodegenerative conditions such as Alzheimer’s disease.”

This study is the first to establish a direct link between somatic CAG repeat expansion, measured in blood, and early brain changes in humans, decades before clinical motor diagnosis in Huntington’s disease.

While somatic CAG expansion was already known to accelerate neurodegeneration, this research demonstrates how it actively drives the earliest detectable changes in the brain: specifically in the caudate and putamen, regions critical to movement and thinking.

By showing that somatic CAG repeat expansion changes measured in blood predicts brain volume changes and other markers of neurodegeneration, the findings provide crucial evidence to support the hypothesis that somatic CAG expansion is a key driver of neurodegeneration.

With treatments aimed at suppressing somatic CAG repeat expansion currently in development, this work validates this mechanistic process as a promising therapeutic target and represents a critical advance towards future prevention trials in Huntington’s disease.

Co-first author of the study, Dr Mena Farag (UCL Huntington’s Disease Research Centre and UCL Queen Square Institute of Neurology) added: “These findings are particularly timely as the Huntington’s disease therapeutic landscape expands and progresses toward preventive clinical trials.”

The research was done in collaboration with experts at the Universities of Glasgow, Gothenburg, Iowa, and Cambridge.

Source: University College London