University of Utah scientists have identified two microRNA molecules that control chronic inflammation, a discovery that one day may help researchers prevent certain fatal or debilitating conditions before they start.
‘We’re living at a time where the aging population is growing,’ said Ryan O’Connell, D.Phil., assistant professor of pathology, whose lab made the discovery. ‘The question is: how can we predict and prevent the onset of disorders that emerge upon growing older?’
After three years of research and building on previous studies, the scientists determined that if a particular microRNA is genetically removed from mice, the animals will develop chronic inflammation spontaneously and die early from subsequent ailments such as cancer or an autoimmune disorder. However, mice that also lack a second type of microRNA don’t develop chronic inflammation. So one microRNA prevents the condition while the other promotes it, identifying a key system in the body that modulates this harmful state.
Certain types of immune cells, called T follicular helper cells, are known to promote the production of antibodies that attack our own tissues and contribute to chronic inflammation. O’Connell and colleagues found that the microRNAs at issue are produced by and act to control these important cell types.
‘Now we know which cells in the body we need to get miRNA inhibitors delivered to if we want to reduce chronic inflammatory conditions,’ said O’Connell, noting that the next step is human research. One question would be whether patients with chronic inflammation who received an inhibitor of a certain microRNA would see their chronic inflammation indicators decrease, preventing fatal conditions from emerging.
Previous studies have shown that chronic inflammation is linked to the development of certain conditions including diabetes, lupus, arthritis, obesity, cancer, neurodegeneration and cardiovascular disease along with a shortened life span. The challenge is that chronic inflammation happens at a low level and is typically not detected by doctors. But certain biomarkers such as elevated levels of cytokines or antibodies can indicate the condition.
‘Everyone waits until they have bad symptoms to go see the doctor,’ he said. ‘However, the goal of medicine is to take a person who is not sick yet and be able to analyze something we can test that can help predict whether they’re going to be sick in the future — and take appropriate measures to prevent terrible outcomes.’
EurekAlert
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Scientists at The Scripps Research Institute (TSRI) have identified the long-sought activating molecules for a rare but crucial subset of immune system cells that help rally other white blood cells to fight infection.
In the process, the team also uncovered a previously unsuspected link between the mammalian immune system and the communication systems of simpler organisms such as bacteria.
The findings could lead to novel therapeutic approaches for diseases such as type 1 diabetes that are the result of immune system over-activity, as well as new ways to boost the effectiveness of vaccines, according to study leader Luc Teyton, a professor in TSRI’s Department of Immunology and Microbial Science.
When a virus, bacteria or foreign substance invades the body, specialised cells known as dendritic cells present in the skin and other organs capture the trespassers and convert them into smaller pieces called antigens that they then display on their cell surfaces. White blood cells known as T and B cells recognize the antigens to launch very specific attacks on the invaders.
Dendritic cells also activate a specialized population of T cells known as natural killer T (NKT) cells. Once activated, NKT cells can commandeer the functions of dendritic cells to make them more effective and also recruit and coordinate the responses of T- and B-type cells.
“Because of their dual functions, NKT cells are a bridge between the body’s innate immunity, which is characterised by rapid but less specific responses to pathogens, and adaptive or acquired immunity, which is composed of specialised white blood cells that can remember past invaders,” Teyton said.
Previous studies indicated that NKT cells are activated by molecules known as glycolipids that dendritic cells produce and then display on their outer surfaces. It was widely assumed that the activating molecules were a class of glycolipids known as beta-glycosylceramides, an important component of nervous system cells.
However, this hypothesis had not been thoroughly examined, in part because there is no chemical test currently available to distinguish between two forms of the molecule that have slightly different configurations—beta-glycosylceramide and alpha-glycosylceramide. In addition, when scientists attempt to create either form synthetically for testing, there is always the possibility of small contamination of one by the other.
“When you’re making glycolipids, there is no completely faithful way of controlling the form that you’re making,” Teyton said. ‘You’re favouring the making of one, but you cannot say for sure that you don’t have a small amount of the other form.”
In their new study, Teyton and his colleagues, who included scientists from Brigham Young University, the La Jolla Institute for Allergy & Immunology and the University of Chicago, abandoned the chemical approach altogether. Instead, they combined a series of biochemical and biological assays to create a test that was sensitive enough to distinguish between the two different forms of glycolipids.
“Biological assays are exquisitely sensitive to low amounts of otherwise unmeasurable molecules,” said study first author Lisa Kain, a research technician in Teyton’s lab.
The scientists used custom antibodies to identify and eliminate alpha-glycosylceramides from their test batches. When the team was confident that their test batch contained only beta forms of the glycolipid, they tested it on NKT cells gathered from mice. To their surprise, however, nothing happened. Contrary to the conventional wisdom, the beta-glycosylceramides failed to activate the NKT cells.
“We were very skeptical about the early results,” Teyton said. “We thought we had used the wrong antibody.”
Next, the team combined enzymes designed to digest molecular linkages found only on beta-glycosylceramides with mice NKT cells inside test tubes. Surprisingly, the NKT cells were still being activated.
Finally, when the team used antibodies to disable alpha-glycosylceramides inside live mice, not only did the NKT cells fail to activate, they disappeared altogether from organs such as the thymus, where NKT cells are produced.
These multiple lines of evidence strongly indicated that it was the alpha form of the glycolipids that were the triggers for NKT cells. “What we thought was the contaminant turned out to be the activating molecule we were looking for,” Teyton said.
The results were surprising for another reason. Until that moment, scientists did not think mammalian cells were capable of producing alpha forms of the glycolipids. The molecules were thought to exist only in bacteria and other simple organisms, which use them primarily as a means of communicating with one another. The findings thus suggest that the roots of a crucial part of the mammalian immune response are even more ancient than previously thought.
“Nobody expected this,” Teyton said. “It’s like discovering that all languages share a common origin.”
Now that scientists know that alpha-glycosylceramides are made by our own body and activate NKT cells, they might be able to exploit it to create new therapies. For example, Teyton said, researchers could use enzymes to reduce alpha-glycosylceramide levels in order to suppress an overactive immune response, which happens with diseases such as type 1 diabetes. Or they could combine the molecules with antigens to create vaccines that elicit a faster and more efficient immune response.
“This opens up an avenue of new therapeutic approaches that we’ve never even thought about,” Teyton said.
The Scripps Research Institute
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Researchers at the University of Connecticut have found a new way to identify protein mutations in cancer cells. The novel method is being used to develop personalized vaccines to treat patients with ovarian cancer.
“This has the potential to dramatically change how we treat cancer,” says Dr. Pramod Srivastava, director of the Carole and Ray Neag Comprehensive Cancer Center at UConn Health and one of the principal investigators on the study. “This research will serve as the basis for the first ever genomics-driven personalised medicine clinical trial in immunotherapy of ovarian cancer, and will begin at UConn Health this fall,” Srivastava says.
Dr. Angela Kueck, a gynecological oncologist at UConn Health, will run the initial clinical study, once it is approved by the FDA. The research team will sequence DNA from the tumours of 15 to 20 women with ovarian cancer, and use that information to make a personalized vaccine for each woman.
The researchers focused their clinical trial on patients with ovarian cancer because the disease usually responds well to surgery and chemotherapy in the short term, but often returns lethally within a year or two. That gives researchers the perfect window to prepare and administer the new therapeutic vaccines, and also means they may be able to tell within two years or so whether the vaccine made a difference. If the personalized vaccines prove to be safe and feasible, they’ll design a Phase II trial to test its clinical effectiveness by determining whether they prolong patients’ lives.
In order for the immune system to attack cancers, it first has to recognize them. Every cell in the body has a sequence of proteins on its exterior that acts like an ID card or secret handshake, confirming that it’s one of the good guys. These protein sequences, called epitopes, are what the immune system ‘sees’ when it looks at a cell. Cancerous cells have epitopes, too. Since cancer cells originate from the body itself, their epitopes are very similar to those of healthy cells, and the immune system doesn’t recognize them as bad actors that must be destroyed.
But just as even the best spy occasionally slips up on the details, cancer cell epitopes have tiny differences or mistakes that could give them away, if only the immune system knew what to look for.
“We want to break the immune system’s ignorance,” Srivastava says. For example, there could be 1,000 subtle changes in the cancer cell epitopes, but only 10 are “real,” meaning significant to the immune system. To find the real, important differences, Mandoiu, the bioinformatics engineer, took DNA sequences from skin tumours in mice and compared them with DNA from the mice’s healthy tissue.
Previous researchers had done this but looked at how strongly the immune system cells bound to the cancer’s epitopes. This works when making vaccines against viruses, but not for cancers. Instead, Srivastava’s team came up with a novel measure: they looked at how different the cancer epitopes were from the mice’s normal epitopes. And it worked. When mice were inoculated with vaccines made of the cancer epitopes differing the most from normal tissue, they were very resistant to skin cancer.
Theoretically, this approach could work for other cancers, although the research has yet to be done.
University of Connecticut
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A team of scientists, led by researchers at The Wistar Institute, has identified a possible explanation for why middle-aged adults were hit especially hard by the H1N1 influenza virus during the 2013-2014 influenza season. The findings offer evidence that a new mutation in H1N1 viruses potentially led to more disease in these individuals. Their study suggests that the surveillance community may need to change how they choose viral strains that go into seasonal influenza vaccines, the researchers say.
“We identified a mutation in recent H1N1 strains that allows viruses to avoid immune responses that are present in a large number of middle-aged adults,” said Scott Hensley, Ph.D., a member of Wistar’s Vaccine Center and an assistant professor in the Translational Tumour Immunology program of Wistar’s Cancer Center.
Historically, children and the elderly are most susceptible to the severe effects of the influenza viruses, largely because they have weaker immune systems. However, during the 2013-2014 physicians saw an unusually high level of disease due to H1N1 viruses in middle-aged adults—those who should have been able to resist the viral assault. Although H1N1 viruses recently acquired several mutations in the haemagglutinin (HA) glycoprotein, standard serological tests used by surveillance laboratories indicate that these mutations do not change the viruses’ antigenic properties.
However, Wistar researchers have shown that, in fact, one of these mutations is located in a region of HA that allows viruses to avoid antibody responses elicited in some middle-aged adults. Specifically, they found that 42 percent of individuals born between 1965 and 1979 possess antibodies that recognize the region of HA that is now mutated. The Wistar researchers suggest that new viral strains that are antigenically matched in this region should be included in future influenza vaccines.
“Our immune systems are imprinted the first time that we are exposed to influenza virus,” Hensley said. “Our data suggest that previous influenza exposures that took place in the 1970s and 1980s influence how middle-aged people respond to the current H1N1 vaccine.”
The researchers noted that significant antigenic changes of influenza viruses are mainly determined using anti-sera isolated from ferrets recovering from primary influenza infections. However humans are typically re-infected with antigenically distinct influenza strains throughout their life. Therefore, antibodies that are used for surveillance purposes might not be fully reflective of human immunity.
Wistar Institute
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A new study led by researchers at King’s College London in collaboration with the University of Manchester and the University of Dundee has found a strong link between exposure to peanut protein in household dust during infancy and the development of peanut allergy in children genetically predisposed to a skin barrier defect.
Around 2% of school children in the UK and the US are allergic to peanuts. Severe eczema in early infancy has been linked to food allergies, particularly peanut allergy. A major break-through in the understanding of eczema developed with the discovery of the FLG gene which codes for the skin barrier protein filaggrin. Mutations in the FLG gene result in an impaired skin barrier which is thought to allow allergens to penetrate the skin and predispose the body towards an allergic response.
Immunology, looked at the amount of peanut protein children were exposed to in household dust in their first year of life by vacuuming dust from the living room sofa and measuring peanut in the dust. A group of 577 children were assessed at 8 and 11 years of age for peanut allergy and their DNA was checked for FLG mutations. The study was conducted in children recruited to the Manchester Asthma and Allergy Study.
A strong link was found between early-life exposure to peanut protein in household dust and peanut allergy in children with FLG mutations. A three-fold increase in house dust peanut exposure during infancy was associated with a three-fold increase in risk of school-age peanut allergy. One in five children with peanut allergy had an FLG mutation. There was no significant effect of environmental peanut exposure in children without FLG mutations.
Dr Helen A Brough, first author from the Department of Paediatric Allergy, Division of Asthma, Allergy & Lung Biology, King’s College London, said: “Our findings provide evidence that peanut allergy may develop via the skin in children with mutations in the gene that codes for filaggrin which damage the function of this important skin protein. These findings are also an example of how an individual’s response to their environment can be modified by their genes. Our study raises the possibility of being able to identify a group of children with FLG mutations through genetic testing in the future, and altering their environmental exposure to peanut early in life to reduce the risk of developing peanut allergy.”
King’s College London
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Tumour cells isolated from the blood of patients with triple negative breast cancer reveal similar cancer-driving mutations as those detected from standard biopsy, suggesting that circulating cells could one day replace tissue biopsies
The genetic fingerprint of a metastatic cancer is constantly changing, which means that the therapy that may have stopped a patient’s cancer growth today, won’t necessarily work tomorrow. Although doctors can continue to biopsy the cancer during the course of the treatment and send samples for genomic analysis, not all patients can receive repeat biopsies. Taking biopsies from metastatic cancer patients is an invasive procedure that it is frequently impossible due to the lack of accessible lesions. Research suggest that tumour cells circulating in the blood of metastatic patients could give as accurate a genomic read-out as tumour biopsies.
“Counting the number of circulating tumour cells (CTCs) can tell us whether a patient’s cancer is aggressive, or whether it is stable and responding to therapy,” says the article’s first author Sandra V. Fernandez, Ph.D., assistant professor of Medical Oncology at Thomas Jefferson University. “Our work suggests that these cancer cells in the blood also accurately reflect the genetic status of the parent tumour or its metastases, potentially giving us a new and easy to source of genomic information to guide treatment.”
First discovered for their diagnostic potential in 2004, circulating tumour cells are beginning to be used in the clinic to help guide treatment decisions and track a patient’s progress as the cancer progresses. Although other studies have pooled the collected CTCs and compared their collective genetic signature to that of the primary tumour, this is the first study to look at the genomic signature of individual tumour cells in circulation. In order to isolate single tumour cells from the blood, the authors used a new technology, DEPArrayTM , in their laboratory.
The researchers compared tissue biopsies surgically removed from two patients with inflammatory breast cancer with circulating tumour cells (CTCs). Breast tissue samples from both patients showed a specific mutation in a region of a cancer-driving gene, p53. The authors studied this mutation in several CTCs isolated from both patients. They found that in several of the CTCs collected, the mutations matched with the tumour biopsy, however in one patient, some of circulating tumour cells had an additional mutation. “Since inflammatory breast cancer is a very rapidly changing disease, we think this additional mutation may have been acquired after the original surgical biopsy was taken,” said Dr. Fernandez. In the case where an additional p53 mutation was found, the blood to isolate CTCs were drawn one year later than the breast tissue biopsy was taken.
Although further work analyzing a greater number of genes and samples is needed, the work shows that CTCs offer the possibility of capturing the most current genomic information in an easy-to-obtain sample such as blood, thus helping guide treatment decisions. It also suggests that it may be necessary to test more than one cell for the most accurate reading, as the CTC population appears to be heterogenous.
Thomas Jefferson University (TJU)
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An international research collaboration led by UC San Francisco researchers has identified a genetic variant common in Latina women that protects against breast cancer.
The variant, a difference in just one of the three billion “letters” in the human genome known as a single-nucleotide polymorphism (SNP), originates from indigenous Americans and confers significant protection from breast cancer, particularly the more aggressive oestrogen receptor–negative forms of the disease, which generally have a worse prognosis.
“The effect is quite significant,” said Elad Ziv, MD, professor of medicine and senior author of the study. “If you have one copy of this variant, which is the case for approximately 20 percent of U.S. Latinas, you are about 40 percent less likely to have breast cancer. If you have two copies, which occurs in approximately 1 percent of the US Latina population, the reduction in risk is on the order of 80 percent.”
The new study showed that women who carry the variant have breast tissue that appears less dense on mammograms. High “mammographic density” is a known risk factor for breast cancer.
“We have detected something that is definitely relevant to the health of Latinas, who represent a large percentage of the population in California, and of other states such as Texas,” said first author Laura Fejerman, PhD, assistant professor of medicine and a member of UCSF’s Institute of Human Genetics. “This work was done as a collaboration of multiple investigators, many of us originally from Latin America. As a Latina myself, I am gratified that there are representatives of that population directly involved in research that concerns them.”
University of California – San Francisco
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Age-related loss of the Y chromosome (LOY) from blood cells, a frequent occurrence among elderly men, is associated with elevated risk of various cancers and earlier death.
This finding could help explain why men tend to have a shorter life span and higher rates of sex-unspecific cancers than women, who do not have a Y chromosome, said Lars Forsberg, PhD, lead author of the study and a geneticist at Uppsala University in Sweden.
LOY, which occurs occasionally as a given man’s blood cells replicate – and thus takes place inconsistently throughout the body – was first reported nearly 50 years ago and remains largely unexplained in both its causes and effects. Recent advances in genetic technology have allowed researchers to use a blood test to detect when only a small fraction of a man’s blood cells have undergone LOY.
Dr. Forsberg and colleagues studied blood samples from 1,153 elderly men aged 70 to 84 years, who were followed clinically for up to 40 years. They found that men whose samples showed LOY in a significant fraction of their blood cells lived an average of 5.5 years less than men whose blood was not affected by LOY. In addition, having undergone LOY significantly increased the men’s risk of dying from cancer during the course of the study. These associations remained statistically significant when results were adjusted for men’s age and other health conditions.
“Many people think the Y chromosome only contains genes involved in sex determination and sperm production,” said Jan Dumanski, MD, PhD, co-author on the study and a professor at Uppsala University. “In fact, these genes have other important functions, such as possibly playing a role in preventing tumours.” When LOY takes place, Y chromosome genes are not expressed, and this tumour prevention would be reduced.
Interestingly, LOY in blood cells is associated with many different cancers, including those outside of the blood system. This may be because Y chromosome genes enable blood cells to assist with immunosurveillance, the process by which the immune system detects and kills tumour cells to prevent cancer.
“Our hypothesis is that LOY disrupts the immunosurveillance normally conducted by blood cells, allowing tumours to grow unchecked and develop into cancer,” Dr. Forsberg said.
These findings suggest a new approach to early detection of cancer risk in men: a blood test to assess LOY. “LOY is not very dangerous in a small fraction of blood cells, but becomes increasingly predictive of cancer as more cells lose their Y chromosome,” Dr. Forsberg explained. “This takes years, so you’d have a window of time to do something to reduce your risk.”
The researchers are currently exploring LOY in more detail, including the effects of various lifestyle factors and other health conditions. They are also examining the frequency and consequences of LOY in different types of cells and throughout the life course.
The American Society of Human Genetics
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A better survival outcome is associated with low blood levels of squamous cell carcinoma antigen, or absence of tumour invasion either into the space between the lungs and chest wall or into blood vessels of individuals with a peripheral squamous cell carcinoma, a type of non-small cell lung cancer (NSCLC).
Lung cancer is the most common cause of cancer-related death worldwide and lung squamous cell carcinomas (SCC) account for 20-30% of all NSCLC. SCC can be classified as either central (c-SCC) or peripheral (p-SCC) depending on the primary location. While c-SCC is the most prevalent, the incidence of p-SCC is increasing and the clinical and biological behaviours of p-SCC remain unclear.
Researchers from Keio University School of Medicine and Saiseikai Utsunomiya Hospital in Japan evaluated several clinical and pathological variables in 280 patients with surgically removed p-SCC in order to identify potential prognostic factors.
Results show that low preoperative levels of squamous cell carcinoma antigen in the serum or either absence of tumour invasion into the pleura (the space between the lungs and chest wall) or tumour vasculature are independent prognostic factors for patients with any stage of p-SCC. These patients had an extended period without disease recurrence and longer overall survival. The same was also seen for the sub-group of patients with early stage I disease.
The authors note that “our study revealed that p-SCCs with pleural or vascular invasion or high serum SCC antigen are more likely to recur than those without it; even in stage I patients. Pleural and/or vascular invasion are thought to be essential steps in the progression and metastasis of p-SCCs and high serum SCC antigen may suggest micro-metastases at the time of surgery.” The authors propose that “patients with high serum SCC levels, vascular invasion or pleural invasion should have their tumour stage upgraded in order to reflect the clear differences in survival. Clinical trials should be performed to evaluate if postoperative chemotherapy would benefit these patients who typically may not receive chemotherapy because of their early stage.”
International Association for the Study of Lung Cancer
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Down syndrome is the most common chromosomal abnormality in humans, involving a third copy of all or part of chromosome 21. In addition to intellectual disability, individuals with Down syndrome have a high risk of congenital heart defects. However, not all people with Down syndrome have them – about half have structurally normal hearts.
Geneticists have been learning about the causes of congenital heart defects by studying people with Down syndrome. The high risk for congenital heart defects in this group provides a tool to identify changes in genes, both on and off chromosome 21, which are involved in abnormal heart development.
Researchers at Emory University School of Medicine, with colleagues at Johns Hopkins University, Oregon Health Science University, and University of Pittsburgh, report results from the largest genetic study of congenital heart defects in individuals with Down syndrome.
The team found that infants with congenital heart defects, in the context of Down syndrome, were more likely to have rare, large genetic deletions. Those deletions tended to involve genes that affect cilia, cellular structures that are important for signalling and patterning in embryonic development.
These new findings, along with other recent studies, suggest that the risk for congenital heart defects in Down syndrome can come from several genes and environmental factors, in addition to the substantial risk from the extra chromosome 21.
“In Down syndrome, there’s a 50-fold increase in risk for heart defects, which is enormous,” says senior author Michael Zwick, PhD, associate professor of human genetics and paediatrics at Emory. “Studying congenital heart defects in the ‘at risk’ Down syndrome population can make it possible to reveal genes that impact the risk of heart defects in all children, including those with typical number of chromosomes.”
“Understanding the origin of heart disorders in individuals with Down syndrome may reveal aspects of biology that would allow better personalization of their health care, since genetic alterations that affect the heart may also affect other organs, such as the lungs or gut,” Zwick says.
“Our partnership with families who have a child with Down syndrome and our investment in a comprehensive clinical data and biorepository will continue to provide resources to study not only heart defects, but also other Down-syndrome associated medical conditions such as cognitive function, leukaemia, and dementia,” says co-author Stephanie Sherman, PhD, professor of human genetics at Emory University School of Medicine.
The study included 452 individuals with Down syndrome. 210 had complete atrioventricular septal defects (AVSDs), a serious heart defect that is relatively common among those with Down syndrome (about 20 percent). The remaining 242 had structurally normal hearts. The Emory team used high density microarrays to probe more than 900,000 sites across the human genome to detect structural variation, including deletions or duplications of DNA.
An atrioventricular septal defect means that the central region of the heart separating the atria from the ventricles has failed to form properly. Such defects increase the workload on the heart, and a complete AVSD leads to heart failure: fluid buildup in the lungs and difficulty breathing, requiring surgery in the first year of life.
The team’s results add to evidence for a connection between AVSDs and cilia. Ciliopathies are a class of genetic disorders that include kidney, eye, and neurodevelopmental disorders. Cells in the airways have mobile cilia which sweep mucus and dirt out of the lungs, but almost every cell in the body has a primary (sensory) cilium.
“The finding that ciliome genes may be disrupted in children with Down syndrome and AVSD may indicate differences in life-time care for these individuals,” Zwick says. “This is a suggestive result that needs replication in a larger group.”
To confirm and strengthen the findings, Zwick and his team are currently performing an independent study of individuals with Down syndrome, using whole genome sequencing to further delineate alterations in genes that perturb heart development in children.
Emory Health Sciences
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MicroRNA molecules serve as on/off switches for inflammation
, /in E-News /by 3wmediaUniversity of Utah scientists have identified two microRNA molecules that control chronic inflammation, a discovery that one day may help researchers prevent certain fatal or debilitating conditions before they start.
‘We’re living at a time where the aging population is growing,’ said Ryan O’Connell, D.Phil., assistant professor of pathology, whose lab made the discovery. ‘The question is: how can we predict and prevent the onset of disorders that emerge upon growing older?’
After three years of research and building on previous studies, the scientists determined that if a particular microRNA is genetically removed from mice, the animals will develop chronic inflammation spontaneously and die early from subsequent ailments such as cancer or an autoimmune disorder. However, mice that also lack a second type of microRNA don’t develop chronic inflammation. So one microRNA prevents the condition while the other promotes it, identifying a key system in the body that modulates this harmful state.
Certain types of immune cells, called T follicular helper cells, are known to promote the production of antibodies that attack our own tissues and contribute to chronic inflammation. O’Connell and colleagues found that the microRNAs at issue are produced by and act to control these important cell types.
‘Now we know which cells in the body we need to get miRNA inhibitors delivered to if we want to reduce chronic inflammatory conditions,’ said O’Connell, noting that the next step is human research. One question would be whether patients with chronic inflammation who received an inhibitor of a certain microRNA would see their chronic inflammation indicators decrease, preventing fatal conditions from emerging.
Previous studies have shown that chronic inflammation is linked to the development of certain conditions including diabetes, lupus, arthritis, obesity, cancer, neurodegeneration and cardiovascular disease along with a shortened life span. The challenge is that chronic inflammation happens at a low level and is typically not detected by doctors. But certain biomarkers such as elevated levels of cytokines or antibodies can indicate the condition.
‘Everyone waits until they have bad symptoms to go see the doctor,’ he said. ‘However, the goal of medicine is to take a person who is not sick yet and be able to analyze something we can test that can help predict whether they’re going to be sick in the future — and take appropriate measures to prevent terrible outcomes.’ EurekAlert
Scientists identify trigger for crucial immune system cell
, /in E-News /by 3wmediaScientists at The Scripps Research Institute (TSRI) have identified the long-sought activating molecules for a rare but crucial subset of immune system cells that help rally other white blood cells to fight infection.
In the process, the team also uncovered a previously unsuspected link between the mammalian immune system and the communication systems of simpler organisms such as bacteria.
The findings could lead to novel therapeutic approaches for diseases such as type 1 diabetes that are the result of immune system over-activity, as well as new ways to boost the effectiveness of vaccines, according to study leader Luc Teyton, a professor in TSRI’s Department of Immunology and Microbial Science.
When a virus, bacteria or foreign substance invades the body, specialised cells known as dendritic cells present in the skin and other organs capture the trespassers and convert them into smaller pieces called antigens that they then display on their cell surfaces. White blood cells known as T and B cells recognize the antigens to launch very specific attacks on the invaders.
Dendritic cells also activate a specialized population of T cells known as natural killer T (NKT) cells. Once activated, NKT cells can commandeer the functions of dendritic cells to make them more effective and also recruit and coordinate the responses of T- and B-type cells.
“Because of their dual functions, NKT cells are a bridge between the body’s innate immunity, which is characterised by rapid but less specific responses to pathogens, and adaptive or acquired immunity, which is composed of specialised white blood cells that can remember past invaders,” Teyton said.
Previous studies indicated that NKT cells are activated by molecules known as glycolipids that dendritic cells produce and then display on their outer surfaces. It was widely assumed that the activating molecules were a class of glycolipids known as beta-glycosylceramides, an important component of nervous system cells.
However, this hypothesis had not been thoroughly examined, in part because there is no chemical test currently available to distinguish between two forms of the molecule that have slightly different configurations—beta-glycosylceramide and alpha-glycosylceramide. In addition, when scientists attempt to create either form synthetically for testing, there is always the possibility of small contamination of one by the other.
“When you’re making glycolipids, there is no completely faithful way of controlling the form that you’re making,” Teyton said. ‘You’re favouring the making of one, but you cannot say for sure that you don’t have a small amount of the other form.”
In their new study, Teyton and his colleagues, who included scientists from Brigham Young University, the La Jolla Institute for Allergy & Immunology and the University of Chicago, abandoned the chemical approach altogether. Instead, they combined a series of biochemical and biological assays to create a test that was sensitive enough to distinguish between the two different forms of glycolipids.
“Biological assays are exquisitely sensitive to low amounts of otherwise unmeasurable molecules,” said study first author Lisa Kain, a research technician in Teyton’s lab.
The scientists used custom antibodies to identify and eliminate alpha-glycosylceramides from their test batches. When the team was confident that their test batch contained only beta forms of the glycolipid, they tested it on NKT cells gathered from mice. To their surprise, however, nothing happened. Contrary to the conventional wisdom, the beta-glycosylceramides failed to activate the NKT cells.
“We were very skeptical about the early results,” Teyton said. “We thought we had used the wrong antibody.”
Next, the team combined enzymes designed to digest molecular linkages found only on beta-glycosylceramides with mice NKT cells inside test tubes. Surprisingly, the NKT cells were still being activated.
Finally, when the team used antibodies to disable alpha-glycosylceramides inside live mice, not only did the NKT cells fail to activate, they disappeared altogether from organs such as the thymus, where NKT cells are produced.
These multiple lines of evidence strongly indicated that it was the alpha form of the glycolipids that were the triggers for NKT cells. “What we thought was the contaminant turned out to be the activating molecule we were looking for,” Teyton said.
The results were surprising for another reason. Until that moment, scientists did not think mammalian cells were capable of producing alpha forms of the glycolipids. The molecules were thought to exist only in bacteria and other simple organisms, which use them primarily as a means of communicating with one another. The findings thus suggest that the roots of a crucial part of the mammalian immune response are even more ancient than previously thought.
“Nobody expected this,” Teyton said. “It’s like discovering that all languages share a common origin.”
Now that scientists know that alpha-glycosylceramides are made by our own body and activate NKT cells, they might be able to exploit it to create new therapies. For example, Teyton said, researchers could use enzymes to reduce alpha-glycosylceramide levels in order to suppress an overactive immune response, which happens with diseases such as type 1 diabetes. Or they could combine the molecules with antigens to create vaccines that elicit a faster and more efficient immune response.
“This opens up an avenue of new therapeutic approaches that we’ve never even thought about,” Teyton said. The Scripps Research Institute
Researchers develop personalized ovarian cancer vaccines
, /in E-News /by 3wmediaResearchers at the University of Connecticut have found a new way to identify protein mutations in cancer cells. The novel method is being used to develop personalized vaccines to treat patients with ovarian cancer.
“This has the potential to dramatically change how we treat cancer,” says Dr. Pramod Srivastava, director of the Carole and Ray Neag Comprehensive Cancer Center at UConn Health and one of the principal investigators on the study. “This research will serve as the basis for the first ever genomics-driven personalised medicine clinical trial in immunotherapy of ovarian cancer, and will begin at UConn Health this fall,” Srivastava says.
Dr. Angela Kueck, a gynecological oncologist at UConn Health, will run the initial clinical study, once it is approved by the FDA. The research team will sequence DNA from the tumours of 15 to 20 women with ovarian cancer, and use that information to make a personalized vaccine for each woman.
The researchers focused their clinical trial on patients with ovarian cancer because the disease usually responds well to surgery and chemotherapy in the short term, but often returns lethally within a year or two. That gives researchers the perfect window to prepare and administer the new therapeutic vaccines, and also means they may be able to tell within two years or so whether the vaccine made a difference. If the personalized vaccines prove to be safe and feasible, they’ll design a Phase II trial to test its clinical effectiveness by determining whether they prolong patients’ lives.
In order for the immune system to attack cancers, it first has to recognize them. Every cell in the body has a sequence of proteins on its exterior that acts like an ID card or secret handshake, confirming that it’s one of the good guys. These protein sequences, called epitopes, are what the immune system ‘sees’ when it looks at a cell. Cancerous cells have epitopes, too. Since cancer cells originate from the body itself, their epitopes are very similar to those of healthy cells, and the immune system doesn’t recognize them as bad actors that must be destroyed.
But just as even the best spy occasionally slips up on the details, cancer cell epitopes have tiny differences or mistakes that could give them away, if only the immune system knew what to look for.
“We want to break the immune system’s ignorance,” Srivastava says. For example, there could be 1,000 subtle changes in the cancer cell epitopes, but only 10 are “real,” meaning significant to the immune system. To find the real, important differences, Mandoiu, the bioinformatics engineer, took DNA sequences from skin tumours in mice and compared them with DNA from the mice’s healthy tissue.
Previous researchers had done this but looked at how strongly the immune system cells bound to the cancer’s epitopes. This works when making vaccines against viruses, but not for cancers. Instead, Srivastava’s team came up with a novel measure: they looked at how different the cancer epitopes were from the mice’s normal epitopes. And it worked. When mice were inoculated with vaccines made of the cancer epitopes differing the most from normal tissue, they were very resistant to skin cancer.
Theoretically, this approach could work for other cancers, although the research has yet to be done. University of Connecticut
Middle-aged adults were more susceptible to the flu last year because of a new viral mutation
, /in E-News /by 3wmediaA team of scientists, led by researchers at The Wistar Institute, has identified a possible explanation for why middle-aged adults were hit especially hard by the H1N1 influenza virus during the 2013-2014 influenza season. The findings offer evidence that a new mutation in H1N1 viruses potentially led to more disease in these individuals. Their study suggests that the surveillance community may need to change how they choose viral strains that go into seasonal influenza vaccines, the researchers say.
“We identified a mutation in recent H1N1 strains that allows viruses to avoid immune responses that are present in a large number of middle-aged adults,” said Scott Hensley, Ph.D., a member of Wistar’s Vaccine Center and an assistant professor in the Translational Tumour Immunology program of Wistar’s Cancer Center.
Historically, children and the elderly are most susceptible to the severe effects of the influenza viruses, largely because they have weaker immune systems. However, during the 2013-2014 physicians saw an unusually high level of disease due to H1N1 viruses in middle-aged adults—those who should have been able to resist the viral assault. Although H1N1 viruses recently acquired several mutations in the haemagglutinin (HA) glycoprotein, standard serological tests used by surveillance laboratories indicate that these mutations do not change the viruses’ antigenic properties.
However, Wistar researchers have shown that, in fact, one of these mutations is located in a region of HA that allows viruses to avoid antibody responses elicited in some middle-aged adults. Specifically, they found that 42 percent of individuals born between 1965 and 1979 possess antibodies that recognize the region of HA that is now mutated. The Wistar researchers suggest that new viral strains that are antigenically matched in this region should be included in future influenza vaccines.
“Our immune systems are imprinted the first time that we are exposed to influenza virus,” Hensley said. “Our data suggest that previous influenza exposures that took place in the 1970s and 1980s influence how middle-aged people respond to the current H1N1 vaccine.”
The researchers noted that significant antigenic changes of influenza viruses are mainly determined using anti-sera isolated from ferrets recovering from primary influenza infections. However humans are typically re-infected with antigenically distinct influenza strains throughout their life. Therefore, antibodies that are used for surveillance purposes might not be fully reflective of human immunity. Wistar Institute
Peanut in house dust linked to allergy
, /in E-News /by 3wmediaA new study led by researchers at King’s College London in collaboration with the University of Manchester and the University of Dundee has found a strong link between exposure to peanut protein in household dust during infancy and the development of peanut allergy in children genetically predisposed to a skin barrier defect.
Around 2% of school children in the UK and the US are allergic to peanuts. Severe eczema in early infancy has been linked to food allergies, particularly peanut allergy. A major break-through in the understanding of eczema developed with the discovery of the FLG gene which codes for the skin barrier protein filaggrin. Mutations in the FLG gene result in an impaired skin barrier which is thought to allow allergens to penetrate the skin and predispose the body towards an allergic response.
Immunology, looked at the amount of peanut protein children were exposed to in household dust in their first year of life by vacuuming dust from the living room sofa and measuring peanut in the dust. A group of 577 children were assessed at 8 and 11 years of age for peanut allergy and their DNA was checked for FLG mutations. The study was conducted in children recruited to the Manchester Asthma and Allergy Study.
A strong link was found between early-life exposure to peanut protein in household dust and peanut allergy in children with FLG mutations. A three-fold increase in house dust peanut exposure during infancy was associated with a three-fold increase in risk of school-age peanut allergy. One in five children with peanut allergy had an FLG mutation. There was no significant effect of environmental peanut exposure in children without FLG mutations.
Dr Helen A Brough, first author from the Department of Paediatric Allergy, Division of Asthma, Allergy & Lung Biology, King’s College London, said: “Our findings provide evidence that peanut allergy may develop via the skin in children with mutations in the gene that codes for filaggrin which damage the function of this important skin protein. These findings are also an example of how an individual’s response to their environment can be modified by their genes. Our study raises the possibility of being able to identify a group of children with FLG mutations through genetic testing in the future, and altering their environmental exposure to peanut early in life to reduce the risk of developing peanut allergy.” King’s College London
Circulating tumour cells provide genomic snapshot of breast cancer
, /in E-News /by 3wmediaTumour cells isolated from the blood of patients with triple negative breast cancer reveal similar cancer-driving mutations as those detected from standard biopsy, suggesting that circulating cells could one day replace tissue biopsies
The genetic fingerprint of a metastatic cancer is constantly changing, which means that the therapy that may have stopped a patient’s cancer growth today, won’t necessarily work tomorrow. Although doctors can continue to biopsy the cancer during the course of the treatment and send samples for genomic analysis, not all patients can receive repeat biopsies. Taking biopsies from metastatic cancer patients is an invasive procedure that it is frequently impossible due to the lack of accessible lesions. Research suggest that tumour cells circulating in the blood of metastatic patients could give as accurate a genomic read-out as tumour biopsies.
“Counting the number of circulating tumour cells (CTCs) can tell us whether a patient’s cancer is aggressive, or whether it is stable and responding to therapy,” says the article’s first author Sandra V. Fernandez, Ph.D., assistant professor of Medical Oncology at Thomas Jefferson University. “Our work suggests that these cancer cells in the blood also accurately reflect the genetic status of the parent tumour or its metastases, potentially giving us a new and easy to source of genomic information to guide treatment.”
First discovered for their diagnostic potential in 2004, circulating tumour cells are beginning to be used in the clinic to help guide treatment decisions and track a patient’s progress as the cancer progresses. Although other studies have pooled the collected CTCs and compared their collective genetic signature to that of the primary tumour, this is the first study to look at the genomic signature of individual tumour cells in circulation. In order to isolate single tumour cells from the blood, the authors used a new technology, DEPArrayTM , in their laboratory.
The researchers compared tissue biopsies surgically removed from two patients with inflammatory breast cancer with circulating tumour cells (CTCs). Breast tissue samples from both patients showed a specific mutation in a region of a cancer-driving gene, p53. The authors studied this mutation in several CTCs isolated from both patients. They found that in several of the CTCs collected, the mutations matched with the tumour biopsy, however in one patient, some of circulating tumour cells had an additional mutation. “Since inflammatory breast cancer is a very rapidly changing disease, we think this additional mutation may have been acquired after the original surgical biopsy was taken,” said Dr. Fernandez. In the case where an additional p53 mutation was found, the blood to isolate CTCs were drawn one year later than the breast tissue biopsy was taken.
Although further work analyzing a greater number of genes and samples is needed, the work shows that CTCs offer the possibility of capturing the most current genomic information in an easy-to-obtain sample such as blood, thus helping guide treatment decisions. It also suggests that it may be necessary to test more than one cell for the most accurate reading, as the CTC population appears to be heterogenous. Thomas Jefferson University (TJU)
Genetic variant protects some Latina women from breast cancer
, /in E-News /by 3wmediaAn international research collaboration led by UC San Francisco researchers has identified a genetic variant common in Latina women that protects against breast cancer.
The variant, a difference in just one of the three billion “letters” in the human genome known as a single-nucleotide polymorphism (SNP), originates from indigenous Americans and confers significant protection from breast cancer, particularly the more aggressive oestrogen receptor–negative forms of the disease, which generally have a worse prognosis.
“The effect is quite significant,” said Elad Ziv, MD, professor of medicine and senior author of the study. “If you have one copy of this variant, which is the case for approximately 20 percent of U.S. Latinas, you are about 40 percent less likely to have breast cancer. If you have two copies, which occurs in approximately 1 percent of the US Latina population, the reduction in risk is on the order of 80 percent.”
The new study showed that women who carry the variant have breast tissue that appears less dense on mammograms. High “mammographic density” is a known risk factor for breast cancer.
“We have detected something that is definitely relevant to the health of Latinas, who represent a large percentage of the population in California, and of other states such as Texas,” said first author Laura Fejerman, PhD, assistant professor of medicine and a member of UCSF’s Institute of Human Genetics. “This work was done as a collaboration of multiple investigators, many of us originally from Latin America. As a Latina myself, I am gratified that there are representatives of that population directly involved in research that concerns them.” University of California – San Francisco
Loss of Y chromosome associated with higher mortality and cancer in men
, /in E-News /by 3wmediaAge-related loss of the Y chromosome (LOY) from blood cells, a frequent occurrence among elderly men, is associated with elevated risk of various cancers and earlier death.
This finding could help explain why men tend to have a shorter life span and higher rates of sex-unspecific cancers than women, who do not have a Y chromosome, said Lars Forsberg, PhD, lead author of the study and a geneticist at Uppsala University in Sweden.
LOY, which occurs occasionally as a given man’s blood cells replicate – and thus takes place inconsistently throughout the body – was first reported nearly 50 years ago and remains largely unexplained in both its causes and effects. Recent advances in genetic technology have allowed researchers to use a blood test to detect when only a small fraction of a man’s blood cells have undergone LOY.
Dr. Forsberg and colleagues studied blood samples from 1,153 elderly men aged 70 to 84 years, who were followed clinically for up to 40 years. They found that men whose samples showed LOY in a significant fraction of their blood cells lived an average of 5.5 years less than men whose blood was not affected by LOY. In addition, having undergone LOY significantly increased the men’s risk of dying from cancer during the course of the study. These associations remained statistically significant when results were adjusted for men’s age and other health conditions.
“Many people think the Y chromosome only contains genes involved in sex determination and sperm production,” said Jan Dumanski, MD, PhD, co-author on the study and a professor at Uppsala University. “In fact, these genes have other important functions, such as possibly playing a role in preventing tumours.” When LOY takes place, Y chromosome genes are not expressed, and this tumour prevention would be reduced.
Interestingly, LOY in blood cells is associated with many different cancers, including those outside of the blood system. This may be because Y chromosome genes enable blood cells to assist with immunosurveillance, the process by which the immune system detects and kills tumour cells to prevent cancer.
“Our hypothesis is that LOY disrupts the immunosurveillance normally conducted by blood cells, allowing tumours to grow unchecked and develop into cancer,” Dr. Forsberg said.
These findings suggest a new approach to early detection of cancer risk in men: a blood test to assess LOY. “LOY is not very dangerous in a small fraction of blood cells, but becomes increasingly predictive of cancer as more cells lose their Y chromosome,” Dr. Forsberg explained. “This takes years, so you’d have a window of time to do something to reduce your risk.”
The researchers are currently exploring LOY in more detail, including the effects of various lifestyle factors and other health conditions. They are also examining the frequency and consequences of LOY in different types of cells and throughout the life course. The American Society of Human Genetics
Prognostic factors identified for peripheral squamous cell carcinomas of the lung
, /in E-News /by 3wmediaA better survival outcome is associated with low blood levels of squamous cell carcinoma antigen, or absence of tumour invasion either into the space between the lungs and chest wall or into blood vessels of individuals with a peripheral squamous cell carcinoma, a type of non-small cell lung cancer (NSCLC).
Lung cancer is the most common cause of cancer-related death worldwide and lung squamous cell carcinomas (SCC) account for 20-30% of all NSCLC. SCC can be classified as either central (c-SCC) or peripheral (p-SCC) depending on the primary location. While c-SCC is the most prevalent, the incidence of p-SCC is increasing and the clinical and biological behaviours of p-SCC remain unclear.
Researchers from Keio University School of Medicine and Saiseikai Utsunomiya Hospital in Japan evaluated several clinical and pathological variables in 280 patients with surgically removed p-SCC in order to identify potential prognostic factors.
Results show that low preoperative levels of squamous cell carcinoma antigen in the serum or either absence of tumour invasion into the pleura (the space between the lungs and chest wall) or tumour vasculature are independent prognostic factors for patients with any stage of p-SCC. These patients had an extended period without disease recurrence and longer overall survival. The same was also seen for the sub-group of patients with early stage I disease.
The authors note that “our study revealed that p-SCCs with pleural or vascular invasion or high serum SCC antigen are more likely to recur than those without it; even in stage I patients. Pleural and/or vascular invasion are thought to be essential steps in the progression and metastasis of p-SCCs and high serum SCC antigen may suggest micro-metastases at the time of surgery.” The authors propose that “patients with high serum SCC levels, vascular invasion or pleural invasion should have their tumour stage upgraded in order to reflect the clear differences in survival. Clinical trials should be performed to evaluate if postoperative chemotherapy would benefit these patients who typically may not receive chemotherapy because of their early stage.” International Association for the Study of Lung Cancer
Clues to genetics of congenital heart defects emerge from Down syndrome study
, /in E-News /by 3wmediaDown syndrome is the most common chromosomal abnormality in humans, involving a third copy of all or part of chromosome 21. In addition to intellectual disability, individuals with Down syndrome have a high risk of congenital heart defects. However, not all people with Down syndrome have them – about half have structurally normal hearts.
Geneticists have been learning about the causes of congenital heart defects by studying people with Down syndrome. The high risk for congenital heart defects in this group provides a tool to identify changes in genes, both on and off chromosome 21, which are involved in abnormal heart development.
Researchers at Emory University School of Medicine, with colleagues at Johns Hopkins University, Oregon Health Science University, and University of Pittsburgh, report results from the largest genetic study of congenital heart defects in individuals with Down syndrome.
The team found that infants with congenital heart defects, in the context of Down syndrome, were more likely to have rare, large genetic deletions. Those deletions tended to involve genes that affect cilia, cellular structures that are important for signalling and patterning in embryonic development.
These new findings, along with other recent studies, suggest that the risk for congenital heart defects in Down syndrome can come from several genes and environmental factors, in addition to the substantial risk from the extra chromosome 21.
“In Down syndrome, there’s a 50-fold increase in risk for heart defects, which is enormous,” says senior author Michael Zwick, PhD, associate professor of human genetics and paediatrics at Emory. “Studying congenital heart defects in the ‘at risk’ Down syndrome population can make it possible to reveal genes that impact the risk of heart defects in all children, including those with typical number of chromosomes.”
“Understanding the origin of heart disorders in individuals with Down syndrome may reveal aspects of biology that would allow better personalization of their health care, since genetic alterations that affect the heart may also affect other organs, such as the lungs or gut,” Zwick says.
“Our partnership with families who have a child with Down syndrome and our investment in a comprehensive clinical data and biorepository will continue to provide resources to study not only heart defects, but also other Down-syndrome associated medical conditions such as cognitive function, leukaemia, and dementia,” says co-author Stephanie Sherman, PhD, professor of human genetics at Emory University School of Medicine.
The study included 452 individuals with Down syndrome. 210 had complete atrioventricular septal defects (AVSDs), a serious heart defect that is relatively common among those with Down syndrome (about 20 percent). The remaining 242 had structurally normal hearts. The Emory team used high density microarrays to probe more than 900,000 sites across the human genome to detect structural variation, including deletions or duplications of DNA.
An atrioventricular septal defect means that the central region of the heart separating the atria from the ventricles has failed to form properly. Such defects increase the workload on the heart, and a complete AVSD leads to heart failure: fluid buildup in the lungs and difficulty breathing, requiring surgery in the first year of life.
The team’s results add to evidence for a connection between AVSDs and cilia. Ciliopathies are a class of genetic disorders that include kidney, eye, and neurodevelopmental disorders. Cells in the airways have mobile cilia which sweep mucus and dirt out of the lungs, but almost every cell in the body has a primary (sensory) cilium.
“The finding that ciliome genes may be disrupted in children with Down syndrome and AVSD may indicate differences in life-time care for these individuals,” Zwick says. “This is a suggestive result that needs replication in a larger group.”
To confirm and strengthen the findings, Zwick and his team are currently performing an independent study of individuals with Down syndrome, using whole genome sequencing to further delineate alterations in genes that perturb heart development in children. Emory Health Sciences