A book containing misprints may cause annoyance for the reader, but typos in an individual’s genetic blueprint (DNA) can mean serious disease or even death. The search for genetic correlates for the wide range of diseases plaguing humankind has inspired a wealth of research falling under the heading of genome-wide association studies (GWAS).
According to Sudhir Kumar, director of the Center for Evolutionary Medicine and Informatics at Arizona State University’s Biodesign Institute, however, results from many such studies become less useful when gene variants or alleles implicated in disease in a given population fail to be discovered in subsequent independent studies. ‘Often, we do not discover the same set of mutations for the same disease in different populations,’ he says. ‘This is a huge problem in genomic medicine.’
Kumar and colleagues Joel T. Dudley, Rong Chen, Maxwell Sanderford, and Atul J. Butte, have developed a statistical method to remedy this problem by using evolutionary information. It is capable of significantly enhancing the likelihood of identifying disease-associated alleles that show better consistency across populations, improving the reliability of GWAS studies. The method makes use of phylogenetics – the comparative study of species genomes through long-term evolutionary history.
The new method is now available to use via the web, so that researchers worldwide can apply it as an aid to discovering disease-associated mutations that are more consistently reproducible and therefore useable as diagnostic markers. Kumar refers to this new approach, combining standard comparative genomic studies with phylogenetic data as phylomedicine, a rapidly developing field that promises to streamline genomic information and improve its diagnostic power.
‘We can take this method and apply it to all the data that has been published,’ Kumar says. ‘It will lead to new discoveries that were sitting right there, but nobody knew about.’
The new method boosts the discovery of reproducible mutations by integrating evolutionary history of humans with contemporary genomic information. Applying the new rankings to a large GWAS study improved the discovery of reliable mutation correlates of complex diseases, which will advance personalised medicine based on each patient’s genomic code.
The basic idea behind GWAS is simple: compare the genomes of two populations of subjects, one with disease trait and a control group without the disease. Next, identify the disparities at each position of the genome in the two populations. Find the alleles occurring in the diseased population that are less frequent in the healthy population and you have just pinpointed the gene mutations associated with disease.
Or have you?
As Kumar explains, matters are not so simple. The mutations studied in such studies are known as SNPs (for single-nucleotide polymorphisms). This simply means that for a given gene sequence, one of the four nucleotides (A,T,C and G) found commonly in the population is replaced by something else. For example, the majority of healthy subjects may carry the ‘A’ at a particular position in the genome, but disease individuals may be more likely to carry a ‘C’ at the same position. If the difference between the groups is striking, the SNP may be associated with the disease trait.
Human genomes are vast structures – consisting of some 3 billion base pairs of nucleotides. Most are littered with SNPs and teasing out which ones sit there without apparent effect and which may translate to disease is often a vexing affair. For some diseases, a one-to-one correspondence between gene mutation and disease exists. Generally, these afflictions, known as monogenic diseases, have particular characteristics. They result from a mutation in just a single gene, rather than multiple genes. They are early-onset diseases, taking their toll when the patient is still young.
Monogenic diseases, which include cystic fibrosis, Tay sachs disease, sickle cell anemia and Huntington’s disease are usually not the targets for genome-wide association studies, because the relationship between gene mutation and occurrence of the disease is straightforward and reliable.
By contrast, so-called complex diseases tend to occur later in life, are triggered by mutations occurring at multiple sites along the genome and often have a significant environmental– that is, non-genetic – component. Finding the alleles responsible for such diseases, which include hypertension, rheumatoid arthritis, Alzheimer’s disease, type II diabetes and countless others through GWAS studies has often been a bewildering endeavor, as alleles identified in one study population frequently fail to turn up in different studies with different populations.
GWAS studies compute the odds of an allele along the genome being disease-related and translate this into a statistic known as the P value. Alleles with the lowest P value are least likely to have occurred by random chance. In the current research, a meta-analysis is conducted using results from thousands of previous GWAS studies and phylogenetics are applied to unearth evolutionary trends in the data.
‘Every position in the human genome among the billions of base pairs has evolved over time,’ Kumar says. ‘As the genome evolves, some positions permit change frequently while others do not.’ The positions least likely to change with time and across mammalian species are known as evolutionarily conserved positions. The group conducted a multispecies genomic analysis of 5,831 putative human risk variants for more than 230 disease phenotypes reported in 2,021 studies. ‘Even if a GWAS variant does not have a functional role in a disease, evolutionary information is still very relevant, because every position in the human genome has an evolutionary signature that gives us prior information on how alleles at that position are likely to vary in modern human populations,’ says Dudley, the study’s lead author.
An analysis of existing data found that most of the presumptively disease-related alleles uncovered in the GWAS studies occurred at relatively slow-evolving, highly conserved sites. According to Kumar, this fact accounts for the poor reproducibility of many putative disease alleles across different populations, as alleles occurring at conserved sites tend to be rare. As Kumar explains ‘You can keep finding rare alleles like this all day, but they would have limited clinical utility in a broader population.’
The new ranking system, known as E-ranking, incorporates phylogenetic information from multi-species studies of mammals, and applies it to human GWAS data. The effect is to remove the inherent sampling bias for rare alleles, allowing the more common alleles occurring at fast-evolving sites in the genome to be more readily discovered. ‘Our method removes this bias, which gives a boost to high-frequency common variants that are more likely to reproduce across populations due to the evolutionary history of the genomic position where they are found,’ says Dudley.
Arizona State University
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:36:242021-01-08 11:13:45Evolutionary information improves discovery of mutations associated with diseases
Cedars-Sinai researchers have linked Kawasaki Disease, a serious childhood illness that causes inflammation of blood vessels throughout the body, with early-onset and accelerated atherosclerosis, a leading cause of heart disease in adults.
In a study, an American Heart Association peer-reviewed medical journal, a team of researchers showed how Kawasaki Disease in young mice predisposed them to develop accelerated atherosclerosis, often called hardening of the arteries, in young adulthood. The study also suggests that aggressive early treatment of the blood vessel inflammation caused by Kawasaki Disease may reduce the future risk of developing accelerated atherosclerosis. Up to 25 percent of children with Kawasaki Disease will develop inflammation of the coronary arteries, making it the leading cause of acquired heart disease among children in developed countries.
‘Heart disease is the leading cause of death in this country and this study suggests that adult cardiovascular diseases likely start during childhood and that Kawasaki Disease may play a role in the childhood origin of adult heart disease,’ said Moshe Arditi, MD, executive vice chair of research in Cedars-Sinai’s Department of Pediatrics in the Maxine Dunitz Children’s Health Center and director of the Division of Pediatric Infectious Diseases and Immunology. ‘By recognising the connection between this vascular inflammatory disease and hardening of the arteries in young adults, physicians will be better prepared to provide preventive care to these vulnerable patients.’
Arditi said the study’s findings also may have implications for children with Kawasaki Disease in that they may need to be closely monitored for future development of early-onset atherosclerosis. Also, doctors treating children who have had Kawasaki Disease should closely monitor other known cardiovascular disease risk factors such as obesity, high blood pressure, high cholesterol and smoking, Arditi said.
Kawasaki Disease is diagnosed in approximately 5,000 U.S. children every year, predominantly affecting children younger than five. Boys are more likely than girls to acquire Kawasaki Disease, which starts with a sudden, persistent fever and causes swollen hands and feet, red eyes and body rash. Scientists suspect Kawasaki Disease is the body’s immune reaction to a virus that has yet to be identified.
Atherosclerosis occurs when fat, cholesterol, and other substances build up in the walls of arteries and form hard structures called plaques. Over the course of years, plaque buildup makes it harder for blood to flow because the plaque narrows arteries and makes them stiffer. When pieces of plaque break off and move to smaller vessels, they can cause stroke, heart attack or pulmonary embolism.
In the study, which was funded with a grant from the National Institute of Allergy and Infectious Diseases, mice with Kawasaki Disease were fed a high-fat diet and then compared to mice that did not have Kawasaki Disease but did eat the same high-fat diet. The Kawasaki mice developed significantly more atherosclerotic plaque at a younger age.
‘This study suggests that timely diagnosis and aggressive initial treatment of the vascular inflammation may be important in preventing this potentially serious future complication,’ said co-author Prediman K. Shah, MD, director of cardiology, director of the and the Shapell and Webb Family Chair in Clinical Cardiology at the Cedars-Sinai Heart Institute.
EurekAlert
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:36:242021-01-08 11:13:44Researchers link Kawasaki Disease in childhood with increased risk of adult heart disease
Scientists have discovered two genetic variants associated with the substantial, rapid weight gain occurring in nearly half the patients treated with antipsychotic medications, according to two studies involving the Centre for Addiction and Mental Health (CAMH).
These results could eventually be used to identify which patients have the variations, enabling clinicians to choose strategies to prevent this serious side-effect and offer more personalised treatment.
‘Weight gain occurs in up to 40 per cent of patients taking medications called second-generation or atypical antipsychotics, which are used because they’re effective in controlling the major symptoms of schizophrenia,’ says CAMH Scientist Dr. James Kennedy, senior author on the most recent study.
This weight gain can lead to obesity, type 2 diabetes, heart problems and a shortened life span. ‘Identifying genetic risks leading to these side-effects will help us prescribe more effectively,’ says Dr. Kennedy, head of the new Tanenbaum Centre for Pharmacogenetics, which is part of CAMH’s Campbell Family Mental Health Research Institute. Currently, CAMH screens for two other genetic variations that affect patients’ responses to psychiatric medications.
Each study identified a different variation near the melanocortin-4 receptor (MC4R) gene, which is known to be linked to obesity.
In the Archives of General Psychiatry study, people carrying two copies of a variant gained about three times as much weight as those with one or no copies, after six to 12 weeks of treatment with atypical antipsychotics. (The difference was approximately 6 kg versus 2 kg.) The study had four patient groups: two from the U.S., one in Germany and one from a larger European study.
‘The weight gain was associated with this genetic variation in all these groups, which included pediatric patients with severe behaviour or mood problems, and patients with schizophrenia experiencing a first episode or who did not respond to other antipsychotic treatments,’ says CAMH Scientist Dr. Daniel Müller. ‘The results from our genetic analysis combined with this diverse set of patients provide compelling evidence for the role of this MC4R variant. Our research group has discovered other gene variants associated with antipsychotic-induced weight gain in the past, but this one appears to be the most compelling finding thus far.’
Three of the four groups had never previously taken atypical antipsychotics. Different groups were treated with drugs such as olanzapine, risperidone, aripiprazole or quetiapine, and compliance was monitored to ensure the treatment regime was followed. Weight and other metabolic-related measures were taken at the start and during treatment.
A genome-wide association study was conducted on pediatric patients by the study’s lead researcher, Dr. Anil Malhotra, at the Zucker Hillside Hospital in Glen Oaks, NY. In this type of study, variations are sought across a person’s entire set of genes to identify those associated with a particular trait. The result pointed to the MC4R gene.
This gene’s role in antipsychotic-induced weight gain had been identified in a CAMH study published earlier this year in The Pharmacogenomics Journal, involving Drs. Müller and Kennedy, and conducted by PhD student Nabilah Chowdhury. They found a different variation on MC4R that was linked to the side-effect.
For both studies, CAMH researchers did genotyping experiments to identify the single changes to the sequence of the MC4R gene – known as single nucleotide polymorphisms (SNPs) – related to the drug-induced weight gain side-effect.
The MC4R gene encodes a receptor involved in the brain pathways regulating weight, appetite and satiety. ‘We don’t know exactly how the atypical antipsychotics disrupt this pathway, or how this variation affects the receptor,’ says Dr. Müller. ‘We need further studies to validate this result and eventually turn this into a clinical application.’
The Centre for Addiction and Mental Health
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:36:242021-01-08 11:13:44Genetic link to rapid weight gain from antipsychotics discovered
Researchers at the Stanford University School of Medicine and Lucile Packard Children’s Hospital have identified several gene mutations responsible for the most common childhood brain tumour, called medulloblastoma, adding evidence to the theory that the diagnosis is a group of genetically distinct cancers with different prognoses. These and accompanying findings are likely to lead to less-toxic, better-targeted treatment approaches over the next two years, the researchers said.
‘We tend to treat all medulloblastomas as one disease without taking into account how heterogeneous the tumours are at the molecular level,’ said Yoon-Jae Cho, MD, an assistant professor of neurology and neurological sciences at Stanford, a pediatric neurologist at Packard Children’s and the senior author of the new research. ‘This paper represents a finer-grained view of the genetic landscape of these tumours and provides us with some leads on how to develop new therapies.’
The research is part of a large, ongoing effort to characterise genetic errors in medulloblastoma. Two companion studies on which Cho is a co-author will be published simultaneously with his paper. The three papers came from a consortium that involves scientists at Stanford, Packard Children’s, the Broad Institute, Children’s Hospital Boston, the Dana-Farber Cancer Institute, the German Cancer Research Center, Brandeis University and the Hospital for Sick Children in Toronto.
Current treatment for medulloblastoma, which originates in the cerebellum and affects about 250 U.S. children each year, begins with surgery to remove as much of the tumour as possible. Patients then receive a combination of radiation and chemotherapy, but the treatments are not tailored to the tumour’s genetic characteristics.
Cho’s team extracted DNA from 92 medulloblastoma tumours and compared it with DNA from matched blood samples from the same patients, uncovering 12 significant ‘point mutations’ — single-letter errors in the genetic code — that occurred frequently in the brain cancer. A handful of the mutations had been previously identified in smaller studies of medulloblastoma, but several mutations were novel in both medulloblastoma and in cancer.
Among the newly identified mutations was one in an RNA helicase gene, DDX3X, which Cho said is the second-most common mutation in medulloblastoma tumours. ‘Mutations in this gene have now also been identified in other tumour types, such as chronic lymphocytic leukaemia, and head and neck tumours,’ he said.
However, the researchers found that it was rare for the same gene mutated in several different patients’ tumours. More commonly, mutations involving a set of genes regulating a single biological pathway were found in the tumours — a pattern that is emerging across cancer genome sequencing efforts.
Though no single tumour in the study carried all 12 mutations, the researchers were able to categorise the tumours according to which mutations they possessed. ‘We now understand that there are certain tumours with particular genetic signatures that are really resistant to standard treatments,’ Cho said. Children with medulloblastoma do not routinely have their tumours’ genetic signatures characterised, but Cho believes that such characterisation coupled with targeted therapies could greatly enhance tumour treatment.
About two-thirds of medulloblastoma patients now survive five years past diagnosis, but many survivors suffer lasting physical or intellectual side effects from their cancer treatments. Drugs tailored to a tumour’s genetic profile have the potential to save more patients while reducing side effects, Cho said.
Several of the mutations discovered affect cellular signals that switch large groups of genes on and off. ‘The dysregulation of these ‘epigenetic programs’ is becoming a common theme not only in medulloblastoma but across cancer,’ Cho said. Such pathways may be good targets for cancer drugs; indeed, drugs targeting one such pathway (histone methyltransferases) are currently in pre-clinical development, while agents against another pathway (Hedgehog signaling pathway) are entering phase-2 clinical trials for medulloblastoma.
EurekAlert
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:36:242021-01-08 11:13:44Genetic mutations that cause common childhood brain tumours identified
A research study led by the Peninsula College of Medicine and Dentistry, University of Exeter, and Boston University School of Medicine, in collaboration with a global consortium, has identified genetic markers that influence a protein involved in regulating oestrogen and testosterone levels in the bloodstream.
The results also reveal that some of the genetic markers for this protein are near genes related to liver function, metabolism and type 2 diabetes, demonstrating an important genetic connection between the metabolic and reproductive systems in men and women.
The study was carried out in collaboration with the Framingham Heart Study and investigators from 15 international epidemiologic studies participating in the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) consortium.
Sex hormone binding globulin (SHBG) is the key protein that carries testosterone and oestrogen in the bloodstream in both men and women. As the main carrier of these sex hormones, SHBG helps to regulate their effects in different tissues and organs in the body. In addition to effects on reproduction in men and women through regulation of sex hormones, SHBG has been linked to many chronic diseases including type 2 diabetes and hormone-sensitive cancers such as breast and prostate.
Previous family studies have demonstrated that approximately 50 per cent of the variation in SHBG concentrations in the bloodstream is inherited from parents, suggesting that SHBG levels are under significant genetic control. However, little has been known about the specific genes that influence SHBG levels.
Investigators examined human genomes from 21,791 men and women to determine which genes influence SHBG levels and validated the results from this genome-wide association study (GWAS) in an additional 7,046 men and women. They identified 12 single-nucleotide polymorphisms (SNPs), or DNA sequence variations, associated with the concentration of SHBG circulating in the bloodstream. Although these genetic variants only explain a small fraction of the sex hormone variability seen between individuals, they could provide insight into the diseases connected to sex hormone regulation.
The results showed that the SNPs that influence SHBG levels are near genes related to liver function, fat and carbohydrate metabolism and type 2 diabetes. In addition, there were genes that had stronger effects in one sex compared to the other.
‘These findings highlight the diverse range of biological processes that may be impacted by sex hormone regulation,’ said Dr. John Perry of the Peninsula College of Medicine and Dentistry, University of Exeter.
EurekAlert
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:36:242021-01-08 11:13:44Genetic markers for testosterone and oestrogen level regulation identified
Scientists behind Olympic Team GB are working on genetic tests to understand why some athletes are prone to injury, BBC’s Newsnight has learned.
Tendon injuries and stress fractures are common in elite athletes, but how and why they happen is less clear.
University College London’s Prof Hugh Montgomery says they have found a gene they think strongly influences the risk of stress fracture and more will come.
It is hoped the research will allow training to be individually tailored.
Diet, repetitive strain and loading are all known to play a part, and scientists say there is clearly a strong genetic element.
Director of the Institute for Human Health and Performance at University College London, Prof Montgomery carried out groundbreaking work on genes and fitness in the 1990s, most notably the ‘ACE’ gene, thought to be linked to endurance.
‘If we understood that genetic component we would have a much better understanding of the patho-physiology – the disease processes that let that happen,’ says Prof Montgomery.
He has been working closely with the English Institute of Sport (EIS), which aims to apply the latest in sports science and medicine for the benefit of Britain’s Olympic and Paralympic athletes.
EIS’s Director of Sport Science, Dr Ken van Someren, told Newsnight he is keen to apply the latest genetics discoveries.
‘If we can identify some particular genes that are associated with a higher risk of injury in certain individuals, and we think we’re close, we can tailor the training, conditioning and preparation that we put those individuals through.’
He added that should injury occur, the research could also influence the medical treatment the person receives.
But Dr van Someren stressed that there is no intention to use genes as a means of identifying sporting talent.
He says that for many people sport is about a fun and healthy lifestyle and genetics should not be used to screen people in or out of sport, adding that although genes might tell us a lot about the likelihood or probability of success, it is not an absolute science and there would be a danger of ‘missing out on some future champions.’
Prof Montgomery believes that looking for tomorrow’s sporting champions should involve looking at a combination of genes and the environment, rather than just relying on screening the genome.
He says we should look a person’s performance and dedication and to the sport rather than trying to ‘predict that dedication and performance by gene screening.’
BBC
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:36:242021-01-08 11:13:44Olympic Team GB trials gene tests for injury
A race to unlock genetic clues behind living to 100 is set to begin next year, after a US team announced it will compete for the $10m Genomics X Prize. Genetic entrepreneur Dr Jonathan Rothberg is entering the challenge to identify genes linked to a long, healthy life. His team – and any other contenders – will be given 30 days to work out the full DNA code of 100 centenarians at a cost of no more than $1,000 per genome.
The race will start in September 2013. Under the rules of the Archon Genomics X Prize, teams have until next May to register for the competition. Dr Rothberg’s team from Life Technologies Corporation in California is the first to formally enter the race.
His latest business venture, Ion Torrent, makes the Personal Genome Machine and the Ion Proton sequencer
Rothberg claims his machines can sequence DNA more quickly and cheaply than ever thought possible
The Ion Proton sequencer will be used for the challenge. Being able to sequence the full human genome at a cost of $1,000 or less is regarded as a milestone in science.
It is seen as the threshold at which DNA sequencing technology becomes cheap enough to be used widely in medicine, helping in diagnosis and in matching drugs to a patient’s genetic make-up.
‘
One hundred people aged 100 have donated their DNA for the project.
Scientists believe people who reach a very old age may have certain rare changes in their genes which protect against common diseases of later life, such as heart disease and cancer. If these genes can be identified by analysing the DNA codes of centenarians, it will help scientists search for new medical treatments and perhaps ways to prolong life. However, many sample DNA sequences will be needed in order to get the accuracy needed to pinpoint changes on the scale of a few genetic letters among the three billion in the human genome.
Dr Jonathan Rothberg, a geneticist and entrepreneur, said the DNA of 100 centenarians is a good start towards finding ‘the fountains of youth’.
He told BBC News: ‘One hundred people will give you a hint. One thousand will make you reasonably sure. Ten thousand will let you say, ‘Hey, these are the genes involved in cancer or heart disease”.
Dr Craig Venter is the originator of the prize and one of the main players in the race to sequence the first human genome, which was completed in 2003.
BBC
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:36:242021-01-08 11:13:43Genetic entrepreneur to compete in Genomics X Prize
The hormone oxytocin—often referred to as the ‘trust’ hormone or ‘love hormone’ for its role in stimulating emotional responses—plays an important role in Williams syndrome (WS), according to a study.
The study, a collaboration between scientists at the Salk Institute for Biological Studies and the University of Utah, found that people with WS flushed with the hormones oxytocin and arginine vasopressin (AVP) when exposed to emotional triggers.
The findings may help in understanding human emotional and behavioural systems and lead to new treatments for devastating illnesses such as WS, post-traumatic stress disorder, anxiety and possibly even autism.
‘Williams syndrome results from a very clear genetic deletion, allowing us to explore the genetic and neuronal basis of social behaviour,’ says Ursula Bellugi, the director of Salk’s Laboratory for Cognitive Neuroscience and a co-author on the paper. ‘This study provides us with crucial information about genes and brain regions involved in the control of oxytocin and vasopressin, hormones that may play important roles in other disorders.’
WS arises from a faulty recombination event during the development of sperm or egg cells. As a result, virtually everyone with WS has exactly the same set of genes missing (25 to 28 genes are missing from one of two copies of chromosome 7). There also are rare cases of individuals who retain one or more genes that most people with the disorder have lost.
To children with WS, people are much more comprehensible than inanimate objects. Despite myriad health problems they are extremely gregarious, irresistibly drawn to strangers, and insist on making eye contact. They have an affinity for music. But they also experience heightened anxiety, have an average IQ of 60, experience severe spatial-visual problems, and suffer from cardiovascular and other health issues. Despite their desire to befriend people, they have difficulty creating and maintaining social relationships, something that is not at all understood but can afflict many people without WS.
In the new study, led by Dr. Julie R. Korenberg, a University of Utah professor and Salk adjunct professor, the scientists conducted a trial with 21 participants, 13 who have WS and a control group of eight people without the disorder. The participants were evaluated at the Cedars-Sinai Medical Center in Los Angeles. Because music is a known strong emotional stimulus, the researchers asked participants to listen to music.
Before the music was played, the participants’ blood was drawn to determine a baseline level for oxytocin, and those with WS had three times as much of the hormone as those without the syndrome. Blood also was drawn at regular intervals while the music played and was analysed afterward to check for real-time, rapid changes in the levels of oxytocin and AVP. Other studies have examined how oxytocin affects emotion when artificially introduced into people, such as through nasal sprays, but this is one of the first significant studies to measure naturally occurring changes in oxytocin levels in rapid, real time as people undergo an emotional response.
There was little outward response to the music, but when the blood samples were analysed, the researchers were happily surprised. The analyses showed that the oxytocin levels, and to a lesser degree AVP, had not only increased but begun to bounce among WS participants while among those without WS, both the oxytocin and AVP levels remained largely unchanged as they listened to music.
Korenberg believes the blood analyses strongly indicate that oxytocin and AVP are not regulated correctly in people with WS, and that the behavioural characteristics unique to people with WS are related to this problem.
‘This shows that oxytocin quite likely is very involved in emotional response,’ Korenberg says.
To ensure accuracy of results, those taking the test also were asked to place their hands in 60-degree Fahrenheit water to test for negative stress, and the same results were produced as when they listened to music. Those with WS experienced an increase in oxytocin and AVP, while those without the syndrome did not.
Salk Institute
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:36:242021-01-08 11:13:47‘Trust’ hormone oxytocin found at heart of rare genetic disorder
A new study shows that loss of a small RNA molecule in liver cells might cause liver cancer and that restoring the molecule might slow tumour growth and offer a new way to treat the disease.
The animal study was led by researchers at the Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).
The scientists examined what happens when liver cells lack a molecule called microRNA-122 (miR-122). They found that when the molecule is missing, the liver develops fat deposits, inflammation and tumours that resemble hepatocellular carcinoma (HCC), the most common form of liver cancer.
When the researchers artificially restored miR-122 to nearly normal levels by delivering the miR-122 gene into liver cells, it dramatically reduced the size and number of tumours, with tumours making up 8 percent on average of liver surface area in treated animals versus 40 percent in control animals.
‘These findings reveal that miR-122 has a critical tumour-suppressor role in the healthy liver, and they highlight the possible therapeutic value of miR-122 replacement for some patients with liver cancer,’ says study leader Dr. Kalpana Ghoshal, associate professor of pathology and a member of the OSUCCC – James Experimental Therapeutics Program.
More than 28,700 new cases of HCC are expected in the United States in 2012, and 20,550 Americans are expected to die of the malignancy. Major risk factors for HCC include hepatitis B and C virus infection and liver damage due to alcohol use. HCC is curable if caught early, but most cases are diagnosed at a late, incurable stage.
MiR-122 is found mainly in liver cells – it is the most abundant microRNA in those cells – and it plays a major role in regulating cholesterol in the body. This microRNA is lost in some people with HCC, however, resulting in a poor prognosis.
For this study, Ghoshal and her colleagues developed a strain of mice that lacks miR-122 and develops HCC through the progression of events that begins with fatty liver deposits followed by inflammation and liver cancer.
The researchers then used a second strain of mice that spontaneously develops liver cancer due to over-expression of a cancer-causing gene called MYC (pronounced ‘mick’). The researchers delivered miR-122 into the animals’ livers during tumour development. Three weeks later, those treated with the molecule had smaller and fewer tumours.
‘The model we developed for these studies will not only facilitate our understanding of liver biology but also be good for testing therapeutic efficacy of newly developed drugs against liver disease, including HCC,’ Ghoshal says.
Ghoshal also notes that research by others has shown that hepatitis C virus requires miR-122 for replication. ‘Because our findings demonstrate what happens when miR-122 is lost in liver cells, they might help improve the safety of new drugs that treat hepatitis C virus infection by blocking miR-122,’ she says.
The Ohio State University Comprehensive Cancer Center
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:36:042021-01-08 11:13:43Loss of a tiny liver molecule might lead to liver cancer
Severe influenza doubles the odds that a person will develop Parkinson’s disease later in life, according to University of British Columbia researchers.
However, the opposite is true for people who contracted a typical case of red measles as children – they are 35 per cent less likely to develop Parkinson’s, a nervous system disorder marked by slowness of movement, shaking, stiffness, and in the later stages, loss of balance.
The findings by researchers at UBC’s School of Population and Public Health and the Pacific Parkinson’s Research Centre are based on interviews with 403 Parkinson’s patients and 405 healthy people in British Columbia, Canada.
Lead author Anne Harris also examined whether occupational exposure to vibrations – such as operating construction equipment – had any effect on the risk of Parkinson’s. In another study she and her collaborators reported that occupational exposure actually decreased the risk of developing the disease by 33 percent, compared to people whose jobs involved no exposure.
Meanwhile, Harris found that those exposed to high-intensity vibrations – for example, by driving snowmobiles, military tanks or high-speed boats – had a consistently higher risk of developing Parkinson’s than people whose jobs involved lower-intensity vibrations (for example, operating road vehicles). The elevated risk fell short of the statistical significance typically used to establish a correlation, but was strong and consistent enough to suggest an avenue for further study, Harris says.
‘There are no cures or prevention programs for Parkinson’s, in part because we still don’t understand what triggers it in some people and not others,’ says Harris, who conducted the research while earning her doctorate at UBC. ‘This kind of painstaking epidemiological detective work is crucial in identifying the mechanisms that might be at work, allowing the development of effective prevention strategies.’
University of British Columbia
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:36:042021-01-08 11:13:43Severe flu increases risk of Parkinson’s: UBC research
We may ask you to place cookies on your device. We use cookies to let us know when you visit our websites, how you interact with us, to enrich your user experience and to customise your relationship with our website.
Click on the different sections for more information. You can also change some of your preferences. Please note that blocking some types of cookies may affect your experience on our websites and the services we can provide.
Essential Website Cookies
These cookies are strictly necessary to provide you with services available through our website and to use some of its features.
Because these cookies are strictly necessary to provide the website, refusing them will affect the functioning of our site. You can always block or delete cookies by changing your browser settings and block all cookies on this website forcibly. But this will always ask you to accept/refuse cookies when you visit our site again.
We fully respect if you want to refuse cookies, but to avoid asking you each time again to kindly allow us to store a cookie for that purpose. You are always free to unsubscribe or other cookies to get a better experience. If you refuse cookies, we will delete all cookies set in our domain.
We provide you with a list of cookies stored on your computer in our domain, so that you can check what we have stored. For security reasons, we cannot display or modify cookies from other domains. You can check these in your browser's security settings.
.
Google Analytics Cookies
These cookies collect information that is used in aggregate form to help us understand how our website is used or how effective our marketing campaigns are, or to help us customise our website and application for you to improve your experience.
If you do not want us to track your visit to our site, you can disable this in your browser here:
.
Other external services
We also use various external services such as Google Webfonts, Google Maps and external video providers. Since these providers may collect personal data such as your IP address, you can block them here. Please note that this may significantly reduce the functionality and appearance of our site. Changes will only be effective once you reload the page
Google Webfont Settings:
Google Maps Settings:
Google reCaptcha settings:
Vimeo and Youtube videos embedding:
.
Privacy Beleid
U kunt meer lezen over onze cookies en privacy-instellingen op onze Privacybeleid-pagina.
Evolutionary information improves discovery of mutations associated with diseases
, /in E-News /by 3wmediaA book containing misprints may cause annoyance for the reader, but typos in an individual’s genetic blueprint (DNA) can mean serious disease or even death. The search for genetic correlates for the wide range of diseases plaguing humankind has inspired a wealth of research falling under the heading of genome-wide association studies (GWAS).
According to Sudhir Kumar, director of the Center for Evolutionary Medicine and Informatics at Arizona State University’s Biodesign Institute, however, results from many such studies become less useful when gene variants or alleles implicated in disease in a given population fail to be discovered in subsequent independent studies. ‘Often, we do not discover the same set of mutations for the same disease in different populations,’ he says. ‘This is a huge problem in genomic medicine.’
Kumar and colleagues Joel T. Dudley, Rong Chen, Maxwell Sanderford, and Atul J. Butte, have developed a statistical method to remedy this problem by using evolutionary information. It is capable of significantly enhancing the likelihood of identifying disease-associated alleles that show better consistency across populations, improving the reliability of GWAS studies. The method makes use of phylogenetics – the comparative study of species genomes through long-term evolutionary history.
The new method is now available to use via the web, so that researchers worldwide can apply it as an aid to discovering disease-associated mutations that are more consistently reproducible and therefore useable as diagnostic markers. Kumar refers to this new approach, combining standard comparative genomic studies with phylogenetic data as phylomedicine, a rapidly developing field that promises to streamline genomic information and improve its diagnostic power.
‘We can take this method and apply it to all the data that has been published,’ Kumar says. ‘It will lead to new discoveries that were sitting right there, but nobody knew about.’
The new method boosts the discovery of reproducible mutations by integrating evolutionary history of humans with contemporary genomic information. Applying the new rankings to a large GWAS study improved the discovery of reliable mutation correlates of complex diseases, which will advance personalised medicine based on each patient’s genomic code.
The basic idea behind GWAS is simple: compare the genomes of two populations of subjects, one with disease trait and a control group without the disease. Next, identify the disparities at each position of the genome in the two populations. Find the alleles occurring in the diseased population that are less frequent in the healthy population and you have just pinpointed the gene mutations associated with disease.
Or have you?
As Kumar explains, matters are not so simple. The mutations studied in such studies are known as SNPs (for single-nucleotide polymorphisms). This simply means that for a given gene sequence, one of the four nucleotides (A,T,C and G) found commonly in the population is replaced by something else. For example, the majority of healthy subjects may carry the ‘A’ at a particular position in the genome, but disease individuals may be more likely to carry a ‘C’ at the same position. If the difference between the groups is striking, the SNP may be associated with the disease trait.
Human genomes are vast structures – consisting of some 3 billion base pairs of nucleotides. Most are littered with SNPs and teasing out which ones sit there without apparent effect and which may translate to disease is often a vexing affair. For some diseases, a one-to-one correspondence between gene mutation and disease exists. Generally, these afflictions, known as monogenic diseases, have particular characteristics. They result from a mutation in just a single gene, rather than multiple genes. They are early-onset diseases, taking their toll when the patient is still young.
Monogenic diseases, which include cystic fibrosis, Tay sachs disease, sickle cell anemia and Huntington’s disease are usually not the targets for genome-wide association studies, because the relationship between gene mutation and occurrence of the disease is straightforward and reliable.
By contrast, so-called complex diseases tend to occur later in life, are triggered by mutations occurring at multiple sites along the genome and often have a significant environmental– that is, non-genetic – component. Finding the alleles responsible for such diseases, which include hypertension, rheumatoid arthritis, Alzheimer’s disease, type II diabetes and countless others through GWAS studies has often been a bewildering endeavor, as alleles identified in one study population frequently fail to turn up in different studies with different populations.
GWAS studies compute the odds of an allele along the genome being disease-related and translate this into a statistic known as the P value. Alleles with the lowest P value are least likely to have occurred by random chance. In the current research, a meta-analysis is conducted using results from thousands of previous GWAS studies and phylogenetics are applied to unearth evolutionary trends in the data.
‘Every position in the human genome among the billions of base pairs has evolved over time,’ Kumar says. ‘As the genome evolves, some positions permit change frequently while others do not.’ The positions least likely to change with time and across mammalian species are known as evolutionarily conserved positions. The group conducted a multispecies genomic analysis of 5,831 putative human risk variants for more than 230 disease phenotypes reported in 2,021 studies. ‘Even if a GWAS variant does not have a functional role in a disease, evolutionary information is still very relevant, because every position in the human genome has an evolutionary signature that gives us prior information on how alleles at that position are likely to vary in modern human populations,’ says Dudley, the study’s lead author.
An analysis of existing data found that most of the presumptively disease-related alleles uncovered in the GWAS studies occurred at relatively slow-evolving, highly conserved sites. According to Kumar, this fact accounts for the poor reproducibility of many putative disease alleles across different populations, as alleles occurring at conserved sites tend to be rare. As Kumar explains ‘You can keep finding rare alleles like this all day, but they would have limited clinical utility in a broader population.’
The new ranking system, known as E-ranking, incorporates phylogenetic information from multi-species studies of mammals, and applies it to human GWAS data. The effect is to remove the inherent sampling bias for rare alleles, allowing the more common alleles occurring at fast-evolving sites in the genome to be more readily discovered. ‘Our method removes this bias, which gives a boost to high-frequency common variants that are more likely to reproduce across populations due to the evolutionary history of the genomic position where they are found,’ says Dudley. Arizona State University
Researchers link Kawasaki Disease in childhood with increased risk of adult heart disease
, /in E-News /by 3wmediaCedars-Sinai researchers have linked Kawasaki Disease, a serious childhood illness that causes inflammation of blood vessels throughout the body, with early-onset and accelerated atherosclerosis, a leading cause of heart disease in adults.
In a study, an American Heart Association peer-reviewed medical journal, a team of researchers showed how Kawasaki Disease in young mice predisposed them to develop accelerated atherosclerosis, often called hardening of the arteries, in young adulthood. The study also suggests that aggressive early treatment of the blood vessel inflammation caused by Kawasaki Disease may reduce the future risk of developing accelerated atherosclerosis. Up to 25 percent of children with Kawasaki Disease will develop inflammation of the coronary arteries, making it the leading cause of acquired heart disease among children in developed countries.
‘Heart disease is the leading cause of death in this country and this study suggests that adult cardiovascular diseases likely start during childhood and that Kawasaki Disease may play a role in the childhood origin of adult heart disease,’ said Moshe Arditi, MD, executive vice chair of research in Cedars-Sinai’s Department of Pediatrics in the Maxine Dunitz Children’s Health Center and director of the Division of Pediatric Infectious Diseases and Immunology. ‘By recognising the connection between this vascular inflammatory disease and hardening of the arteries in young adults, physicians will be better prepared to provide preventive care to these vulnerable patients.’
Arditi said the study’s findings also may have implications for children with Kawasaki Disease in that they may need to be closely monitored for future development of early-onset atherosclerosis. Also, doctors treating children who have had Kawasaki Disease should closely monitor other known cardiovascular disease risk factors such as obesity, high blood pressure, high cholesterol and smoking, Arditi said.
Kawasaki Disease is diagnosed in approximately 5,000 U.S. children every year, predominantly affecting children younger than five. Boys are more likely than girls to acquire Kawasaki Disease, which starts with a sudden, persistent fever and causes swollen hands and feet, red eyes and body rash. Scientists suspect Kawasaki Disease is the body’s immune reaction to a virus that has yet to be identified.
Atherosclerosis occurs when fat, cholesterol, and other substances build up in the walls of arteries and form hard structures called plaques. Over the course of years, plaque buildup makes it harder for blood to flow because the plaque narrows arteries and makes them stiffer. When pieces of plaque break off and move to smaller vessels, they can cause stroke, heart attack or pulmonary embolism.
In the study, which was funded with a grant from the National Institute of Allergy and Infectious Diseases, mice with Kawasaki Disease were fed a high-fat diet and then compared to mice that did not have Kawasaki Disease but did eat the same high-fat diet. The Kawasaki mice developed significantly more atherosclerotic plaque at a younger age.
‘This study suggests that timely diagnosis and aggressive initial treatment of the vascular inflammation may be important in preventing this potentially serious future complication,’ said co-author Prediman K. Shah, MD, director of cardiology, director of the and the Shapell and Webb Family Chair in Clinical Cardiology at the Cedars-Sinai Heart Institute. EurekAlert
Genetic link to rapid weight gain from antipsychotics discovered
, /in E-News /by 3wmediaScientists have discovered two genetic variants associated with the substantial, rapid weight gain occurring in nearly half the patients treated with antipsychotic medications, according to two studies involving the Centre for Addiction and Mental Health (CAMH).
These results could eventually be used to identify which patients have the variations, enabling clinicians to choose strategies to prevent this serious side-effect and offer more personalised treatment.
‘Weight gain occurs in up to 40 per cent of patients taking medications called second-generation or atypical antipsychotics, which are used because they’re effective in controlling the major symptoms of schizophrenia,’ says CAMH Scientist Dr. James Kennedy, senior author on the most recent study.
This weight gain can lead to obesity, type 2 diabetes, heart problems and a shortened life span. ‘Identifying genetic risks leading to these side-effects will help us prescribe more effectively,’ says Dr. Kennedy, head of the new Tanenbaum Centre for Pharmacogenetics, which is part of CAMH’s Campbell Family Mental Health Research Institute. Currently, CAMH screens for two other genetic variations that affect patients’ responses to psychiatric medications.
Each study identified a different variation near the melanocortin-4 receptor (MC4R) gene, which is known to be linked to obesity.
In the Archives of General Psychiatry study, people carrying two copies of a variant gained about three times as much weight as those with one or no copies, after six to 12 weeks of treatment with atypical antipsychotics. (The difference was approximately 6 kg versus 2 kg.) The study had four patient groups: two from the U.S., one in Germany and one from a larger European study.
‘The weight gain was associated with this genetic variation in all these groups, which included pediatric patients with severe behaviour or mood problems, and patients with schizophrenia experiencing a first episode or who did not respond to other antipsychotic treatments,’ says CAMH Scientist Dr. Daniel Müller. ‘The results from our genetic analysis combined with this diverse set of patients provide compelling evidence for the role of this MC4R variant. Our research group has discovered other gene variants associated with antipsychotic-induced weight gain in the past, but this one appears to be the most compelling finding thus far.’
Three of the four groups had never previously taken atypical antipsychotics. Different groups were treated with drugs such as olanzapine, risperidone, aripiprazole or quetiapine, and compliance was monitored to ensure the treatment regime was followed. Weight and other metabolic-related measures were taken at the start and during treatment.
A genome-wide association study was conducted on pediatric patients by the study’s lead researcher, Dr. Anil Malhotra, at the Zucker Hillside Hospital in Glen Oaks, NY. In this type of study, variations are sought across a person’s entire set of genes to identify those associated with a particular trait. The result pointed to the MC4R gene.
This gene’s role in antipsychotic-induced weight gain had been identified in a CAMH study published earlier this year in The Pharmacogenomics Journal, involving Drs. Müller and Kennedy, and conducted by PhD student Nabilah Chowdhury. They found a different variation on MC4R that was linked to the side-effect.
For both studies, CAMH researchers did genotyping experiments to identify the single changes to the sequence of the MC4R gene – known as single nucleotide polymorphisms (SNPs) – related to the drug-induced weight gain side-effect.
The MC4R gene encodes a receptor involved in the brain pathways regulating weight, appetite and satiety. ‘We don’t know exactly how the atypical antipsychotics disrupt this pathway, or how this variation affects the receptor,’ says Dr. Müller. ‘We need further studies to validate this result and eventually turn this into a clinical application.’ The Centre for Addiction and Mental Health
Genetic mutations that cause common childhood brain tumours identified
, /in E-News /by 3wmediaResearchers at the Stanford University School of Medicine and Lucile Packard Children’s Hospital have identified several gene mutations responsible for the most common childhood brain tumour, called medulloblastoma, adding evidence to the theory that the diagnosis is a group of genetically distinct cancers with different prognoses. These and accompanying findings are likely to lead to less-toxic, better-targeted treatment approaches over the next two years, the researchers said.
‘We tend to treat all medulloblastomas as one disease without taking into account how heterogeneous the tumours are at the molecular level,’ said Yoon-Jae Cho, MD, an assistant professor of neurology and neurological sciences at Stanford, a pediatric neurologist at Packard Children’s and the senior author of the new research. ‘This paper represents a finer-grained view of the genetic landscape of these tumours and provides us with some leads on how to develop new therapies.’
The research is part of a large, ongoing effort to characterise genetic errors in medulloblastoma. Two companion studies on which Cho is a co-author will be published simultaneously with his paper. The three papers came from a consortium that involves scientists at Stanford, Packard Children’s, the Broad Institute, Children’s Hospital Boston, the Dana-Farber Cancer Institute, the German Cancer Research Center, Brandeis University and the Hospital for Sick Children in Toronto.
Current treatment for medulloblastoma, which originates in the cerebellum and affects about 250 U.S. children each year, begins with surgery to remove as much of the tumour as possible. Patients then receive a combination of radiation and chemotherapy, but the treatments are not tailored to the tumour’s genetic characteristics.
Cho’s team extracted DNA from 92 medulloblastoma tumours and compared it with DNA from matched blood samples from the same patients, uncovering 12 significant ‘point mutations’ — single-letter errors in the genetic code — that occurred frequently in the brain cancer. A handful of the mutations had been previously identified in smaller studies of medulloblastoma, but several mutations were novel in both medulloblastoma and in cancer.
Among the newly identified mutations was one in an RNA helicase gene, DDX3X, which Cho said is the second-most common mutation in medulloblastoma tumours. ‘Mutations in this gene have now also been identified in other tumour types, such as chronic lymphocytic leukaemia, and head and neck tumours,’ he said.
However, the researchers found that it was rare for the same gene mutated in several different patients’ tumours. More commonly, mutations involving a set of genes regulating a single biological pathway were found in the tumours — a pattern that is emerging across cancer genome sequencing efforts.
Though no single tumour in the study carried all 12 mutations, the researchers were able to categorise the tumours according to which mutations they possessed. ‘We now understand that there are certain tumours with particular genetic signatures that are really resistant to standard treatments,’ Cho said. Children with medulloblastoma do not routinely have their tumours’ genetic signatures characterised, but Cho believes that such characterisation coupled with targeted therapies could greatly enhance tumour treatment.
About two-thirds of medulloblastoma patients now survive five years past diagnosis, but many survivors suffer lasting physical or intellectual side effects from their cancer treatments. Drugs tailored to a tumour’s genetic profile have the potential to save more patients while reducing side effects, Cho said.
Several of the mutations discovered affect cellular signals that switch large groups of genes on and off. ‘The dysregulation of these ‘epigenetic programs’ is becoming a common theme not only in medulloblastoma but across cancer,’ Cho said. Such pathways may be good targets for cancer drugs; indeed, drugs targeting one such pathway (histone methyltransferases) are currently in pre-clinical development, while agents against another pathway (Hedgehog signaling pathway) are entering phase-2 clinical trials for medulloblastoma. EurekAlert
Genetic markers for testosterone and oestrogen level regulation identified
, /in E-News /by 3wmediaA research study led by the Peninsula College of Medicine and Dentistry, University of Exeter, and Boston University School of Medicine, in collaboration with a global consortium, has identified genetic markers that influence a protein involved in regulating oestrogen and testosterone levels in the bloodstream.
The results also reveal that some of the genetic markers for this protein are near genes related to liver function, metabolism and type 2 diabetes, demonstrating an important genetic connection between the metabolic and reproductive systems in men and women.
The study was carried out in collaboration with the Framingham Heart Study and investigators from 15 international epidemiologic studies participating in the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) consortium.
Sex hormone binding globulin (SHBG) is the key protein that carries testosterone and oestrogen in the bloodstream in both men and women. As the main carrier of these sex hormones, SHBG helps to regulate their effects in different tissues and organs in the body. In addition to effects on reproduction in men and women through regulation of sex hormones, SHBG has been linked to many chronic diseases including type 2 diabetes and hormone-sensitive cancers such as breast and prostate.
Previous family studies have demonstrated that approximately 50 per cent of the variation in SHBG concentrations in the bloodstream is inherited from parents, suggesting that SHBG levels are under significant genetic control. However, little has been known about the specific genes that influence SHBG levels.
Investigators examined human genomes from 21,791 men and women to determine which genes influence SHBG levels and validated the results from this genome-wide association study (GWAS) in an additional 7,046 men and women. They identified 12 single-nucleotide polymorphisms (SNPs), or DNA sequence variations, associated with the concentration of SHBG circulating in the bloodstream. Although these genetic variants only explain a small fraction of the sex hormone variability seen between individuals, they could provide insight into the diseases connected to sex hormone regulation.
The results showed that the SNPs that influence SHBG levels are near genes related to liver function, fat and carbohydrate metabolism and type 2 diabetes. In addition, there were genes that had stronger effects in one sex compared to the other.
‘These findings highlight the diverse range of biological processes that may be impacted by sex hormone regulation,’ said Dr. John Perry of the Peninsula College of Medicine and Dentistry, University of Exeter. EurekAlert
Olympic Team GB trials gene tests for injury
, /in E-News /by 3wmediaScientists behind Olympic Team GB are working on genetic tests to understand why some athletes are prone to injury, BBC’s Newsnight has learned.
Tendon injuries and stress fractures are common in elite athletes, but how and why they happen is less clear.
University College London’s Prof Hugh Montgomery says they have found a gene they think strongly influences the risk of stress fracture and more will come.
It is hoped the research will allow training to be individually tailored.
Diet, repetitive strain and loading are all known to play a part, and scientists say there is clearly a strong genetic element.
Director of the Institute for Human Health and Performance at University College London, Prof Montgomery carried out groundbreaking work on genes and fitness in the 1990s, most notably the ‘ACE’ gene, thought to be linked to endurance.
‘If we understood that genetic component we would have a much better understanding of the patho-physiology – the disease processes that let that happen,’ says Prof Montgomery.
He has been working closely with the English Institute of Sport (EIS), which aims to apply the latest in sports science and medicine for the benefit of Britain’s Olympic and Paralympic athletes.
EIS’s Director of Sport Science, Dr Ken van Someren, told Newsnight he is keen to apply the latest genetics discoveries.
‘If we can identify some particular genes that are associated with a higher risk of injury in certain individuals, and we think we’re close, we can tailor the training, conditioning and preparation that we put those individuals through.’
He added that should injury occur, the research could also influence the medical treatment the person receives.
But Dr van Someren stressed that there is no intention to use genes as a means of identifying sporting talent.
He says that for many people sport is about a fun and healthy lifestyle and genetics should not be used to screen people in or out of sport, adding that although genes might tell us a lot about the likelihood or probability of success, it is not an absolute science and there would be a danger of ‘missing out on some future champions.’
Prof Montgomery believes that looking for tomorrow’s sporting champions should involve looking at a combination of genes and the environment, rather than just relying on screening the genome.
He says we should look a person’s performance and dedication and to the sport rather than trying to ‘predict that dedication and performance by gene screening.’ BBC
Genetic entrepreneur to compete in Genomics X Prize
, /in E-News /by 3wmediaA race to unlock genetic clues behind living to 100 is set to begin next year, after a US team announced it will compete for the $10m Genomics X Prize. Genetic entrepreneur Dr Jonathan Rothberg is entering the challenge to identify genes linked to a long, healthy life. His team – and any other contenders – will be given 30 days to work out the full DNA code of 100 centenarians at a cost of no more than $1,000 per genome.
The race will start in September 2013. Under the rules of the Archon Genomics X Prize, teams have until next May to register for the competition. Dr Rothberg’s team from Life Technologies Corporation in California is the first to formally enter the race.
His latest business venture, Ion Torrent, makes the Personal Genome Machine and the Ion Proton sequencer
Rothberg claims his machines can sequence DNA more quickly and cheaply than ever thought possible
The Ion Proton sequencer will be used for the challenge. Being able to sequence the full human genome at a cost of $1,000 or less is regarded as a milestone in science.
It is seen as the threshold at which DNA sequencing technology becomes cheap enough to be used widely in medicine, helping in diagnosis and in matching drugs to a patient’s genetic make-up.
‘
One hundred people aged 100 have donated their DNA for the project.
Scientists believe people who reach a very old age may have certain rare changes in their genes which protect against common diseases of later life, such as heart disease and cancer. If these genes can be identified by analysing the DNA codes of centenarians, it will help scientists search for new medical treatments and perhaps ways to prolong life. However, many sample DNA sequences will be needed in order to get the accuracy needed to pinpoint changes on the scale of a few genetic letters among the three billion in the human genome.
Dr Jonathan Rothberg, a geneticist and entrepreneur, said the DNA of 100 centenarians is a good start towards finding ‘the fountains of youth’.
He told BBC News: ‘One hundred people will give you a hint. One thousand will make you reasonably sure. Ten thousand will let you say, ‘Hey, these are the genes involved in cancer or heart disease”.
Dr Craig Venter is the originator of the prize and one of the main players in the race to sequence the first human genome, which was completed in 2003. BBC
‘Trust’ hormone oxytocin found at heart of rare genetic disorder
, /in E-News /by 3wmediaThe hormone oxytocin—often referred to as the ‘trust’ hormone or ‘love hormone’ for its role in stimulating emotional responses—plays an important role in Williams syndrome (WS), according to a study.
The study, a collaboration between scientists at the Salk Institute for Biological Studies and the University of Utah, found that people with WS flushed with the hormones oxytocin and arginine vasopressin (AVP) when exposed to emotional triggers.
The findings may help in understanding human emotional and behavioural systems and lead to new treatments for devastating illnesses such as WS, post-traumatic stress disorder, anxiety and possibly even autism.
‘Williams syndrome results from a very clear genetic deletion, allowing us to explore the genetic and neuronal basis of social behaviour,’ says Ursula Bellugi, the director of Salk’s Laboratory for Cognitive Neuroscience and a co-author on the paper. ‘This study provides us with crucial information about genes and brain regions involved in the control of oxytocin and vasopressin, hormones that may play important roles in other disorders.’
WS arises from a faulty recombination event during the development of sperm or egg cells. As a result, virtually everyone with WS has exactly the same set of genes missing (25 to 28 genes are missing from one of two copies of chromosome 7). There also are rare cases of individuals who retain one or more genes that most people with the disorder have lost.
To children with WS, people are much more comprehensible than inanimate objects. Despite myriad health problems they are extremely gregarious, irresistibly drawn to strangers, and insist on making eye contact. They have an affinity for music. But they also experience heightened anxiety, have an average IQ of 60, experience severe spatial-visual problems, and suffer from cardiovascular and other health issues. Despite their desire to befriend people, they have difficulty creating and maintaining social relationships, something that is not at all understood but can afflict many people without WS.
In the new study, led by Dr. Julie R. Korenberg, a University of Utah professor and Salk adjunct professor, the scientists conducted a trial with 21 participants, 13 who have WS and a control group of eight people without the disorder. The participants were evaluated at the Cedars-Sinai Medical Center in Los Angeles. Because music is a known strong emotional stimulus, the researchers asked participants to listen to music.
Before the music was played, the participants’ blood was drawn to determine a baseline level for oxytocin, and those with WS had three times as much of the hormone as those without the syndrome. Blood also was drawn at regular intervals while the music played and was analysed afterward to check for real-time, rapid changes in the levels of oxytocin and AVP. Other studies have examined how oxytocin affects emotion when artificially introduced into people, such as through nasal sprays, but this is one of the first significant studies to measure naturally occurring changes in oxytocin levels in rapid, real time as people undergo an emotional response.
There was little outward response to the music, but when the blood samples were analysed, the researchers were happily surprised. The analyses showed that the oxytocin levels, and to a lesser degree AVP, had not only increased but begun to bounce among WS participants while among those without WS, both the oxytocin and AVP levels remained largely unchanged as they listened to music.
Korenberg believes the blood analyses strongly indicate that oxytocin and AVP are not regulated correctly in people with WS, and that the behavioural characteristics unique to people with WS are related to this problem.
‘This shows that oxytocin quite likely is very involved in emotional response,’ Korenberg says.
To ensure accuracy of results, those taking the test also were asked to place their hands in 60-degree Fahrenheit water to test for negative stress, and the same results were produced as when they listened to music. Those with WS experienced an increase in oxytocin and AVP, while those without the syndrome did not. Salk Institute
Loss of a tiny liver molecule might lead to liver cancer
, /in E-News /by 3wmediaA new study shows that loss of a small RNA molecule in liver cells might cause liver cancer and that restoring the molecule might slow tumour growth and offer a new way to treat the disease.
The animal study was led by researchers at the Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).
The scientists examined what happens when liver cells lack a molecule called microRNA-122 (miR-122). They found that when the molecule is missing, the liver develops fat deposits, inflammation and tumours that resemble hepatocellular carcinoma (HCC), the most common form of liver cancer.
When the researchers artificially restored miR-122 to nearly normal levels by delivering the miR-122 gene into liver cells, it dramatically reduced the size and number of tumours, with tumours making up 8 percent on average of liver surface area in treated animals versus 40 percent in control animals.
‘These findings reveal that miR-122 has a critical tumour-suppressor role in the healthy liver, and they highlight the possible therapeutic value of miR-122 replacement for some patients with liver cancer,’ says study leader Dr. Kalpana Ghoshal, associate professor of pathology and a member of the OSUCCC – James Experimental Therapeutics Program.
More than 28,700 new cases of HCC are expected in the United States in 2012, and 20,550 Americans are expected to die of the malignancy. Major risk factors for HCC include hepatitis B and C virus infection and liver damage due to alcohol use. HCC is curable if caught early, but most cases are diagnosed at a late, incurable stage.
MiR-122 is found mainly in liver cells – it is the most abundant microRNA in those cells – and it plays a major role in regulating cholesterol in the body. This microRNA is lost in some people with HCC, however, resulting in a poor prognosis.
For this study, Ghoshal and her colleagues developed a strain of mice that lacks miR-122 and develops HCC through the progression of events that begins with fatty liver deposits followed by inflammation and liver cancer.
The researchers then used a second strain of mice that spontaneously develops liver cancer due to over-expression of a cancer-causing gene called MYC (pronounced ‘mick’). The researchers delivered miR-122 into the animals’ livers during tumour development. Three weeks later, those treated with the molecule had smaller and fewer tumours.
‘The model we developed for these studies will not only facilitate our understanding of liver biology but also be good for testing therapeutic efficacy of newly developed drugs against liver disease, including HCC,’ Ghoshal says.
Ghoshal also notes that research by others has shown that hepatitis C virus requires miR-122 for replication. ‘Because our findings demonstrate what happens when miR-122 is lost in liver cells, they might help improve the safety of new drugs that treat hepatitis C virus infection by blocking miR-122,’ she says. The Ohio State University Comprehensive Cancer Center
Severe flu increases risk of Parkinson’s: UBC research
, /in E-News /by 3wmediaSevere influenza doubles the odds that a person will develop Parkinson’s disease later in life, according to University of British Columbia researchers.
However, the opposite is true for people who contracted a typical case of red measles as children – they are 35 per cent less likely to develop Parkinson’s, a nervous system disorder marked by slowness of movement, shaking, stiffness, and in the later stages, loss of balance.
The findings by researchers at UBC’s School of Population and Public Health and the Pacific Parkinson’s Research Centre are based on interviews with 403 Parkinson’s patients and 405 healthy people in British Columbia, Canada.
Lead author Anne Harris also examined whether occupational exposure to vibrations – such as operating construction equipment – had any effect on the risk of Parkinson’s. In another study she and her collaborators reported that occupational exposure actually decreased the risk of developing the disease by 33 percent, compared to people whose jobs involved no exposure.
Meanwhile, Harris found that those exposed to high-intensity vibrations – for example, by driving snowmobiles, military tanks or high-speed boats – had a consistently higher risk of developing Parkinson’s than people whose jobs involved lower-intensity vibrations (for example, operating road vehicles). The elevated risk fell short of the statistical significance typically used to establish a correlation, but was strong and consistent enough to suggest an avenue for further study, Harris says.
‘There are no cures or prevention programs for Parkinson’s, in part because we still don’t understand what triggers it in some people and not others,’ says Harris, who conducted the research while earning her doctorate at UBC. ‘This kind of painstaking epidemiological detective work is crucial in identifying the mechanisms that might be at work, allowing the development of effective prevention strategies.’ University of British Columbia