June 26, 2017 Credit: martha sexton/public domain

The sex of animals frequently has an effect in biomedical research and therefore should be considered in the study of science, report scientists from the Wellcome Trust Sanger Institute and the International Mouse Phenotyping Consortium. In the largest study of its kind, researchers found that the differences between male and female mice had an effect that could impact research results in more than half of their studies.

The study, published today (26 June) in Nature Communications, quantified the differences between males and females - known as sexual dimorphism. The results have implications for the design of future animal studies which underpin research into treatments for human diseases.

Historically, a woman has been thought of as a small man in medicine and biomedical research. Even today, medical practice is less evidence-based for women than for men due to a bias towards the study of males in biomedical research.

Sex influences the prevalence, course and severity of the majority of common diseases and disorders, including cardiovascular diseases, autoimmune diseases and asthma. In spite of this, the usual approach in biomedical research is to ignore sex or to analyse only one sex and assume the results apply to the other sex.

In this new study, researchers have quantified the difference between male and female mice, looking across multiple experiments and institutes. In the largest study of its kind, scientists analysed up to 234 physical characteristics of more than 50,000 mice.

The team found that in the standard group of mice - the control mice - their sex had an impact on 56.6 per cent of quantitative traits, such as bone mass, and on 9.9 per cent of qualitative traits, including whether the shape of the head was normal or abnormal. In mice that had a gene switched off - the mutant mice - their sex modified the effect of the mutation in 13.3 per cent of qualitative traits and up to 17.7 per cent of quantitative traits.

Dr Natasha Karp, lead author who carried out the research at the Wellcome Trust Sanger Institute, and now works in the IMED Biotech Unit at AstraZeneca, said: "This was a scientific blindspot that we really thought needed exploration. A person's sex has a significant impact on the course and severity of many common diseases, and the consequential side effects of treatments - which are being missed. Now we have a quantitative handle on how much sexual dimorphism has an impact in biomedical research. In the movement towards precision medicine, we not only have to account for genetic differences between people when we consider disease, but also their sex."

In the study, scientists analysed 14,250 control mice and 40,192 mutant mice from 10 centres that are part of the International Mouse Phenotyping Consortium (IMPC). At each institution, scientists studied up to 234 physical characteristics of the mice, including body composition, metabolic profile, blood components, behavioural traits and whole body characterisation - whether the head shape, coat, paws and other areas of their bodies were normal or abnormal.

In the first half of the study, scientists studied the differences between the physical traits of control male and female mice to see if their sex had an effect.

In the second part of the study, scientists then looked at how the sex of a mouse impacted on the effect of a genetic modification. For example, researchers switched off a gene and assessed whether any differences in the resulting trait depended on the sex of the mice.

Professor Judith Mank, an author of the study from University College London, said: "This study illustrates how often sex differences occur in traits that we would otherwise assume to be the same in males and females. More importantly, the fact that a mouse's sex influenced the effects of genetic modification indicates that males and females differ right down to the underlying genetics behind many traits. This means that only studying males paints half the picture."

This study presents implications for the design of future animal studies and clinical trials. It has been more than twenty years since it became a requirement that women were included within clinical trials in the US. Whilst more women are taking part in clinical trials, increasing from 9 per cent in 1970 to 41 per cent 2006, women are still under-represented.

The bias is even stronger in the earlier stages of biomedical research. A review of international animal research between 2011 and 2012 found that 22 per cent of studies did not state the sex of the animals, and of those that did, 80 per cent of studies used solely males and only 3 per cent included both males and females.

Professor Steve Brown, an author of the study who is Director of the MRC Harwell Institute and Chair of the International Mouse Phenotyping Consortium Steering Committee, said: "It is likely that important scientific information is missed by not investigating more thoroughly how males and females differ in biomedical research. Rather than extrapolate the results to account for the opposite sex, these results suggest designing experiments to include both sexes in the study of disease. This study is a major step to highlighting the impact of sex differences in research and will help in accounting for those differences in the future of biomedicine."

Explore further: Lab mice may not be effective models for immunology research

More information: Natasha Karp et al. (2017) Prevalence of sexual dimorphism in mammalian phenotypic traits. Nature Communications. DOI: 10.1038/NCOMMS15475

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Study reveals how sex 'blindspot' could misdirect medical research - Medical Xpress

Do you lie awake at night, wishing you could sleep for hours on end? Do you toss and turn, raging against your inability to enter the land of dreams? Worrying about the end of the world aside, your lack of snoozes could be down to your parents and their pesky genetics.

Were not talking about a few hours of sleep lost here and there, by the way. Were referring to full-blown insomnia, which can last for months or even years at a time. It has a number of causes, including anxiety, a bad sleeping environment, physical and mental health conditions, and adverse reactions to medication.

There have been hints that there are genetic markers that make someone predispositioned towards suffering from insomnia too, but a new study in Nature Genetics gives more credence to the idea than ever before.

A team from Vrije Universiteit Amsterdam (VU) have found seven risk genes in a sample of 113,006 individuals that make someone more likely but not certain to suffer from insomnia compared to those that lacked the genes. These genes arent directly related to sleep patterns, but rather their presence creates an unintended side-effect that appears to trigger sleep loss.

The primary purpose of these genes is two-fold: to read DNA and make RNA copies, and to allow cells to release signaling molecules so that they can communicate with their environment. For some reason, their existence appears to overlap with an increased risk of several conditions, including anxiety disorders, depression, neuroticism, perceived lack of wellbeing, educational difficulties, and insomnia.

The team note that one of these risk genes, MEIS1, has been found on previous occasions to be related to restless legs syndrome and periodic limb movements of sleep. These are characterized by sporadic physical movements, whereas insomnia is of course typified by a disruptive state of consciousness.

Curiously, the risk genes and the associated insomnia was more prevalent in men (33 percent of sample) than women (24 percent of the sample). At present, this discrepancy has no known explanation.

This suggests that, for some part, different biological mechanisms may lead to insomnia in men and women, co-author Danielle Posthuma, a professor of statistical genetics at VU, said in a statement.

In short, theres still a lot we dont know about insomnia, but this study suggests that genes inherited from your parents play a larger role than previously thought. In several people, its likely that their affliction is not a purely psychological condition.

In any case, severe insomnia brings with it a heavy mental and physical toll. If it gets serious enough, you shouldnt rely on sleeping pills every night go and see a clinical practitioner tofind out what they recommend.

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Insomnia May Be A Partly Genetic Condition - IFLScience

Regular exercise may offer some protection against Alzheimer's disease, even for people who are genetically at risk, according to recent research.

In the study, published in the Journal of Alzheimers Disease, people who did more moderate-intensity physical activity were more likely to have healthy patterns of glucose metabolism in their brainsa sign of healthy brain activitythan those who did less. Light-intensity physical activity, on the other hand, was not associated with similar benefits.

The study involved 93 adults with an average age of 64, all of whom had at least one parent with Alzheimers disease, at least one gene variation linked to Alzheimers disease, or both. This put them at high risk for developing the disease themselves, although none showed any cognitive impairment at the time of the study.

To illuminate the relationship between brain activity and exercise levels, everyone wore an accelerometer for a week to measure their daily physical activity and received PET scans to measure glucose metabolism, which reveals neuron health and activity, in several regions of the brain. For people with Alzheimers disease, these regions tend to have depressed glucose metabolism.

Researchers found that people who spent at least 68 minutes a day engaged in physical activity at a moderate levelthe equivalent of a brisk walkhad better glucose metabolism in all of those regions than those who spent less time doing so.

The amounts of time spent being sedentary or doing less-intense physical activity (like slow walking) were not associated with changes in any of the brain regions studied. Vigorous activity was linked to better glucose metabolism in one brain regionthe hippocampus but not in the others.

Larger doses of high-intensity exercise may be needed to provide the benefits of just a modest increase in moderate activity, the authors wrote, suggesting that you don't have to exercise to the extreme to get brain benefits. Past research comparing the brain-boosting power of moderate- and vigorous-intensity exercise has been mixed, says lead author Ozioma Okonkwo, assistant professor of medicine at the University of Washington School of Medicine and Public Health. But in general, he says, the evidence suggests that light activity is insufficient, and vigorous activity might be unnecessary.

Being able to quantify the connection between moderate-intensity activity and brain health is an exciting and important step in Alzheimers research, the researchers say, although further studies are needed in order to show a cause-and-effect relationship between exercise and glucose metabolismand to demonstrate real-life benefits. (The team is currently recruiting people with concerns about their brain health for a clinical trial to help determine the right dose of exercise for people with mild memory problems.)

But Okonkwo points out that previous research has already established a connection between glucose metabolism and cognitive function. Were showing now that a moderate-intensity active lifestyle actually boosts neuronal function, he says. "I dont think its too much of a leap to make the argument that this probably is one of the pathways through which exercise prevents cognitive decline in middle life.

Okonkwo says this research offers reassurance that people can take steps to protect themselves against Alzheimers disease, even if they are at high genetic risk. The evidence shows that its never too late to take up and maintain a physically active regimen, he says. It also suggests that the earlier you begin and the longer you continue it, the more benefits you tend to accrue.

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How Exercise May Protect the Brain From Alzheimer's Disease - TIME

June 25, 2017

BySTEVE FREKER

MALDEN More than 1,000 local high school students in Malden and Medford have benefited from a unique partnership pairing them with Tufts University staff and students to study genetics.

The students will participate in Tufts Universitys Bioinformatics Inquiry through Sequencing (BioSeq) program with part of the program paid for by a $100,000 grant from the Cummings Foundation.

Were very grateful for Cummings Foundations generosity and its continued commitment to both Tufts University and the goal of enhancing STEM education for young students from our local communities, said Matthew Fierman, Ph.D., BioSeqs program administrator.

BioSeq uses an interactive curriculum to explain genetic science and prepare students for research careers and enhancing understanding of how genetics work can shape and save lives.

The BioSeq program is part of Tufts and Cummings Foundations legacy of support for science, technology, engineering and mathematics (STEM) education opportunities for students in greater Boston.

Founded with funding from the National Institutes of Health Science Education Partnership Award and now in its fifth year, BioSeq has reached many students in Medford, Malden and Somerville schools.

Until recently, genetic sequencing was labor-intensive, slow and expensive. Thanks to next-generation sequencing, however, scientists are employing new tools to gather genetic data and to draw meaningful conclusions on how the data can push the boundaries of medical knowledge and bring the promise of personalized medicine closer to reality.

Despite these tremendous advances, genetic science technology is largely out of the reach of the high school audience.

Because of the Cummings Foundations support, students will have opportunities to learn by asking and answering their own questions about genetics, Fierman said.

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Tufts teams up with Malden and Medford students - Daily Item

In his lab in Lake Nona, Dr. Peter Crawford has been studying nonalcoholic fatty liver disease, a condition thats closely linked to obesity and type 2 diabetes.

He is using cutting edge metabolic and genetic tools to try to figure out how and why nonalcoholic fatty liver disease, or fatty liver, progresses into a more severe form, putting the patients at a higher risk of developing cirrhosis and liver cancer.

Its a real scare, and its directly linked to the obesity epidemic, said Crawford, a physician and research scientist at Sanford Burnham Prebys Medical Discovery Institute.

In nonalcoholic fatty liver disease, liver cells retain fat. The condition has a strong association with developing cardiovascular disease. In a small portion of individuals it can progress to the point that they need a transplant or get cancer.

The disease began making its mark on medical charts not long after obesity became an epidemic in the 1980s.

Its cause is not exactly known, but it is strongly linked to diabetes, obesity and high cholesterol, making it the most common liver disorder in Western industrialized countries. By 2030 the condition will be the most common reason for liver transplants in the United States, according to a 2014 study by researchers at the Cleveland Clinic.

Meanwhile, most patients who have fatty liver arent aware of it, and the condition can evade primary care providers too, because it usually doesnt affect the results of routine blood work. For those who are eventually diagnosed usually after the disease progresses to its more severe form there are no drugs available.

When you combine the fact that the natural history of the disease is unclear; its difficulty to diagnose, treat and stage it; and theres no FDA-approved medicine, it becomes a huge issue, said Dr. Jaideep Behari, associate professor of medicine at the University of Pittsburgh and director of the Fatty Liver Clinic.

The issue is more pronounced in states like Florida, where more than a quarter of the population is obese, and as a result, more likely to have type 2 diabetes.

For local doctors, who continue to see liver disease cases related to hepatitis infections and alcohol abuse, fatty liver is a rapidly growing third category.

Its becoming an epidemic, said Dr. Nasim Ahmed, a gastroenterologist at Gastroenterology Consultants CFL in Orlando.

At Digestive and Liver Center of Florida, one of the large local independent practices, the proportion of patients who have liver disease because of alcohol, hepatitis and obesity is almost equal these days, said Dr. Srinivas Seela, one of the practices founding partners.

Its frustrating that these patients have no medical treatment, said Dr. Harinath Sheela, Seelas partner and brother.

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About 10 percent to 15 percent of the patients develop the more severe condition called nonalcoholic steatohepatitis, or NASH, but its not yet known which patients are more likely to fall in this category, adding to doctors frustration.

For now, the standard treatment is lifestyle change. Patients are advised to lose weight and get their diabetes under control, although not all patients follow the advice.

But theres hope, because fatty liver has become an active area of research.

At least 200 drugs targeting the conditions are in clinical trials and a handful are in the advanced stages of research. The National Institute of Diabetes and Digestive and Kidney Disease has created a nationwide clinical research network to conduct studies for preventing and treating the disease.

So its possible that there will be a therapies within the next three to five years that will decrease the rates [of the disease], said Behari of University of Pittsburgh.

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He was also encouraged by Crawfords research.

Crawfords recent findings from animal studies has amplified the silent dialogue between liver cells and their neighboring immune cells, showing that when certain fuels produced by the liver cells are off balance, the immune cells in the liver go rogue and cause scarring and worsening of fatty liver disease.

Thats a very exciting finding, said Behari, whos not involved in the research. Anything that helps us open up that black box and understand the disease at the molecular level is a big deal.

Crawford, whos working to publish the results of his most recent study, hopes the findings will pave the way toward developing a drug and help identify patients who are at a higher risk of developing severe forms of nonalcoholic fatty liver disease.

He added that the findings also reiterate another important point.

One way to look at it is that even in one strict cell type, having a balanced nutrition is important, Crawford said.

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Fatty liver disease target of cutting-edge genetic research - Orlando Sentinel

After decades of research and theoretical debates, it seems precision oncology is finally falling into place.

At the end of May, FDA triggered a seismic shift in the field with its decision to approve a therapy based on a genetic signature,not a tissue of origin. The ruling solidified the fields move towards the use of biomarkers to precisely target each persons cancer, rather than blindly administering toxic agents.

On Thursday, another big milestone was reached with FDAs premarket approval (PMA) of the first companion diagnostic for multiple drugs, the Oncomine Dx Target Test. A PMA is the most stringent type of device marketing application required by FDA.

Developed by Thermo Fisher Scientific, the assay uses next-generation sequencing (NGS) to simultaneously screen for 23 cancer genes. Three of those genes are tied to three different FDA-approved therapies for non-small cell lung cancer (NSCLC).

And thats just the beginning.

Via phone, Thermo Fishers President of Clinical NGSJoydeep Goswami noted that the regulatory work has already been done for further indications.

While we presented evidence of analytical validation of all the different genes, given the initial companion drugs were all non-small cell lung cancer-related, the FDA chose to initially limit this approval to that patient group, he said.

After all, its all new territory for the agency as well.

Its the first-ever multi-biomarker NGS, IVD [in vitro diagnostic], companion diagnostic that was ever approved. And also, I think for the FDA, for multiple drugs being approved for a companion diagnostic at the same time.

The company intends to work with the FDA to get more genes added to the panel, more companion therapies matched, and more indications for use in different tissues.At least one other company,Foundation Medicine, is working on a multi-biomarker, multi-drug companion test.

Lung cancer is a good starting point for a number of reasons: The genes are actionable, the samples are hard to collect, and time is of the essence.

With this NGS test, the sample requirement is very small and it delivers results in a matter of days, Goswami said. That compares to the single biomarker, sequential testing techniques using PCR or IHC, which take weeks and use a large amountof sample with each test. Oncologists dont want to go back for more.

The cost of a lung biopsy, at the best of times, is somewhere in the $5,000-$20,000 range, Goswami explained. But if there are complications, which is often the case with compromised patients, it can go up to $40,000 or more.

Perhaps more importantly, the procedure is an immense burden on already sick patients, he stated.

The companion therapies are made by Pfizer, AstraZeneca, and Novartis. The latter also received approval for its combination therapy on Thursday, in concert with the approval of the Oncomine Dx Target Test. FDA noted both in its announcement.

For Goswami, the greatest advantage of a companion diagnostic tied to multiple drugs is its ability to democratize access to precision medicine.

When FDA announced its approval of Keytruda for a biomarker, it incited a lot of debate about the number of patients that were getting their tumors sequenced. As it stands, an NSCLC patient at a top academic institution, such as Mayo Clinic, will likely get the tests required to confirm their eligibility for all the approved therapies or clinical trials. Yet these are laboratory-developed tests (LDTs), which are tied to a single clinical location.

The Oncomine Dx Target Test will be available nationwide;LabCorps Diagnostics and Covance Businesses, NeoGenomics Laboratories, and Cancer Genetics have all signed up as early adopters.

I dont see why any patient should not have access to this technology, Goswami said.

Thermo will start discussions with payers and the Centers for Medicare and Medicaid Services now that the approval is finalized.

If the trend continues, biomarkers will become an increasingly important part of cancer treatment. But its not always a one-to-one equation.These mutations are often actionable in unexpected ways.

Take, for example, Mercks flagship immunotherapy Keytruda. In an early June interview, Mercks SVP, Head of Global Clinical Development, and CMO Roy Baynes said the company is currently taking a four-pronged approach to its diagnostics. The first is testing for PDL-1, the biomarker that the drug targets and binds. The next is testing for inflammatory signals more broadly. The third is looking for tumors that are MSI-high, the mutation tied to the landmark FDA approval. And finally, there is evidence to suggest that a broadly high tumor mutational burden correlates with a response to checkpoint inhibitors such as Keytruda.

If physicians only tested for PDL-1, they wouldnt be maximizing the drugs potential.

Its a reminder that we need to cast the net as wide as possible for potential mutations, in all patients.

Photo: Nataniil, Getty Images

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Another win for precision medicine: FDA approves companion diagnostic panel - MedCity News

This allows us to illuminate dark corners of the genome like never before, Ashley said. Technology is such a powerful force in medicine. Its mind-blowing that we are able to routinely sequence patients genomes when just a few years ago this was unthinkable.

The study was conducted in collaboration with Pacific Biosciences, a biotechnology company in Menlo Park, California, that has pioneered a type of long-read sequencing. Lead authorship of the paper is shared by Jason Merker, MD, PhD, assistant professor of pathology and co-director of the Stanford Clinical Genomics Service, and Aaron Wenger, PhD, of Pacific Biosciences.

The type of long-read sequencing developed by the research teams collaborators at the company can continuously spool long threads of DNA for letter-by-letter analysis, limiting the number of cuts needed.

This is exciting, said Ashley, because instead of having 100-base-pair words, you now have 7,000- to 8,000-letter words.

Thanks to technological advances and increased efficiency, the cost of long-read sequencing has been falling dramatically. Ashley estimated the current cost of the sequencing used for this study at between $5,000 and $6,000 per genome.

Though the cost of short-read sequencing is now below $1,000, according to Ashley, parts of the genome not accessible when cutting DNA into small fragments. Throughout the genome, series of repeated letters, such as GGCGGCGGC, can stretch for hundreds of base pairs. With only 100-letter words, it is impossible to know how long these stretches are, and the length can critically determine someones predisposition to disease.

Additionally, some portions of the human genome are redundant, meaning there are multiple places a 100-base pair segment could potentially fit in, said Ashley. This makes it impossible to know where to place those segments when reassembling the genome. With longer words, that happens much less often.

Given these issues, 5 percent of the genome cannot be uniquely mapped, the researchers wrote. And any deletions or insertions longer than about 50 letters are too long to detect.

For patients with undiagnosed conditions, short-read sequencing can help doctors provide a diagnosis in about one-third of cases, said Ashley. But Ramons case was not one of those.

The technique initially used to analyze Ramons genes failed to identify a mutation in the gene responsible for Carney complex, though Ashley said co-author Tam Sneddon, DPhil, a clinical data scientist at Stanford Health Care who browsed through the database of Ramons sequenced genome by hand, did notice something looked wrong. Ultimately, the long-read sequencing of Ramons genome identified a deletion of about 2,200 base-pairs and confirmed that a diagnosis of Carney complex was indeed correct.

This work is an example of Stanford Medicines focus on precision health, the goal of which is to anticipate and prevent disease in the healthy and precisely diagnose and treat disease in the ill.

Carney complex arises from mutations in the PRKAR1A gene, and is characterized by increased risk for several tumor types, particularly in the heart and hormone-producing glands, such as ovaries, testes, adrenal glands, pituitary gland and thyroid. According to the National Institutes of Health, fewer than 750 individuals with this condition have been identified.

The most common symptom is benign heart tumors, or myxomas. Open heart surgery is required to remove cardiac myxomas; by the time Ramon was 18 years old, hed had three such surgeries. He is under consideration for a heart transplant, and having the correct diagnosis for his condition was important for the transplant team. Beyond the typical screening for a transplant, Ashley said the team needed to ensure there werent other health issues that could be exacerbated by immune suppressants, which heart transplant patients must take to avoid rejection of the donated organ.

Though it helps his medical team to have a confirmed diagnosis of Carney complex, Ramon has found it disheartening to face the fact that he cannot escape his condition. I was pretty sad, he said. It took me a while to come to terms with the fact that Ill have this until the day I die.

He tries not to dwell on it, though. Live one day at a time, he said. The bad days are temporary storms, and theyll pass.

His story is quite incredible, said Ashley, who said it was a privilege to be working on Ramons team. To have such a burden on such young shoulders, and to decide whether or not he wants a transplant, requires incredible courage.

Because he couldnt wait any longer for a transplant, Ramon recently underwent his fourth surgery to remove three tumors in his heart. Joseph Woo, MD, professor and chair of cardiothoracic surgery, performed the operation at Stanford Hospital. It is exceedingly rare to have tumors in the heart, said Ashley. It was a particularly heroic operation. Though Ramon is still under consideration for a transplant, the need is less urgent now.

Im in good hands, Ramon said of the Stanford team. Im glad to be here.

Ashley said he and many other doctors believe that long-read technology is part of the future of genomics.

Now we get to see how to do it better, said Ashley. If we can get the cost of long-read sequencing down to where its accessible for everyone, I think it will be very useful.

Other Stanford co-authors of the study are genetic counselor Megan Grove; former graduate student Zach Zappala, PhD; postdoctoral scholar Laure Fresard, PhD; senior research engineer Daryl Waggott, MSc; Sowmi Utiramerur, MS, director of bioinformatics for Stanfords Clinical Genomics Service; research assistant Yanli Hou, PhD; research scientist Kevin Smith, PhD; Stephen Montgomery, PhD, assistant professor of pathology and of genetics; Matthew Wheeler, MD, PhD, clinical assistant professor of cardiovascular medicine; Jillian Buchan, PhD, clinical assistant professor of pathology; and James Ford, MD, professor of medicine and of genetics.

Ashley is a member of Stanford Bio-X, the Stanford Cardiovascular Institute and the Stanford Child Health Research Institute. He is also the founding director of the Stanford Center for Inherited Cardiovascular Disease, the co-director of the Stanford Clinical Genomics Service and the steering committee co-chair for the National Institutes of Health Undiagnosed Diseases Network.

Pacific Biosciences paid for the sequencing.

Stanfords Department of Pathology and the Stanford Cancer Institute also supported the work.

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Researchers use long-read genome sequencing for first time in a patient - Stanford Medical Center Report

THURSDAY, June 22, 2017 (HealthDay News) -- Certain genes linked to heart disease may also improve your chances of having children, a new study suggests.

Australian researchers said the findings seem to offer a potential explanation for why evolution has allowed these genes to persist for centuries.

While lifestyle is clearly important in heart disease risk, scientists have found many genes also influence those odds.

"Genes play a very important role in coronary artery disease risk across an individual's lifetime," said study author Sean Byars, a research fellow at the University of Melbourne. In fact, it's estimated that genes account for about 50 percent of the risk.

The rest, he said, is due to other factors, including habits like smoking and eating a poor diet.

Heart disease is a major killer worldwide, and it has long plagued humanity. Scientists have found evidence of clogged arteries in Egyptian mummies, Byars and his colleagues pointed out.

The researchers said that raises a fundamental question: Why haven't the genes that promote heart disease been weeded out by natural selection?

Natural selection is the process by which organisms -- including humans -- evolve to have better survival odds.

The new study suggests one answer: Byars' team found that a few dozen genes tied to heart disease might also contribute to people's "reproductive success."

Since heart disease usually strikes later in life, after people have had their kids, it would be a reasonable trade-off for better fertility -- at least in terms of survival of the species.

The findings, published online recently in the journal PLOS Genetics, do not have any immediate implications for managing heart disease or fertility, Byars said.

"This study is more about potentially helping to provide a fundamental understanding of why [heart disease] is so prevalent in modern humans," he explained.

Byars did, however, point to a big-picture issue: The findings may sound a cautionary note about "gene-editing" -- a technology scientists are studying with the hope of correcting genetic flaws that cause disease.

"One potential concern a study like this raises," Byars said, "is that in an era of gene-editing, we need to be very careful about unintended consequences of modifying our genomes -- due to shared functions of these genes that are not always obvious."

For the study, the researchers used two large databases with a wealth of genetic information, along with data from a long-running health study of U.S. adults.

The investigators first focused on 76 genes that are linked to heart disease -- the kind caused by clogged arteries. From there, the researchers found that 40 genes were also tied to at least one aspect of reproductive "fitness."

Some were related to the number of children people had, while others were tied to a woman's age at her first and last menstrual period. There were 19 to 29 genes, the researchers said, that were tied to "traits" that can directly sway male or female fertility.

Heart disease is, of course, a complex condition that involves many different factors. Even if Mother Nature insists that humans carry heart-disease genes, there is still plenty that people can do about it, according to Dr. Robert Rosenson.

Rosenson, a cardiologist at Mount Sinai Health System in New York City, pointed to the example of familial hypercholesterolemia (FH).

FH is an inherited disorder caused by a single genetic defect, and it leads to very high "bad" cholesterol levels and a substantial risk of premature heart disease.

But even with those genetic cards stacked against them, Rosenson said, people with FH can prevent or delay heart complications -- by taking cholesterol medication, exercising regularly, not smoking and eating a healthy diet.

"Even if you have a disease-causing genetic trait, lifestyle absolutely makes a difference," Rosenson said.

Most genes tied to heart disease do not have such a dramatic effect -- a large number, he noted, have a "minor" impact on heart disease risk.

But studying the genetics of heart disease will hopefully lead to better treatments, Rosenson said.

Genes, he explained, may help explain why one person responds well to a cholesterol-lowering statin, while someone else "gains weight and develops diabetes," for example.

"Someone might develop a drug side effect simply because they've inherited a trait that interferes with a drug-elimination pathway," Rosenson said.

The hope for the future, he said, is to use genetic information to help predict which treatments will likely benefit an individual patient.

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Heart Disease: A Price Humans Pay for Fertility? - Sioux City Journal

Meeting a young patient with Zellweger syndrome, a rare, life-threatening genetic disease, started a scientific investigation that culminated with an unexpected discovery. The condition, also known as peroxisomal biogenesis disorder, had been linked only to lipid or fat metabolism. Now, as a team of scientists from several institutions, including Baylor College of Medicine, reveals in PLoS Genetics, the condition also affects sugar metabolism. The discovery of this connection in animal models can potentially lead to treatments that might improve the condition.

Meeting this patient at Texas Childrens Hospital inspired me to begin a research investigation to learn more about this disorder, said first and corresponding author Dr. Michael Wangler, assistant professor of molecular and human genetics at Baylor College of Medicine. The family of the patient found out about this research and offered to help. They started Zellfest, a fundraising event in San Antonio, Texas, that has partially supported our investigation. This led us to study this disorder in the fruit fly model in collaboration with the research team led by Dr. Hugo Bellen, professor of molecular and human genetics and investigator at the Howard Hughes Medical Institute at Baylor College of Medicine.

Peroxisomal biogenesis disorder results from defects in the genes that form the peroxisomes, essential micro-machines inside the cell that are involved in breaking down and producing certain lipids. When peroxisomes do not form, people develop a wide range of conditions that may include poor muscle tone, seizures, hearing and vision loss, poor feeding, skeletal abnormalities, as well as life-threatening problems in organs such as the liver, heart and kidney. There is no cure or treatment, other than palliative care.

Its been well established that several lipid pathways are altered in this disease; these are known peroxisomal functions, but there has been very little focus on other parts of metabolism. Everybody was thinking this was mainly a lipid disorder, Wangler said.

The researchers genetically engineered the laboratory fly, Drosophila, to lack two of the genes that are needed to make peroxisomes, PEX2 and PEX16, and then analyzed the flies metabolism.

We began a collaboration with Dr. James McNew, professor in biosciences at Rice University, who had started looking at flies using a metabolomics approach, Wangler said. Metabolomics is like taking a snapshot of all the metabolism of an organism by measuring hundreds of small molecules all at once, rather than focusing on one molecule at a time. We analyzed lipids, small carbohydrates, amino acids, cholesterol and small lipids. This approach gave us a general view of the metabolism of the organism.

The scientists found that the flies lacking the peroxisome genes had many of the problems observed in patients. The scientists learned, for instance, that these flies had short lives and locomotor problems. Their thorough analysis suggests that flies without PEX genes represent an animal model in which to further investigate the human condition.

In addition, we were surprised to discover that these flies were very sensitive to low-sugar diet, Wangler said. They cannot tolerate a low-sugar diet as well as normal flies; without sugar, flies without peroxisomes appear to be starving.

The researchers also applied a metabolomics approach to mice genetically engineered to lack a mouse PEX gene. As they had found in the flies, mice without peroxisomes also had alterations in the metabolism of sugars.

Our understanding is that the enzymes that break down sugars are not directly connected to peroxisomes, Wangler said. We are continuing our investigations and hope they will lead us to better understand how sugar metabolism is linked to peroxisomal biogenesis disorders.

Peroxisomes also play a role in common diseases such as Alzheimers and cancer, Wangler said. Studying this rare disease can help us understand peroxisomes better, and, in turn, that knowledge will help clarify the role of peroxisomes in Alzheimers and other disorders. Rare diseases can help understand issues that also contribute to more common diseases.

Other authors that contributed to this work include Yu-Hsin Chao, Vafa Bayat, Nikolaos Giagtzoglou, Abhijit Babaji Shinde, Nagireddy Putluri, Cristian Coarfa, Taraka Donti, Brett H. Graham, Joseph E. Faust, Ann Moser, Marco Sardiello and Myriam Baes. The authors are affiliated with one of more of the following institutions: Baylor College of Medicine, Texas Childrens Hospital, KU Leuven, Rice University and the Howard Hughes Medical Institute.

This work was supported by the Clayton Murphy Peroxisomal Disorders Research Fund at Baylor College of Medicine, National Institutes of Health K08 (NS076547) award to Michael Wangler, a grant by the Simmons Family Foundation to foster collaborative efforts between Rice University and Texas Childrens Hospital, awarded to Michael Wangler, Hugo Bellen and James McNew, as well as the support of Hugo Bellen, a Howard Hughes Medical Investigator.

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Patient-inspired research uncovers new link to rare disorder | Baylor ... - Baylor College of Medicine News (press release)

Soon, couriers will drive infant blood samples 90 miles south down Interstate 5 from Orange County to San Diego for high-speed genetic sequencing and analysis at the Rady Childrens Institute for Genomic Medicine.

The organization, which recently built its own hot rod genetics lab that can do full DNA work-ups in days instead of weeks, announced this week that it has made a pact with Childrens Hospital of Orange County, offering quick-turnaround service for infants in that facilitys intensive care units who need the speed.

Though most young patients dont need results in days, a break-neck pace can benefit those with unexplained, life-threatening and progressive symptoms which force physicians to make treatment decisions very quickly.

In these situations, doctors sometimes must choose one therapy or another without enough time to fully understand what, exactly, is causing deadly medical problems ranging from seizures to cardiac arrest.

Genetic analysis can spot DNA mutations and help doctors make more informed choices about which procedures are most likely to work and also allow them to test for multiple possible genetic diseases with a single test rather than several, putting less strain on babies already struggling to survive after birth.

Rady began using its own sequencing machines from the San Diego-based company Illumina, stationed in an office building just across the street from the hospital, last year for the time-sensitive minority of patients who have immediate genetic information needs.

Out of the gate, rapid analysis clarified a set of confusing symptoms and ended up canceling a surgery for a newborn because the procedure turned out to be unnecessary, hospitals officials said.

The Rady Childrens institute said this week that it has now sequenced 100 patients enrolled in its research studies. Forty percent have received a genomic diagnosis of their disease while 80 percent have had some sort of change in their plan of care as a result of undergoing sequencing.

About one in 20 is a life saved, and wed like to save as many as we can, said Dr. Stephen Kingsmore, director of the institute.

CHOC is just the start, he added. He expects to help 10 childrens hospitals across the nation start offering high-speed sequencing to their patients by the end of June 2018. And Kingsmore hopes to go far beyond that initial goal.

Ideally, he said in a previous interview, every hospital should have access to rapid sequencing and analysis. Though a request for a $100 million MacArthur Grant that would have jump started that larger ambition did not come through, plans are still underway to move forward as quickly as possible with another hospital in the Midwest expected to announce a collaboration this week or next.

Cost is one of the biggest obstacles for pediatric sequencing which must include the patient, both parents and sometimes siblings. Only by comparing a childs genetic sequence to their parents can new mutations be spotted quickly. A full analysis can cost $20,000 per family in rapid-turnaround situations.

Most families dont have that kind of cash on hand, and it can take weeks or months to convince health insurance companies to cover the expense, a time lag that is too long when a babys condition is deteriorating rapidly.

Rady is able to temporarily circumvent this limitation by getting seed funding from the South Dakota-based Sanford Health Foundation, Kingsmore said. Hospitals will still seek reimbursement from patients health insurance companies whenever they can, but Sanfords contribution allows work to begin immediately rather than waiting for insurance approval.

For this to be sustainable and nationwide, we will need to convince insurers to reimburse, Kingsmore said, adding that he expects Rady to begin receiving samples from CHOC next week.

paul.sisson@sduniontribune.com

(619) 293-1850

Twitter: @paulsisson

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Rady Children's ambitious genomics expansion to start in Orange County - The San Diego Union-Tribune

How might the shift towards personalized medicine and towards precision medicinetwo related but different conceptsimpact cancer care within the United States healthcare system? That question was explored in some depth during a presentation entitled, Using Precision Medicine and Personalized Medicine to Build a Patient-Centered Strategy, the first presentation given on June 15, during the Health IT Summit in Boston, held at Bostons Revere Hotel, and sponsored by Healthcare Informatics. The presentation was given by Kristin Darby, CIO at the Boca Raton, Fla.-based Cancer Treatment Centers of America, and John Halamka, M.D., CIO at Beth Israel Deaconess Medical Center in Boston.

After explaining in some detail the broad treatment philosophy and strategy at Cancer Treatment Centers of America, Darby noted that There are a lot of paradigm shifts going on as we start to change our industry, and some of the themes involved in oncology are similar to those emerging across U.S. healthcare as a whole. Among them, she said, are the move from predictive to reactive care, from sick care to wellness, and moving towards care thats specific to a patient. And when you look at precision medicine, there are specifics that can be determined about the classification of disease at the molecular level, rather than organ or body location.

What about the two terms? Personalized medicine and precision medicine are terms that are often used interchangeably, Darby said. But there is a difference, she pointed out. Precision medicine focuses on the specific needs of a patient and their known response to specific biomarkers. Patients typically go through genomic testing, and the results are tested based on known biomarkers, and their treatment is then adjusted. Meanwhile, personalized medicine can include precision medicine as one of its components, but also includes such things as lifestyle, patient preferences, and the patients lifestyle.

Darby went on to say that, As you start to look at the value of precision medicinehistorically, prior to this, the approach has been population-based, with the same approach for everyone, and only a certain percentage of those approaches working. And when it comes to oncology, those approaches kill healthy genes as well as diseased genes. But with personalized medicine, you take into account elements important to the patient. And it also includes looking at lifestyle and other factors that can really help the patient individually. She said that a famous quote from science fiction writer Isaac Asimov applies here: One of the saddest things in life, he said, is that science gains knowledge much faster than society gains wisdom, she said. And you can see that with precision medicine: advances are happening at such a rapid rate that individuals cannot absorb the new knowledge.

Kristin Darby and John Halamka, M.D. on June 15

Darby continued, Thats where technology comes in, to help individual patients. And typically, most healthcare providers are doing partial genome sequencing, which might include a 300-gene panel, followed by targeted therapies for specific abnormalities. What youll see sometime in the near future, she said, is an evolution of maturity where, when the test is done, the goal is to move that to time of diagnosis. And we believe at Cancer Treatment Centers of America that well continue to move closer to diagnosis in order to avert going through failed rounds of care. Often, she said, patients dont pursue genomic testing until after two or three rounds of treatment have already failed; meanwhile, overall health tends to decline with each round of chemotherapy. In contrast, she said, in the future, a personalized approach to treatment will be available. And it will mature from partial genome sequencing to full genome sequencing, which will look at healthy DNA. And instead of just looking at DNA, from a targeted therapy perspective, the abnormality causing the disease may only affect the patient as its expressed. And with proteomics, physicians will be able to offer more specific, targeted treatment.

Darby went on to share with the audience a case study that had been approved for public sharing, by the patient involved. The patient is Christine Bray, who was diagnosed at the age of 30 with metastatic ovarian cancer in 2010, when her youngest daughter was just three months old. Bray was given five months to live. Her goal was to survive at least a few years, so that her youngest daughter would have a memory of her. She went through a horrendous experience, with numerous treatments and surgeries, Darby said of Bray. Then she came to CTCA in Philadelphia, and received advanced genomic testing, which identified a therapy that would target the tumors genetic mutation (everolimus). It was when she got her third diagnosis of recurrence that she came to CTCA. And it was identified that she would benefit from genetic testing, and received targeted therapy. Within three months, she was cancer-free and has lived a normal life for five years now, with no evidence of disease. That shows the promise of precision medicine.

Continued here:

At the Health IT Summit in Boston, a Fresh Look at the Emergence of Personalized Medicine - Healthcare Informatics

June 23, 2017

Imagine being able to take cells from your skin, transform them into other types of cells, such as lung, brain, heart or muscle cells, and use those to cure your ailments, from diabetes to heart disease or macular degeneration. To realise this, however, challenges still remain, Professor Janet Rossant, a pioneer in the field, says.

All across the world, scientists have begun clinical trials to try and do just that, by making use of the incredible power and versatility of stem cells, which are special cells that can make endless copies of themselves and transform into every other type of cell.

While human embryos contain embryonic stem cells, which help them to develop, the use of those cells has been controversial. The scientists are using induced pluripotent stem cells instead, which are other cells that have been reprogrammed to behave like stem cells.

"There are still significant challenges that we need to overcome, but in the long run we might even be able to create organs from stem cells taken from patients. That would enable rejection-free transplants," said Professor Janet Rossant, a pioneer in the field.

The mouse that changed everything

A speaker at the recent Commonwealth Science Conference 2017 held in Singapore and organised by Britain's Royal Society and Singapore's National Research Foundation, Prof Rossant gave an overview of stem cells' origins, history, uses and potential.

Now a senior scientist at The Hospital for Sick Children (also known as Sick Kids) in Toronto, Canada, after a decade as its chief of research, she was the first scientist to demonstrate the full power of stem cells in mice.

In the early 1990s, scientists believed that stem cells could only become certain types of cells and carry out limited functions. Based on her own research and that of others, however, Prof Rossant believed that they were capable of far more.

Working with other scientists, she created an entire mouse out of stem cells in 1992, upending the conventional wisdom. "We went on to create many baby mice that were completely normal, and completely derived from stem cells grown in a petri dish," she said.

"That was an amazing experiment, and it was instrumental in making people believe that human embryonic stem cells could have the full potential to make every cell type in the body," she added.

When scientists learned how to remove stem cells from human embryos in 1998, however, controversy ensued. Many lobbied against the cells' use in medical research and treatment due to the moral implications of destroying even unwanted embryos to gain the cells.

In Canada, Prof Rossant chaired the working group of the Canadian Institutes of Health Research on Stem Cell Research, establishing guidelines for the field. These guidelines helped to keep the field alive in Canada, and were influential well beyond the country's borders.

In 2006, Japanese researchers succeeded in taking skin cells from adult mice and reprogramming them to behave like embryonic stem cells. These revolutionary, induced pluripotent stem (IPS) cells allowed scientists to sidestep the ongoing controversy.

The challenges in the way

While stem cells have been used for medical treatment in some cases bone marrow transplants, for example, are a form of stem cell therapy there are several challenges that need to be overcome before they can be used more widely to treat diseases and injuries.

"We need to get better at turning stem cells into the fully mature cells that you need for therapy. That's going to take more work. Another issue is that of scale-up. If you're going to treat a patient, you need to be able to grow millions of cells," said Prof Rossant.

She added: "Safety is another concern. One of the most exciting things about pluripotent stem cells is that they can divide indefinitely in the culture dish. But that's also one of the most scary things about them, because that's also how cancer works.

"Furthermore, because we need to genetically manipulate cells to get IPS cells, it's very hard to know whether we've got completely normal cells at the end of the day. These are all issues that need to be resolved."

She noted that some scientists are working on making "failsafe" IPS cells, which have a built-in self-destruct option if they become dangerous. "Bringing stem cells into regenerative medicine is going to require interdisciplinary, international collaboration," she said.

In the meantime, stem cells have been a boon to medical research, as scientists can use them to create an endless supply of different cells to study diseases and injuries, and test drugs. "That's the biggest use of IPS cells right now," Prof Rossant said.

Sick kids and how to help them

At SickKids, which is Canada's largest paediatric research hospital, she has been using stem cells to study cystic fibrosis, a frequently fatal genetic disorder that causes mucus to build up and clog some organs such as the lungs. It affects primarily children and young adults.

SickKids discovered the CFTR gene that, when mutated, causes the disease. It was also the first to produce mature lung cells, from stem cells, that can be used to study the disease and test drugs against it.

Even better, Prof Rossant and her team were able to turn skin cells from cystic fibrosis patients into IPS cells and then into lung cells with the genetic mutation specific to each of them. This is critical to personalising treatment for each patient.

"Drugs for cystic fibrosis are extraordinarily expensive, and patients can have the same mutation and yet respond differently to the same drug," Prof Rossant explained. "With our work, we can make sure that each patient gets the right drug at the right time."

In 1998, Prof Rossant also discovered a new type of stem cell in mice, now called the trophoblast stem cell. These surround an embryo and attach it to the uterine wall, eventually becoming the placenta. She is using such cells to study placenta defects and pregnancy problems.

By using IPS cells to create heart cells and other cells, pharmaceutical companies can also test their new drugs' effectiveness and uncover potential side effects, as well as develop personalised medicines.

"There are still huge amounts of opportunities in pluripotent stem cells," said Prof Rossant, who has won numerous awards for her research, including the Companion of the Order of Canada and the 2016 Friesen International Prize in Health Research.

She is also president and scientific director of the Toronto-based Gairdner Foundation, which recognises outstanding biomedical research worldwide, and a professor at the University of Toronto's molecular genetics, obstetrics and gynaecology departments.

"Meetings like the Commonwealth Science Conference are a fantastic opportunity for scientists to come together, learn about each other's work and establish new relationships, which will help to push science forward, including in stem cell research," she said.

She noted: "The world of science is becoming increasingly interdisciplinary, so this kind of meeting of minds across nations, cultures and scientific fields is really the way of the future."

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Stem cells: the future of medicine - Medical Xpress

June 22, 2017 Credit : Susanna M. Hamilton, Broad Communications

Scientists at the Broad Institute of MIT and Harvard have found that a set of genetic mutations in blood cells that arises during aging may be a major new risk factor for cardiovascular disease. In contrast to inherited genetic predispositions and traditional lifestyle risk factors, such as smoking or an unhealthy diet, the new mutations are "somatic mutations" that originate in stem cells in the bone marrow as people age.

Because the mutations are relatively common in older people (over 10% of people over the age of 70 harbor at least one of these mutations), potential future efforts to screen for the mutations in blood cells, identify people at increased risk for coronary heart disease, and reduce risk in those individuals through lifestyle changes or therapeutic interventions could have a significant clinical impact, according to the researchers.

"There is more work to be done, but these results demonstrate that pre-malignant mutations in blood cells are a major cause of cardiovascular disease that in the future may be treatable either with standard therapies or new therapeutic strategies based on these findings," said Benjamin Ebert, a co-senior author of the new study, an institute member at the Broad, a professor of medicine at Harvard Medical School, and a hematologist at Brigham and Women's Hospital.

Featured in the New England Journal of Medicine, the work also contributes to the broader understanding of pathogenesis in coronary heart disease by supporting the hypothesis that inflammation, in addition to elevated cholesterol levels, plays an important role in this illness and potentially other diseases of aging.

"A key finding from this study is that somatic mutations are actually modulating risk for a common disease, something we haven't seen other than in cancer," said first author Siddhartha Jaiswal, a pathologist at Massachusetts General Hospital and researcher in the Ebert lab. "It opens up interesting questions about other diseases of aging in which acquired mutations, in addition to lifestyle and inherited factors, could modulate disease risk."

Previous research led by Ebert and Jaiswal revealed that some somatic mutations that are able to confer a selective advantage to blood stem cells become much more frequent with aging. They named this condition "clonal hematopoiesis of indeterminate potential," (CHIP), and found that it increases the risk of developing a blood cancer more than 10-fold and it appeared to increase mortality from heart attacks or stroke. In the new study, the researchers analyzed data from four case-control studies on more than 8,000 people and found that having one of the CHIP-related mutations nearly doubled the risk for coronary heart disease, with the mutations conferring an even greater risk in people who have previously had a heart attack before age 50.

While the human genetics data showed a strong association between CHIP and coronary heart disease, the team hoped to uncover the underlying biology. Using a mouse model prone to developing atherosclerosis, the scientists showed that loss of one of the CHIP-mutated genes, Tet2, in bone marrow cells leads to larger atherosclerotic plaques in blood vessels, evidence that this mutation can accelerate atherosclerosis in mice.

Atherosclerosis is believed to be a disease of chronic inflammation that can arise in response to excess cholesterol in the vessel wall. To examine this on a cellular level the team turned to the macrophage, an immune cell found in atherosclerotic plaques that can develop from CHIP stem cells and carry the same mutations. Because Tet2 and other CHIP-related mutations are known to be so-called "epigenetic regulators" that can alter the activity of other genes, the team examined gene expression levels in the Tet2-mutated macrophages from mice. They found that the mutated cells appear to be "hyper-inflammatory" with increased expression of inflammatory molecules that contribute to atherosclerosis. In support of this finding, humans with TET2 mutations also had higher levels of one of these molecules, IL-8, in their blood.

The work demonstrates that CHIP associates with coronary heart disease in humans, that mutation of the CHIP-related gene Tet2 causes atherosclerosis in mice, and that an inflammatory mechanism likely underlies the process. More work is needed to show whether other genes that are mutated in CHIP also lead to increased inflammation. The team is also exploring whether interventions such as cholesterol lowering therapy or anti-inflammatory drugs might have benefit in people with CHIP.

Inflammation is also thought to modulate several other diseases of aging besides cardiovascular disease, such as autoimmune disorders and neurodegenerative disease. Because CHIP also increases in frequency with age, somatic mutations that alter inflammatory processes could influence several diseases of aging, though more work is needed to test this possibility.

"By combining genetic analysis on large cohorts with disease model and gene expression studies, we've been able to confirm the earlier hints of CHIP's surprising role in cardiovascular disease," said co-senior author Sekar Kathiresan, director of the Broad's Cardiovascular Disease Initiative, associate professor of medicine at Harvard Medical School, and director of the Center for Genomic Medicine at Massachusetts General Hospital. "Beyond the mutations that you inherit from your parents, this work reveals a new genetic mechanism for atherosclerosismutations in blood stem cells that arise with aging."

Explore further: A role for mutated blood cells in heart disease?

More information: Siddhartha Jaiswal et al. Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease, New England Journal of Medicine (2017). DOI: 10.1056/NEJMoa1701719

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Aging-related mutations in blood cells represent major new risk factor for cardiovascular disease - Medical Xpress

June 22, 2017 by David Amor, The Conversation If you were destined for dementia in your 60s, but there was nothing you could do about it, would you want to know? Credit: shutterstock.com

The launch in Australia of a genomic testing service aimed at healthy people heralds a new era of individual patient care. A scan of your genome, which is the complete set of your genes, to find out if you are at risk of particular diseases, can mean you can then go on to take preventive measures against them.

The CEO of the Garvan Institute's Genome.One lab, which is offering the testing, said it would transform the health system, making it more focused on prevention than treatment of disease.

Genomic testing can have tremendous benefits, as in the case of diagnosing children with rare diseases. When applied to the right patients, genomic testing can provide a diagnosis for more than half of patients with unusual symptoms. And the cost of this to the health system is much lower than for traditional diagnostic tests.

Certainly that all sounds like a good thing, but genomic testing is not yet the precision diagnostic and treatment tool we hope it will one day be. And all genetic knowledge is not necessarily helpful. As with any medical intervention, genomic testing carries risks as well as benefits.

Why genomic testing?

Genomic testing takes advantage of recent advances in our knowledge of genetic causes of disease, as well as technology. It's a test of all 23,000 genes in the body at once.

The success of genomic testing in diagnosing rare disorders has raised the question of whether these tests should be performed in healthy people before they become sick. The potential benefits of testing healthy people are obvious, especially when it comes to conditions that have a proven treatment or prevention.

Cancer is a good example of where genomic testing can save lives. A person found to carry a genetic predisposition to bowel cancer can choose to have regular colonoscopies, which can detect and remove pre-cancerous growths before they cause harm.

And because genetic disorders run in families, potential health benefits can extend to other family members who may have the same genetic predisposition.

The ultimate goal of genomic testing, as part of personalised medicine, is that it will be available to everyone, allowing each person's health care to be tailored to their individual genetic make-up. In the future, this "lifetime health resource" promises to improve health care from conception to death.

Are we ready for this?

A considerable challenge of genomic testing is the extraordinary complexity of each person's genome. To try to interpret a single human genome is to grapple with literally millions of genetic variants, or points where the person's genetic code differs from the average person's.

Perhaps a handful of these variants will cause disease, but the rest will most likely be harmless. Determining which is which is far from straightforward.

Another problem is that even when specific genetic variants are judged to be harmful, the benefits of knowing this information are not always as clear cut as in the case of bowel cancer. It is an unfortunate reality that most disorders detectable by genomic testing have no proven treatment or means of prevention.

For instance, particular gene variants may put you at risk of developing dementia in your 60s. But if there was nothing you could do to prevent it, would you want to know?

Even when treatments are available, the benefits of knowing you have a certain genetic predisposition may not outweigh the disadvantages.

Consider that genomic testing finds you carry a predisposition to sudden heart death, such as Long QT syndrome. This is an outcome you would certainly wish to avoid. But what if knowing this information caused you to worry more, and the treatment required you to give up sport and take a medication that caused you to feel lethargic every day?

And what if, in the absence of symptoms, your risk of actually dying was only slightly increased compared to the general population? Would you still want to know this information, or perhaps prefer to remain ignorant?

Should we get the test?

The Genome.One clinic at the Garvan Institute in Sydney has addressed some of these concerns by taking a cautious approach.

Genetic counselling is provided before and after testing, and although the whole genome is sequenced, analysis and reporting is limited to just 1% of all genes. Most of these selected genes are associated with heart conditions and cancers, and have been chosen because these diseases are well understood, with treatment strategies available.

Genes that cause untreatable diseases, such as dementia, have deliberately been excluded from analysis. This strategy minimises the risk of harm that may come from the test, but the trade-off is that the likelihood of actually finding something useful is greatly diminished. In fact, Genome.One reportedly estimates only 5-10% of people tested will receive an abnormal result; that is, one that will show them to be at risk of disease.

While it is hard to argue against a test that just might save your life, currently there is insufficient evidence that the benefits of genomic testing outweigh the risks. Even for those who can afford the price tag of A$6,400, there are probably more effective targets for our health-related spending. Like many years of gym membership, for example.

Explore further: Routine genomic testing is feasible, but only a subset of patients benefit

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Gene testing for the publica way to ward off disease, or a useless worry? - Medical Xpress

In Brief A team of geneticists discovered a growth hormone mutation which can increase the average lifespan of men by 10 years. Their study is a step towards understanding the genetic triggers of aging in humans. Agings Genetic Factors

Ever since many scientists started to consider aging as a disease that could and should be cured, a number of efforts working towards this goal have begun. Researchersapproaches differ, of course. Some workto develop medicines, others try blood transfusions, while others arefiguring out thegenetic factors involved in aging. Of the latter, a team of geneticists recently madea discovery that could prolong the life of men.

In a study published in the journal Science Advances, the researchers discussed how they found a genetic mutation that has effects specific to men. Apparently, a deletion of a few base pairs from a growth hormone receptor (d3-GHR) could add an average of 10 more years to a mans lifespan. In studying the genes of 841 people from four different populations that exhibited longevity, the researchers discovered that two copies of d3-GHR become more prevalent with the age of men, but not women.

Researcher Gil Atzmon from the Albert Einstein College of Medicine and the University of Haifa in Israel found it amazing that with the d3-GHR deletion you still have a functional protein that now makes people live longer, he told Gizmodo. I think this is phenomenal.

Although the exact biological effects of d3-GHRremain unclear, Atzmon and his colleagues are almost certain about its life-extending effects in males. They saw the same pattern in each of the populations they studied, and this makes our result more accurate and globally translated, Atzmon said.

Furthermore, they also discovered that those with two copies of the deletion tended to grow an inch taller than other men. The researchers theory is thatd3-GHR deletion increased the response of the receptor to growth hormone surges, particularly during puberty, causing the increased height. At the same time, however, the mutationcouldlimit these growth spurts in adulthood. This would makethe cells divide at a slower rate, causing aging to slow down.

Further studies are needed to better understand how this mutation works and why its longevity effects are only present in men. Although, there are also anti-aging treatments that work only for women, so this is not the first evidence that aging pathways can be gender specific. For now, the researchers urge caution in growth hormone treatments to keep a youthful body, as these may trigger the opposite effect.

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A Genetic Mutation May Cause Men to Live An Extra 10 Years - Futurism

WASHINGTON, June 22, 2017 /PRNewswire-USNewswire/ -- A review published today in AACC's Clinical Chemistry journal has identified 10 genes that show promise in predicting how patients will respond to opioid pain medications. Using these genetic markers, healthcare providers could potentially tailor opioid therapy better to curb the skyrocketing rate of deaths from these drugs.

More than 17,500 Americans died in 2015 from prescription opioid overdoses, which is more than quadruple the amount of people who died from this cause in 1999. But it is not just abuse of these medications that can lead to overdoses. Even in patients with severe pain and a legitimate need for opioids, the dose required to alleviate pain varies widely and unpredictably between individuals. This means that clinicians must essentially use a trial and error strategy to determine the correct type of opioid and dosage that will help a patient. This approach puts some patients at increased risk of life-threatening side effects such as respiratory depression, while leaving other patients undertreated and in pain. To date, researchers have identified numerous genes that could potentially guide opioid treatment to make it more precise and safe. Despite this, the medical community has only developed treatment guidelines based on one of these genes (CYP2D6) and has not determined which of the other genes should be used in practice.

To identify the genes that could impact patient care the most, a team of researchers led by Ron H.N. van Schaik, PhD, of Erasmus University Medical Center in Rotterdam, the Netherlands, conducted a systematic review of 4,257 studies on opioid genetics. The researchers assessed the utility of each gene studied based on whether a) several independent studies confirmed the gene's effect on patient opioid response and b) the gene's frequency in the white population was high enough for use in screening tests. Using these criteria, van Schaik's team pinpointed 10 genes that show the highest potential of refining the way opioids are prescribed and that healthcare providers should focus on implementing clinically. In addition to the already well-known CYP2D6, the most notable of these 10 include SLC22A1, the OPRM1 variant 118A>G, and COMT.

Research shows that the presence of two inactive SLC22A1 genes leads to high blood concentrations of tramadol's active metabolite and, in children, to significantly lower clearance of morphine. This means that patients with these mutations might be at increased risk of overdosing from tramadol and morphine, particularly if they also have certain CYP2D6 mutations. On the flip side, studies demonstrate that patients with the OPRM1 118A>G variant need higher doses of opioids prescribed but have a lower risk for adverse events. Finally, certain COMT mutations are associated with both lower opioid requirements and fewer side effects, while still other COMT mutations have been linked with the highest pain scores and opioid consumption in patients who have undergone surgery.

"The most solid evidence of a clinically relevant pharmacogenetics effect on the analgesic treatment with opioids is available for genetic variation in CYP2D6, COMT, SLC22A1, and the genetic variant OPRM1 118A>G," said van Schaik. "As clinical guidelines for codeine and CYP2D6 genotyping have been formulated and CYP2D6 genotyping has been successfully implemented in pediatric clinical practice the application of pharmacogenetics in the management of pain with opioids certainly has the potential to improve therapy."

About AACC Dedicated to achieving better health through laboratory medicine, AACC brings together more than 50,000 clinical laboratory professionals, physicians, research scientists, and business leaders from around the world focused on clinical chemistry, molecular diagnostics, mass spectrometry, translational medicine, lab management, and other areas of progressing laboratory science. Since 1948, AACC has worked to advance the common interests of the field, providing programs that advance scientific collaboration, knowledge, expertise, and innovation. For more information, visit http://www.aacc.org.

Clinical Chemistry is the leading international journal of clinical laboratory science, providing 2,000 pages per year of peer-reviewed papers that advance the science of the field. With an impact factor of 8.008, Clinical Chemistry covers everything from molecular diagnostics to laboratory management.

Christine DeLongAACCManager, Communications & PR(p) 202.835.8722cdelong@aacc.org

Molly Polen AACC Senior Director, Communications & PR (p) 202.420.7612 (c) 703.598.0472mpolen@aacc.org

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Healthcare Providers Could Prevent Opioid-Related Deaths by Testing for Certain Genes - PR Newswire (press release)

Its common to think of cancer as a disease driven by the buildup of mutations in the DNA of cells. Everything from pollutants to cigarettes to exposure to everyday chemicals can alter genes, and continued exposure over a lifetime can lead to a critical mass of mutations.

Now, researchers say the same process may be at work in heart disease. In a paper published in the New England Journal of Medicine, Dr. Sekar Kathiresan, from the Broad Institute of Harvard and MIT, and Dr. Benjamin Ebert from Brigham and Womens Hospital and their colleagues found a gene that builds up mutations over a lifetime and can double the risk of heart events.

MORE: Single Gene Responsible for Group of Heart Disease Risk Factors

While there are genes associated with greater heart disease risk, most of them are inherited. The new mutations linked to heart problems are among the first to be acquired, or picked up over a lifetime. The mutations develop among a group of blood cells known as stem cells, which divide throughout a person's lifetime to replenish the supply of blood cells. The genetic changes the researchers found are also linked to a higher risk of developing blood cancer, but they seem to have a stronger effect on heart disease than cancer.

This is a totally different type of risk factor than hypertension or hypercholestserolemia [high blood cholesterol] or smoking, says Kathiresan. And since its a totally different risk factor that works through a different mechanism, it may lead to new treatment opportunities very different from the ones we have for heart disease at present.

Kathiresan and his team actually found the gene several years ago when they linked it to a 10-fold higher risk of developing blood cancers. Although the mutations increased cancer risk, the cancers were still relatively rare, but people who had them had a 40% higher risk of dying of other causes. Among those was heart disease. In the new paper, the researchers looked at four different populations of nearly 8,000 people who had their genomes sequenced. Even among younger people, those with the mutationscalled clonal hematopoiesis of indeterminate potential, or CHIPshowed a higher rate of heart disease.

We were fully expecting not to find anything here, says Kathiresan. But the odds of having an early heart attack are four-fold higher among younger people with CHIP mutations.

MORE: This New Kind of Stem Cell May Revolutionize How We Treat Diseases

Whats significant about the CHIP mutations are that they arent inherited. They are accumulated over time, from exposures to all sorts of things that can damage DNA. Among people over 70, 10% of people have these mutations, says Kathiresan. Whether they develop heart problems (or cancer) depends on how many of the mutated cells are circulating in the blood. The load of mutations increases over time," Kathiresan says. "The higher the load, the more the risk of heart disease.

Fortunately, there are ways to detect the mutated cells. Currently available blood tests for blood cancers can easily keep track of the volume of mutated cells, which means that monitoring the CHIP mutations could be a new way to identify people at higher risk of having heart problems, keep track of their risk and guide treatments.

When the researchers introduced the CHIP mutations into mice, they learned more about how a cancer-causing gene can contribute to heart disease. It appears that the CHIP mutations cause atherosclerotic plaques in the blood vessels, which contributes inflammation and hardening of the arteries that can trigger heart attacks.

There's still a lot to learn. As exciting as the findings are, its still too early to add CHIP testing to routine blood screening to identify people at higher risk of having heart problems. And because CHIP contributes to heart disease in a new way, its possible that the mechanisms to control CHIP-related heart events have nothing to do with cholesterol, exercise and blood pressure. The mouse work suggests that the path to heart disease is something different from what we have been working on so far, says Kathiresan.

More work needs to be done to determine if there are ways to counteract the effect of the mutation on plaques or control the rate at which the mutations build up in these cells. Currently there isnt a drug thats safe enough or efficacious enough to treat people with, says Ebert. But its a very active area of research to identify interventions that can decrease the size of the mutated cell population or potentially eliminate them.

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The Unexpected Way Genes Can Double Heart Disease Risk - TIME

June 21, 2017

An international research team led by investigators at Massachusetts General Hospital (MGH) and the University of California at Los Angeles (UCLA) - along with their facilitating partner the Tourette Association of America - has identified rare mutations in two genes that markedly increase the risk for Tourette syndrome (TS), a neurodevelopmental disorder characterized by chronic involuntary motor and vocal tics. The report in the June 21 issue of Neuron also describes finding an overall increase in the presence of large, rare, risk-associated copy-number variants - areas of the genome that are either duplicated or deleted - in TS patients, many being observed in just a single patient.

"TS has long been considered a model disorder to study the parts of the brain that function at the intersection of our traditional concepts of neurology and psychiatry," says Jeremiah Scharf, MD, PhD, of the Psychiatric & Neurodevelopmental Genetics Unit in the MGH Departments of Psychiatry and Neurology and the Center for Genomic Medicine , co-senior author of the report. "These first two definitive genes for TS give us strong footholds in our efforts to understand the biology of this disease, and future studies of how these genes work both in health and disease may lead to discoveries that are more broadly relevant to neuropsychiatric disorders in general."

Co-senior author Giovanni Coppola, MD - a professor of Psychiatry and Neurology at UCLA and member of the Semel Institute for Neuroscience and Human Behavior - adds, "Identifying genes associated with Tourette syndrome is a first, key step in understanding their role in the disease process and ultimately in pointing the field toward possible therapeutic strategies. Often patients agree to be involved in genetic studies with uncertainty about the likelihood of results, and often these projects take years to complete. We hope that findings like this will encourage more people to participate in genetic studies."

Patients with TS often have other neurodevelopmental conditions like attention-deficit hyperactivity disorder or obsessive compulsive disorder, along with increased risk for mood and anxiety disorders. Evidence from previous studies, including the high risk of TS in children of individuals with the disorder, points to genetic risk factors as the main cause of the disorder; but that risk appears to be very complex, involving interactions between different genes in different individuals. Several small studies have identified structural variants in several neurodevelopmental genes that appear to contribute to TS risk, but none of them met the statistical threshold of genome-wide significance.

The current study was designed to assess the impact of rare copy-number variants in more than 6,500 individuals - around 2,400 patients with TS and almost 4,100 unaffected controls - analyzing data collected by the Tourette Syndrome Association International Consortium for Genetics (TSAICG) and the Gilles de la Tourette Syndrome GWAS Replication Initiative. The results identified an overall increase in large copy-number variants - most of them over 1 Mb in size - among participants with TS, with each variant primarily occurring in just one individual. The two sites meeting genome-wide significance involved deletions in a portion of NRXN1 - a gene known to have a role in the development of the synapses that transmit signals between neurons - and duplications within CNTN6 - which also has a role in the development of neuronal connections, particularly in areas involved in movement control.

While these gene variants were present in 1 percent of individuals affected with TS in this study, the investigators note that finding these genes is a key starting point towards understanding the neurologic pathways that contribute to TS in a broader group of patients. Coppola says, "We will continue to screen large cohorts to identify additional rare events; and we also plan to study cells from patients with these rare variants, to understand more precisely how they are involved in the disease process."

Scharf, an assistant professor of Neurology at Harvard Medical School, adds, "Even more importantly, identifying additional genes will give us additional points on the map to let us focus in on exactly which cells in the brain are not functioning correctly at which specific times in brain development. That will open up a whole range of biological studies that could lead to new targets for treatment."

John Miller, president and CEO of the Tourette Association of America, which provided support for this study, says, "Pinpointing the cause of Tourette Syndrome has been a primary research goal of the Tourette Association of America since it began more than 45 years ago. Identifying these two genetic markers is an enormous step forward, and we are absolutely thrilled to reach this medical milestone. The TAA is proud to have been instrumental in bringing these partners together for such an important discovery and of the real progress it means for individuals with Tourette."

Explore further: First clear-cut risk genes for Tourette disorder revealed

More information: Neuron (2017). DOI: 10.1016/j.neuron.2017.06.010

Tourette disorder (also known as Tourette syndrome) afflicts as many as one person in a hundred worldwide with potentially disabling symptoms including involuntary motor and vocal tics. However, researchers have so far failed ...

Two papers that will appear in the journal Molecular Psychiatry, both receiving advance online release, may help identify gene variants that contribute to the risks of developing obsessive-compulsive disorder (OCD) or Tourette ...

Yale scientists produced increased grooming behavior in mice that may model tics in Tourette syndrome and discovered these behaviors vanish when histaminea neurotransmitter most commonly associated with allergiesis ...

An international research consortium led by investigators at Massachusetts General Hospital (MGH) and the University of Chicago has answered several questions about the genetic background of obsessive-compulsive disorder ...

A new study of Tourette syndrome (TS) led by researchers from UC San Francisco and Massachusetts General Hospital (MGH) has found that nearly 86 percent of patients who seek treatment for TS will be diagnosed with a second ...

Many of the genetic variations that increase risk for schizophrenia are rare, making it difficult to study their role in the disease. To overcome this, the Psychiatric Genomics Consortium, an international team led by Jonathan ...

Scientists at the RIKEN Brain Science Institute (BSI) in Japan have linked early serotonin deficiency to several symptoms that occur in autism spectrum disorder (ASD). Published in Science Advances, the study examined serotonin ...

For most people having a good memory means being able to remember more information clearly for long periods of time. For neuroscientists too, the inability to remember was long believed to represent a failure of the brain's ...

Although "multitasking" is a popular buzzword, research shows that only 2% of the population actually multitasks efficiently. Most of us just shift back and forth between different tasks, a process that requires our brains ...

While concussion awareness has improved over the past decade, understanding the nuances of these sports injuries, their severity, symptoms, and treatment, is still a work in progress. In the June 21 issue of Neuron, UCLA ...

The optic nerve is vital for visiondamage to this critical structure can lead to severe and irreversible loss of vision. Fengfeng Bei, PhD, a principal investigator in the Department of Neurosurgery at Brigham and Women's ...

People who suffer a stroke often undergo a brain scan at the hospital, allowing doctors to determine the location and extent of the damage. Researchers who study the effects of strokes would love to be able to analyze these ...

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Rare genetic variants found to increase risk for Tourette syndrome - Medical Xpress

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The power of a billion: India's genomics revolution BBC News At the same time, there's a growing interest in developing new, more effective therapies tailored to an individual's genetic makeup - an idea known as precision or personalised medicine. Missing out on mapping worldwide genetic diversity is a big ... and more »

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The power of a billion: India's genomics revolution - BBC News

Scores of bacteria live on the many surfaces of the Baltimore-area subway and light rail systems, and three University of Maryland School of Medicine scientists set out Wednesday to learn more about the microscopic organisms found there.

Emmanuel F. Mongodin, Lynn M. Schriml and Lauren Hill, microbe researchers at the medical school's Institute for Genome Sciences, began their mission at the Charles Center Metro stop in downtown Baltimore.

There they and a group of student volunteers used synthetic swabs to wipe handrails, ticket kiosks and floors to collect samples of bacteria. They placed the swabs in tubes that will be sent to a New York lab for DNA and RNA sequencing and analysis.

The research is part of a global project started last year by Weill Cornell Medicine in New York to collect and catalogue bacteria in public transportation systems around the world. Researchers descended on more than 50 cities Wednesday swabbing for samples.

The information will be used to develop a giant genetic map, or microbiome, that details the community of microorganisms that live on the surfaces of transportation hubs.

That information could be used to aid in new drug discoveries and influence the way transportation systems of the future are built. It will also allow scientists to better study antimicrobial resistance and potentially make cities safer, the researchers said.

Kenneth K. Lam / Baltimore Sun

"We really want to understand how these microbes interact and move around," Schriml said.

Cornell first did testing for bacteria in subways in New York two years ago and expanded globally last year.

Baltimore had a small pilot program last year to figure out logistics and protocols. This year, they did a full-scale collection at all 14 Metro subway stations and a handful of light rail stations.

A human body contains about 50 trillion to100 trillion bacterial cells, said Dr. Christopher Mason, principal investigator on the global project. The number on subway systems, by comparison, "is almost certainly in the 100s of trillions," he said

Researchers discovered lots of food bacteria. One sample included a large amount of chickpeas and cucumber. Researchers guessed that people were eating falafel. "A huge amount of it," Mason said.

In New York, scientists found fish and other bacteria related to the ocean in one station that had flooded during Hurricane Sandy. They were also able to learn the ancestry of people who used the stations based on the human DNA left behind. An area of North Harlem in New York had a strong mix of African-American and Hispanic genes.

Riders looked perplexed as the University of Maryland scientists wearing green rubber gloves swirled their swabs on various parts of the subway.

"I would hate to see what's on this seat," said 33-year-old Melissa Meissinger, who was riding the subway from Johns Hopkins Hospital.

"Ewww, scary!" said Curtis Rice, a 56-year-old retiree who was coming into the Charles Center station.

The scientists said that is a common reaction. But the research from other subways systems shows that most of the bacteria are actually good and not harmful to humans. Harmful bacteria are usually found in trace amounts or disappear quickly.

"There's nothing nasty in the subways," Schriml said. "They're clean. They're cleaner than bathrooms."

Said Cornell's Mason: "Most people have relatively healthy skin microbiome, and that is what they leave behind."

Researcher say the project should serve as a lesson to people that exposure to bacteria helps build up immune systems.

Baltimore Mayor Catherine Pugh was on hand Wednesday to try her hand at swabbing. She said that although the subways are cleaned regularly, it's easy to see how people might think they are dirty because the systems handle so many people.

"We have to learn not to be such germaphobes and realize that some bacteria is good for us," she said.

The Maryland researchers plan to publish a report on their findings in the next few months.

Rice is looking forward to the results. Although he still thinks subways are dirty, he believes his body has built up resistance to all that bacteria.

"I take public transportation all the time, and I never get sick," he said.

amcdaniels@baltsun.com

Twitter.com/ankwalker

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UM medical school scientists studying bacteria found in subway systems - Baltimore Sun