PUBLIC RELEASE DATE:

15-Oct-2014

Contact: Duska Anastasijevic newsbureau@mayo.edu 507-284-5005 Mayo Clinic @MayoClinic

Rochester, Minn. The American Academy of Neurology (AAN) and the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) offer a new guideline on how to determine what genetic tests may best diagnose a person's subtype of limb-girdle or distal muscular dystrophy. The guideline is published in the October 14, 2014, print issue of Neurology, the medical journal of the AAN.

Researchers reviewed all of the available studies on the muscular dystrophy, a group of genetic diseases in which muscle fibers are unusually susceptible to damage, as part of the process in developing the new guideline.

Doctors should conduct a thorough evaluation of symptoms, family history, ethnicity, and results of physical exam and certain lab tests to determine what genetic tests may be more appropriate to order.

"The guideline should help physicians arrive at the right diagnosis quicker so patients will not need to take unnecessary test", says Mayo Clinic neurologist Duygu Selcen, M.D., who was part of the multi-center research team led by Julie Bolen, PhD, MPH, from the National Center on Birth Defects and Developmental Disabilities, at the Centers for Disease Control and Prevention (CDC). "This is particularly important because the muscle diseases are often hard to diagnose", adds Dr. Selcen.

There are several known subtypes of limbgirdle muscular dystrophy and distal muscular dystrophy. Experts continue to discover new subtypes and the guidance should help shorten the time to the right treatment.

While there is no cure for these disorders, complications can be managed. The guideline makes recommendations about treating and managing complications, which may include muscle symptoms, heart problems and breathing problems.

The guideline recommends that care for people with these disorders should be coordinated through treatment centers specializing in muscular dystrophy. People with these disorders should tell their doctors about any symptoms such as the heart beating too fast or skipping beats, shortness of breath and pain or difficulty in swallowing, as treatments may be available. People should also talk to their doctors about exercises that are safe.

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New guideline in genetic testing for certain types of muscular dystrophy

Muscular Dystrophy (MD) is well-known as a disease that progressively weakens muscles, leading to muscle spasms, difficulty walking, and eventually difficulty breathing. What many people dont know is that MD is actually a group of diseases, each of which can have different effects on the human body. Doctors are still discovering and classifying new forms of MD.

This week the American Academy of Neurology (AAN) and the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) issued guidelines meant to differentiate between MD disease types in preparation for genetic testing. The guidelines, published in this weeks Neurology, use symptoms, physical exams, lab tests, family history, and ethnicity to determine which genetic tests doctors should perform.

According to the guidelines lead author, Dr. Pushpa Narayanaswami, MD can often be difficult to diagnose. The guidelines should help doctors determine MD subtypes, leading to better treatments and avoiding unnecessary tests.

Looking at a range of clinical signs and symptoms such as which muscles are weak and if there is muscle wasting or enlargement, winging out of the shoulder blades, early signs of contracted limbs, rigidity of the neck or back, or heart or lung involvement can help doctors determine which genetic test to order, said Dr. Anthony Amato, senior author of the guidelines and a neurologist at Brigham and Womens Hospital. This in turn can shorten the time to diagnosis and start of treatment while helping avoid more extensive and expensive testing.

According to the guidelines MD treatment should take place at facilities that specialize in the disease. No cure for MD yet exists, so the guidelines also suggest that MD patients inform their doctors of treatable symptoms such as shortness of breath or irregular heartbeat and that they seek out safe exercises.

Before this publication, there were no care guidelines that covered both limb-girdle muscular dystrophy and distal MD and were based on the evidence, said Julie Bolen, team lead on the guidelines and a member of the National Center on Birth Defects and Developmental Disabilities at the U.S. Centers for Disease Control and Prevention (CDC). We hope that this guideline will fill that gap for both the people who live with these rare disorders and the health care professionals who treat them.

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Genetic Testing Guidelines Issued For Muscular Dystrophy

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Newswise (NEW YORK - Oct. 15) A team led by researchers at The Rockefeller University and the Icahn School of Medicine at Mount Sinai has explained the function of key immune protein and solved an international medical mystery, according to a letter published this week in the journal Nature.

In previous work, the research team lead had linked small changes in a key gene with a reduced ability to fight off a set of rare bacterial infections. Shortly afterward, a team of Chinese scientists reached out to say they had found three Chinese children with mutated versions of the same gene. Strangely, the Chinese children had no history of the severe bacterial infections, but instead had seizures and unusual calcium deposits in their brains.

The disconnect led to the discovery of an immune protein with two seemingly opposing roles: amplifying and tamping down aspects of an immune system response, according the study, published on Sunday, Oct. 12. The roles explained how the protein, or lack of it, could weaken response to an infectious disease in one instance, but contribute to the attack by the immune system on a persons own tissues (autoimmune disease) in another.

It has turned out that mutations in a single gene eliminates the immune protein ISG15, giving rise to two different problems: an inability to resolve harmful inflammation, which can lead to autoimmune disease, and susceptibility to infections caused by the tuberculosis bacterium and its cousins, said Jean-Laurent Casanova of the St. Giles Laboratory of Human Genetics of Infectious Diseases at Rockefeller. By identifying the source of this genetic disorder, we have taken a first step toward finding treatments for those facing the autoimmune disease and severe TB-related infections it may produce.

When under attack, the immune system releases signaling proteins known as interferons, which further activate the bodys defenses. In previous research, Dusan Bogunovic, PhD, Assistant Professor at the Department of Microbiology at Icahn School of Medicine at Mount Sinai and study author, had linked a lack of ISG15 to an unusual vulnerability to infections by mycobacteria, a group of common bacteria that include the tuberculosis bug.

He and colleagues had previously found children, one from Turkey, two from Iran, who became severely ill after receiving the anti-tuberculosis BCG vaccine. Normally, ISG15 protects against infection by mycobacteria by prompting the release of type 2 interferon, but all three children had two copies of a defective form of the ISG15 gene, and became infected by a TB-related component of the vaccine.

When Bogunovic and his colleagues reported this link publically, scientists in China reached out saying they had also seen loss-of-function mutations in three patients, all from a single Chinese family. But none of these three had had unexplained mycobacterial infections, such as those caused by the vaccine.

We asked why these children were patients; our Chinese colleagues said these kids had seizures, said Dr. Bogunovic. When we looked into their BCG vaccination history, we found these children, who were born at home in a remote village, never received their shots, so they never became sick.

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Genetic Defect Links Rare Infections to Autoimmune Diseases

PUBLIC RELEASE DATE:

14-Oct-2014

Contact: Jim Fessenden james.fessenden@umassmed.edu 508-856-2688 University of Massachusetts Medical School @UMassMedNow

WORCESTER, MA A team of scientists led by researchers at the University of Massachusetts Medical School (UMMS) and the University of Miami Miller School of Medicine (UMMSM) have identified what is likely a key genetic pathway underlying bipolar (manic depressive) disorder, a breakthrough that could lead to better drugs for treating bipolar affective disorder, as well as depression and other related mood disorders.

The new findings, published online this week in Nature Molecular Psychiatry, show that a rare genetic dwarfism called Ellis van-Creveld (EvC) syndrome protects against bipolar affective disorder. The discovery was made thanks to decades of translational research in a few Old Order Amish families of Pennsylvania with a high incidence of both diseases. Forty years of documented research across multiple generations showed that no person with EvC has been reported with bipolar disorder.

"No one doubts that bipolar affective disorder has an important, disease causing genetic component," said neurologist and geneticist Edward I. Ginns, MD, PhD, professor of psychiatry at UMMS and lead author of the study. "In our search for the causes of bipolar affective disorder, this is a paradigm changing discovery that could lead to better treatments."

Bipolar affective disorder is a common psychiatric illness characterized by recurring swings from periods of high energy and mania to periods of low energy and sadness. During periods of mania the need for sleep is reduced and a person feels or acts abnormally happy, energetic and impulsive. They often make poorly thought out decisions with little regard for the consequences. Cycles of depression may include crying, poor eye contact with others, and a negative outlook on life. Patients suffering from bipolar disorder have a higher risk for suicide and self-harm and suffer from other ailments, such as heart disease, related to poor lifestyle choices.

Though many factors likely contribute to onset of the disease, various studies over the years have provided ample evidence that there is an important genetic component to the illness. However, previous attempts to isolate individual genes connected to bipolar disorder have been unsuccessful.

In her research among the Old Order Amish, which extends back more than 40 years, Janice A. Egeland, PhD, professor emerita of psychiatry and behavioral sciences at UMMSM and co-author of the current study, found that both EvC and bipolar were prevalent in an extended family descended from the same progenitor. Both conditions clearly travelled together over the generations in a few families extending from this same pioneer. Yet no person with EvC was ever reported with bipolar disorder despite decades of research across multiple generations.

"Few research efforts can claim to have extended over half a century using various building stones to reach a goal," said Dr. Egeland.

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Rare genetic disease protects against bipolar disorder

New technologies, and a little help from the U.S. Supreme Court, have made it possible for large numbers of women to find out whether they carry genetic mutations that increase their risk of breast cancer - a development warmly welcomed by experts in the field.

But the availability and relative affordability of multigene-panel tests can also lead to anxiety and confusion about what course of action to choose, because the risk associated with many of those genes remains unknown.

"Genetic testing holds a lot of potential and a whole lot of uncertainty," said Beth Peshkin, a professor of oncology and senior genetic counselor at Georgetown Universitys Lombardi Comprehensive Cancer Center in Washington.

"The more genes we test, the more variants were likely to find," explained Peshkin. "A recent study found that about 40 percent of people who underwent panel testing had variants, or genetic changes, that we dont know how to interpret."

In 2013 the Supreme Court invalidated Myriad Genetics patents on the two major genes that predispose women to breast and ovarian cancer, ruling that human genes cannot be patented.

Since then, several companies have begun testing for mutations in those genes, BRCA1 and BRCA2, which are responsible for about 80 percent of hereditary breast cancer cases; and the genes have been incorporated into panels that use so-called next-generation sequencing to test for multiple genes simultaneously.

The problem arises because some of the mutations detected in those panels are relatively rare and scientists do not yet know how much additional risk they confer, if any.

In August, the New England Journal of Medicine published a study showing that certain mutations in a gene called PALB2 were associated with a lifetime risk of between 33 percent (for carriers with no family history of breast cancer) and 58 percent (for those with a strong family history). Thats similar to the risk associated with a BRCA2 mutation, but lower than that for BRCA1.

The average lifetime risk for an American woman is about 12 percent. The vast majority of breast cancer cases are not linked to any known hereditary factor.

"Investigators from 14 centers around the world pooled data from all of their families with PALB2 mutations," said Dr. Jane Churpek, co-director of the Comprehensive Cancer Risk and Prevention Program at University of Chicago Medicine. "So, for the first time, we had a large enough series to get an estimate (of risk) for carriers of mutations in this gene. The hope is well see similar efforts for each gene on these panels."

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Breast cancer genetic screening offers vital information, uncertainty

PUBLIC RELEASE DATE:

14-Oct-2014

Contact: Katie Delach katie.delach@uphs.upenn.edu 215-349-5964 University of Pennsylvania School of Medicine @PennMedNews

PHILADELPHIA - The University of Pennsylvania's Basser Research Center for BRCA has announced $6.9 million to research teams both at Penn and at five other institutions across the United States, aimed at advancing the care of patients living with BRCA1 and BRCA2 mutations through multi-disciplinary collaboration. Penn Medicine's Abramson Cancer Center, home to the Basser Center, will serve as steward of the grants.

The new funding includes the first recipients of the new Basser External Research Grant Program, a unique funding mechanism for high-impact translational cancer research projects with the potential to advance rapidly into clinical practice.

"The projects funded this year are at the forefront of BRCA-related cancer research, and will help bring targeted therapies to a new level," said Susan Domchek, MD, executive director of the Basser Research Center for BRCA and the Basser Professor of Oncology at the Abramson Cancer Center. "BRCA research has come so far since the initial discovery twenty years ago, and working in collaboration with colleagues across the nation, we are making strides every day toward providing better care for these high-risk patients."

Among the five external recipients is a multi-institutional team led by Junjie Chen, PhD, chair of the department of Experimental Radiation Oncology at the University of Texas MD Anderson Cancer Center in Houston. The group is the recipient of the first Basser Team Science Award, which will fund a project focusing on developing new forms of chemotherapy for BRCA1/2-related cancers, and overcoming resistance to these medications.

Other recipients of funding through the External Grants Program include research teams at Johns Hopkins University, Fox Chase Cancer Center, and Drexel University College of Medicine, all of whom will work to enhance the effectiveness of various therapies which have potential for alleviating BRCA1/2-related cancers. For example, the project led by researchers at Drexel University College of Medicine will work to analyze the effect of specific genetic inhibitors in BRCA1/2 cells alone and in combination with therapeutic drugs, and to study the mechanisms of homologous recombination a key pathway to repairing DNA damage in human cells. In contrast, the project led by the team at Fox Chase Cancer Center, will aim to identify and characterize additional BRCA1 mutations that are capable of contributing to DNA repair and drug resistance. Researchers at Columbia University, who will design and conduct a community outreach effort aimed at minority women to determine eligibility for genetic counseling, also received funding.

The External Grants Program was made possible by a $5 million donation made earlier this year by University of Pennsylvania alumni Mindy and Jon Gray. Their latest gift brings their total giving to Penn to $30 million, following a $25 million gift which established the Basser Center in 2012. The Center was created in memory of Mindy Gray's sister Faith Basser, who died of BRCA-related ovarian cancer at age 44.

"We are enormously grateful to the Grays for extending their generosity to support these research programs," said Domchek. "Their gift allows us to work more closely in collaboration with colleagues at academic institutions around the world. In a time when medicine is making such great strides but federal funding for biomedical research is waning, it's vital that we find new channels to continue supporting progress across the field of BRCA research."

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Penn Medicine's Basser Research Center for BRCA announces $6.9 million in new grants

PUBLIC RELEASE DATE:

13-Oct-2014

Contact: Rachel Seroka rseroka@aan.com 612-928-6129 American Academy of Neurology @GreenJournal

MINNEAPOLIS A new guideline from the American Academy of Neurology (AAN) and the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) recommends guidance on how doctors should evaluate the full picturefrom symptoms, family history and ethnicity to a physical exam and certain lab test resultsin order to determine what genetic tests may best diagnose a person's subtype of limb-girdle or distal muscular dystrophy. The guideline is published in the October 14, 2014, print issue of Neurology, the medical journal of the American Academy of Neurology. To develop the guideline, researchers reviewed all of the available studies on the disorders, which cause muscles to waste away.

"These are rare muscle diseases that can be difficult to diagnose," said guideline lead author Pushpa Narayanaswami, MD, of Harvard Medical School in Boston and a Fellow of the AAN and AANEM. "With an accurate diagnosis, unnecessary tests or treatments may be avoided. Knowing the specific subtype is important for getting the best possible care."

"Limb girdle" refers to the hip and shoulder areas, where the limbs attach to the body. Limb-girdle muscular dystrophy most affects muscles close to the center of the body, such as in the areas near the tops of the arms and legs. Distal muscular dystrophy most affects muscles farther away from the center of the body, such as muscles in the hands and feet. There are several known subtypes of limb-girdle muscular dystrophy and distal muscular dystrophy. Experts continue to discover new subtypes.

Certain signs and symptoms and other information such as family history can help doctors determine a person's subtype. "Looking at a range of clinical signs and symptomssuch as which muscles are weak and if there is muscle wasting or enlargement, winging out of the shoulder blades, early signs of contracted limbs, rigidity of the neck or back, or heart or lung involvementcan help doctors determine which genetic test to order," said senior author Anthony A. Amato, MD, also of the Harvard Medical School and a Fellow of the AAN and AANEM. "This in turn can shorten the time to diagnosis and start of treatment while helping avoid more extensive and expensive testing."

While there is no cure for these disorders, complications can be managed. The guideline makes recommendations about treating and managing complications, which may include muscle symptoms, heart problems and breathing problems.

"Before this publication, there were no care guidelines that covered both limb-girdle muscular dystrophy and distal MD and were based on the evidence," said Julie Bolen, PhD, MPH, team lead, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention (CDC). "We hope that this guideline will fill that gap for both the people who live with these rare disorders and the health care professionals who treat them."

The guideline recommends that care for people with these disorders should be coordinated through treatment centers specializing in muscular dystrophy. People with these disorders should tell their doctors about any symptoms such as the heart beating too fast or skipping beats, shortness of breath and pain or difficulty in swallowing, as treatments may be available. People should also talk to their doctors about exercises that are safe.

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Guideline offers direction in genetic testing for certain types of muscular dystrophy

Image Caption: This female mountain lion, known as F52, was collared in the middle portion of the Santa Ana range. She later died near a busy highway of unknown causes. Credit: UC Davis

Provided by University of California Davis

Cut off by freeways and human development, mountain lions in southern California are facing a severe loss of genetic diversity, according to a new study led by the University of California, Davis in partnership with The Nature Conservancy.

The study, published today in the journal PLOS ONE, represents the largest genetic sampling of mountain lions, or pumas, in southern California. It raises concerns about the current status of mountain lions in the Santa Ana and Santa Monica mountains, as well as the longer-term outlook for mountain lions across southern California.

UC Davis School of Veterinary Medicine scientists collected and analyzed DNA samples from 354 mountain lions statewide, including 97 from southern California. Pumas in the Santa Ana Mountains displayed lower genetic diversity than those from nearly every other region in the state.

Santa Ana mountain lions show dramatic genetic isolation and have less in common with their neighbors in the Santa Monica Mountains than with those in the Sierra Nevada, underscoring the increasing seclusion of pumas in southern California.

The Santa Ana Mountain range, located south of Los Angeles and north of San Diego, is surrounded by urbanization and a growing population of about 20 million people. A small habitat linkage to the southeast connects pumas to the Peninsular Range, but it is bisected by Interstate 15 a busy 10-lane highway and associated human development. The study highlights the urgency to maintain and enhance the little connectivity remaining for coastal mountain lions, particularly across I-15.

The study also showed that the Santa Ana pumas recently went through a population bottleneck, when the populations size sharply decreased to a fraction of its original size.

The genetic samples give us a clear indication that there was a genetic bottleneck in the last 80 or so years, said lead author Holly Ernest, a professor with the Karen C. Drayer Wildlife Health Center and the Veterinary Genetic Laboratory at UC Davis at the time of the study. She is now a professor at the University of Wyoming, Laramie. That tells us its not just natural factors causing this loss of genetic diversity. Its us people impacting these environments.

Pumas in the Santa Monica Mountains are similarly threatened by low genetic diversity, inbreeding, and lions killing other lions, according to a study co-authored by Ernest published in Septembers issue of Current Biology. Just one lion was known to cross Highway 101 during the study period, and he significantly increased the genetic diversity of that population, the study found.

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Mountain Lions In Southern California Face Genetic Decay

PUBLIC RELEASE DATE:

8-Oct-2014

Contact: Holly Ernest hernest@uwyo.edu 307-766-6605 University of California - Davis @ucdavis

Cut off by freeways and human development, mountain lions in southern California are facing a severe loss of genetic diversity, according to a new study led by the University of California, Davis in partnership with The Nature Conservancy.

The study, published today in the journal PLOS ONE, represents the largest genetic sampling of mountain lions, or pumas, in southern California. It raises concerns about the current status of mountain lions in the Santa Ana and Santa Monica mountains, as well as the longer-term outlook for mountain lions across southern California.

UC Davis School of Veterinary Medicine scientists collected and analyzed DNA samples from 354 mountain lions statewide, including 97 from southern California. Pumas in the Santa Ana Mountains displayed lower genetic diversity than those from nearly every other region in the state.

Santa Ana mountain lions show dramatic genetic isolation and have less in common with their neighbors in the Santa Monica Mountains than with those in the Sierra Nevada, underscoring the increasing seclusion of pumas in southern California.

The Santa Ana Mountain range, located south of Los Angeles and north of San Diego, is surrounded by urbanization and a growing population of about 20 million people. A small habitat linkage to the southeast connects pumas to the Peninsular Range, but it is bisected by Interstate 15 -- a busy 10-lane highway -- and associated human development. The study highlights the urgency to maintain and enhance the little connectivity remaining for coastal mountain lions, particularly across I-15.

The study also showed that the Santa Ana pumas recently went through a "population bottleneck," when the population's size sharply decreased to a fraction of its original size.

"The genetic samples give us a clear indication that there was a genetic bottleneck in the last 80 or so years," said lead author Holly Ernest, a professor with the Karen C. Drayer Wildlife Health Center and the Veterinary Genetic Laboratory at UC Davis at the time of the study. She is now a professor at the University of Wyoming, Laramie. "That tells us it's not just natural factors causing this loss of genetic diversity. It's us people impacting these environments."

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A highway runs through it: Mountain lions in southern California face genetic decay

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As Breast Cancer Awareness month continues, Dr. Bhuma Krishnamachari, an epidemiologist and genetics expert at NYIT College of Osteopathic Medicine, is available to talk about the changing landscape of genetic tests and what it means for patients and doctors.

Genetic testing has changed from a single gene approach to a multiple gene approach, says Krishnamachari, who specializes in hereditary cancers.

Yet, doctors may not understand the clinical significance of the gene mutations found in these more comprehensive tests.

With more information comes more questions, says Krishnamachari.

For patients, Krishnamachari offers several tips to navigate the often confusing world of genetic tests.

Its important to find a doctor who is well-versed in hereditary factors and who involves many disciplines in patient care because the complexity of testing has increased, she says. Were moving toward more individualized treatments so the team should include genetic counselors, surgeons, oncologists, and primary care physicians.

Krishnamachi recently led NYIT research teams that published three separate studies on the need for physicians to learn more about genetic testing so they can help patients who may have a high risk of developing breast, ovarian, and colorectal cancers.

Physicians, she says, should be aware of the limitations that occurred in past, less comprehensive tests their patients may have had. Ethnicity-specific differences for mutations measured in BRCA tests, for example, must be understood since some patients may be at higher risk for certain cancers.

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Genetic Tests: With More Info Comes More Questions. NYIT Expert Available to Comment

PUBLIC RELEASE DATE:

6-Oct-2014

Contact: Robert Perkins perkinsr@usc.edu 213-740-9226 University of Southern California @USC

Imagine being able to take a pill that lets you eat all of the ice cream, cookies, and cakes that you wanted without gaining any weight.

New research from USC suggests that dream may not be impossible. A team of scientists led by Sean Curran of the USC Davis School of Gerontology and the Keck School of Medicine of USC found a new way to suppress the obesity that accompanies a high-sugar diet, pinning it down to a key gene that pharmaceutical companies have already developed drugs to target.

So far, Curran's work has been solely on the worm Caenorhabditis elegans and human cells in a petri dish but the genetic pathway he studied is found in almost all animals from yeast to humans. Next, he plans to test his findings in mice.

Curran's research is outlined in a study that will be published on Oct. 6 by Nature Communications.

Building on previous work with C. elegans, Curran and his colleagues found that certain genetic mutants those with a hyperactive SKN-1 gene could be fed incredibly high-sugar diets without gaining any weight, while regular C. elegans ballooned on the same diet.

"The high-sugar diet that the bacteria ate was the equivalent of a human eating the Western diet," Curran said, referring to the diet favored by the Western world, characterized by high-fat and high-sugar foods, like burgers, fries and soda.

The SKN-1 gene also exists in humans, where it is called Nrf2, suggesting that the findings might translate, he said. The Nrf2 protein, a "transcription factor" that binds to a specific sequence of DNA to control the ability of cells to detox or repair damage when exposed to chemically reactive oxygen (a common threat to cells' well being), has been well studied in mammals.

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High-sugar diet no problem for genetic mutants

Many of those who are genetically predisposed to develop atrial fibrillation, which dramatically raises the risk of stroke, can be identified with a blood test. This is shown by new research from Lund University in Sweden.

The number of people affected by atrial fibrillation is rising rapidly, partly as a result of the ageing population.

Over recent years, a research group at Lund University in Sweden, working with other universities and hospitals in Europe and the USA, has identified twelve genetic variants in the human genome that increase the risk of atrial fibrillation. The research group has now studied the possible clinical benefits of a DNA test:

One in five people have a genetic weakness that means they have twice as high a risk of developing atrial fibrillation as those with a low genetic risk. This genetic risk is therefore one of the strongest risk factors for atrial fibrillation that we know of in people without overt cardiac disease. It increases the risk as much as high blood pressure, for example, said Olle Melander, Professor of Internal Medicine, and Gustav Smith, Associate Professor in Cardiology, both from Lund University.

Since the symptoms of atrial flutter can be weak and unclear, they are sometimes difficult to pick up. However, even those with weak or absent symptoms of atrial flutter are at significantly higher risk of stroke.

In patients who are suspected of having temporary but recurrent episodes of atrial fibrillation, or in people with high blood pressure, it can be important for doctors to look at their genetic predisposition using a blood test. The test can give guidance as to how often and how intensively doctors need to screen for presence of atrial fibrillation in these individuals. We also consider that more widespread treatment of high blood pressure may be justified in those with a high genetic risk of atrial fibrillation, explained Professor Melander.

Patients already diagnosed with atrial fibrillation were also studied, and the researchers observed that if they had the risk genes, their risk of stroke was increased by a further 7080 per cent.

If an individual with atrial fibrillation is regarded as having a sufficiently high stroke risk, lifelong treatment with anticoagulant drugs such as warfarin is required in order to lower the risk.

There are also benefits of checking the genetic risk of those who have already been diagnosed with atrial fibrillation. The test makes it easier to correctly assess whether anticoagulant medication is necessary to prevent stroke, especially for those under 65, said Olle Melander.

The research data was taken from a long-term follow-up of 27400 participants in a population study.

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Genetic test reveals risk of atrial fibrillation, stroke

PUBLIC RELEASE DATE:

3-Oct-2014

Contact: Olle Melander Olle.Melander@med.lu.se 46-704-546-820 Lund University @lunduniversity

Many of those who are genetically predisposed to develop atrial fibrillation, which dramatically raises the risk of stroke, can be identified with a blood test. This is shown by new research from Lund University in Sweden.

The number of people affected by atrial fibrillation is rising rapidly, partly as a result of the ageing population.

Over recent years, a research group at Lund University in Sweden, working with other universities and hospitals in Europe and the USA, has identified twelve genetic variants in the human genome that increase the risk of atrial fibrillation. The research group has now studied the possible clinical benefits of a DNA test:

"One in five people have a genetic weakness that means they have twice as high a risk of developing atrial fibrillation as those with a low genetic risk. This genetic risk is therefore one of the strongest risk factors for atrial fibrillation that we know of in people without overt cardiac disease. It increases the risk as much as high blood pressure, for example", said Olle Melander, Professor of Internal Medicine, and Gustav Smith, Associate Professor in Cardiology, both from Lund University.

Since the symptoms of atrial flutter can be weak and unclear, they are sometimes difficult to pick up. However, even those with weak or absent symptoms of atrial flutter are at significantly higher risk of stroke.

"In patients who are suspected of having temporary but recurrent episodes of atrial fibrillation, or in people with high blood pressure, it can be important for doctors to look at their genetic predisposition using a blood test. The test can give guidance as to how often and how intensively doctors need to screen for presence of atrial fibrillation in these individuals. We also consider that more widespread treatment of high blood pressure may be justified in those with a high genetic risk of atrial fibrillation", explained Professor Melander.

Patients already diagnosed with atrial fibrillation were also studied, and the researchers observed that if they had the risk genes, their risk of stroke was increased by a further 7080 per cent.

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Genetic test reveals risk of atrial fibrillation and stroke

PUBLIC RELEASE DATE:

1-Oct-2014

Contact: Sarah Avery sarah.avery@duke.edu 919-660-1306 Duke University Medical Center @Duke_Medicine

DURHAM, N.C. A new genetic finding from Duke Medicine suggests that some people who are prone to hostility, anxiety and depression might also be hard-wired to gain weight when exposed to chronic stress, leading to diabetes and heart disease.

An estimated 13 percent of people, all of whom are Caucasian, might carry the genetic susceptibility, and knowing this could help them reduce heart disease with simple interventions such as a healthy diet, exercise and stress management.

"Genetic susceptibility, psychosocial stress and metabolic factors act in combination to increase the risk of cardiovascular disease," said Elizabeth Hauser, Ph.D. director of Computational Biology at the Duke Molecular Physiology Institute. Hauser is senior author of a study detailing the findings in the Oct. 1, 2014, online issue of the European Journal of Human Genetics.

Hauser and colleagues analyzed genome-wide association data from nearly 6,000 people enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA). The MESA study began in 2000 to better understand how heart disease starts, compiling the participants' genetic makeup as well as physical traits such as hip circumference, body mass index, cholesterol readings, glucose levels, blood pressure and other measures.

In the Duke analysis, the researchers first pinpointed a strong correlation between participants who reported high levels of chronic life stress factors and increased central obesity, as measured by hip circumference.

They then tested genetic variations across the genome to see which ones, in combination with stress, seemed to have the biggest influence on hip circumference. It turns out that variations called single-nucleotide polymorphisms (SNPs) in the EBF1 gene showed a strong relationship with hip circumference, depending on levels of chronic psychosocial stress. What's more, among those with this particular genotype, hips grew wider as stress levels increased.

"With further analysis, we found a significant pathway from high chronic life stress to wide hip circumference, to high blood glucose and diabetes, to increased cardiovascular disease, notably atherosclerosis," said Abanish Singh, Ph.D., a researcher in computational biology at Duke and the study's lead author. "But we found this only in people who were carriers of the EBF1 single-nucleotide polymorphism, and this was limited to participants who were white."

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Gene interacts with stress and leads to heart disease in some people

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Newswise Studying mice with a genetic change similar to what is found in Kabuki syndrome, an inherited disease of humans, Johns Hopkins researchers report they have used an anticancer drug to open up DNA and improve mental function.

Along with a potential treatment for the intellectual disability seen in Kabuki syndrome, the studys findings also suggest a new way of thinking about a category of genetic diseases known as Mendelian disorders of the epigenetic machinery, the researchers say. In these disorders, a genetic mutation causes errors in the way proteins and chemicals bind to DNA, which in turn affects the rate at which DNA make proteins. In the case of a Kabuki syndrome-like condition in mice, the researchers found that those errors lead to a persistent but treatable decrease in new cell growth in one part of the brain. Their study adds to the growing evidence that intellectual disability may not always be irreversible.

A report on the research appears online Oct. 1 in the journal Science Translational Medicine.

Mendelian disorders of the epigenetic machinery affect how cells package and use DNA, so they tend to have complicated and far-reaching effects, says Hans Bjornsson, M.D., Ph.D., an assistant professor of pediatrics and genetics in the Johns Hopkins University School of Medicines McKusick-Nathans Institute of Genetic Medicine. Finding that a drug can ease some of the symptoms in this group of disorders suggests that other Mendelian disorders of the histone machinery may be treated in a similar manner. Bjornsson led the study in collaboration with Harry "Hal" Dietz, M.D., the Victor A. McKusick Professor of Medicine and Genetics and director of the William S. Smilow Center for Marfan Syndrome Research.

Bjornsson heads the McKusick-Nathans Epigenetics and Chromatin Clinic. His research focuses on Kabuki syndrome, which is caused by mutations in one of two genes that govern proteins that DNA wrap around. DNA wound around the packaging proteins is known as chromatin; only by forming chromatin can several feet of DNA fit inside the tiny command centers of each cell. But in order for a cell to read the DNA and put it to use making new proteins of its own, the chromatin must temporarily open up.

Specialized enzymes, often called writers and erasers, add or subtract chemical groups to the packaging proteins to help induce the chromatin to open or close. In recent years, other researchers have found that Kabuki syndrome can be caused by mutations to one of two genes one for a writer, one for an eraser with the same net effect on chromatin opening. That finding led Bjornsson and his collaborators to suspect that Kabuki syndrome and similar conditions might be caused by an imbalance between chromatins open and closed states.

If true, that would mean that disorders of the histone machinery could be treated by altering the balance between open and closed states, Bjornsson says. To test the idea, Joel Benjamin, a graduate student in Bjornssons lab, used mice with a mutation in one of the Kabuki syndrome genes and a condition similar to Kabuki syndrome.

When the mice were at their young adult phase, the team treated them with AR-42, a drug developed for cancers of the blood that was already known to open up compacted chromatin. After two weeks of treatment, they put the mice through a drill called the Morris water maze, which tests their ability to form memories in a region of the brain called the hippocampus. The treated mice performed better than the untreated mice with the Kabuki-like condition about as well as healthy mice.

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Drug Treats Inherited Form Of Intellectual Disability In Mice

A vitamin D pill cant substitute for a healthy diet and sunshine,a new genetic study published inThe Lancet Diabetes & Endocrinologysuggests.In recent years many people have been seduced by observational studies that found low levels of vitamin D in people who developed type 2 diabetes. The new study instead suggests that the association is not causal, and that raising vitamin D by itself will not be helpful.

Researchers in the U.K. performed a Mendelian Randomization study in more than 100,000 peoplein which they examined the effect of four separate, single-nucleotide polymorphisms (SNPs) on genes that have a known effect on vitamin D levels. Despite the significant effect of these genetic variations on circulating levels of vitamin D (25(OH)D), the researchers found no relationship between genetically determined levels of vitamin D and the risk for developing type 2 diabetes.

Added to previous evidence, write the authors, the results suggest that interventions to reduce the risk of type 2 diabetes by increasing concentrations of 25(OH)D are not currently justified. Instead, they write, our findings emphasize the need for investigation of the discrepancy between the observational evidence and the absence of causal evidence. Two possible confounders are physical activity and adiposity, they add.

Results of several long-term randomized trials will be needed to definitively prove that vitamin D supplements are not beneficial, say Brian Buijsse in anaccompanying editorial. He cautions that Mendelian randomisation studies need careful interpretation, but an analysis of previous trials do not offer much hope that vitamin D supplementation can be used to prevent type 2 diabetes. He concludes that the sky is becoming rather clouded for vitamin D in the context of preventing type 2 diabetes.

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Genetic Analysis Fails To Support Vitamin D To Prevent Diabetes

PUBLIC RELEASE DATE:

30-Sep-2014

Contact: Anita Srikameswaran SrikamAV@upmc.edu 412-578-9193 University of Pittsburgh Schools of the Health Sciences @UPMCnews

Researchers at the University of Pittsburgh School of Dental Medicine have been awarded a $11.8 million, five-year grant from the National Institute of Dental and Craniofacial Research, part of the National Institutes of Health, to continue their exploration of the genetic roots of cleft lip and cleft palate and to expand the effort to include populations in Colombia, Nigeria, the Philippines and Pennsylvania.

Orofacial clefts (OFCs), which are small gaps in the lip or palate that can form when a baby's mouth doesn't develop properly during pregnancy, occurs in 1 out of 700 live births worldwide, said Mary L. Marazita, Ph.D., professor and vice chair, Department of Oral Biology, and director of the Center for Craniofacial and Dental Genetics (CCDG).

"Orofacial clefts present a significant public health challenge as these patients typically require surgical, nutritional, dental, speech and behavioral treatments for years," Dr. Marazita said. "We hope to build on the progress we've made in our previous studies by identifying genetic susceptibility not only for the overt defects, but also for more subtle features such as changes in facial structure that we have found in relatives of participants with OFCs."

Dr. Marazita and Seth M. Weinberg, Ph.D., assistant professor of oral biology, and director of the CCDG Imaging and Morphometrics Lab, lead the coordinating center for the project, which includes researchers from the University of Iowa, the Newborn Screening Foundation in the Philippines, the Lancaster Cleft Palate Clinic, Nigeria's University of Lagos, Colombia's Foundation Clinica Noel, and KU Leuven University in Belgium.

For the work's next phase, the team will recruit for genetic studies about 6,100 individuals from more than 1,500 families with a history of cleft lip with or without cleft palate, or cleft palate alone, from a low-risk population in Nigeria; high-risk populations in the Philippines and Colombia; and mid-risk populations in Pittsburgh and Lancaster, Pa., as well as 2,000 unrelated individuals with no history of OFC.

"Recent studies indicate different genes seem to be involved in different ethnic groups, so we must broaden our perspective to understand the factors that lead to clefts," Dr. Weinberg said. "We have limited information about the development of cleft palate alone, for example. This research effort will greatly add to our knowledge."

The team also will assess participants for subclinical manifestations of genetic predisposition for OFCs with high-resolution ultrasound scanning of mouth muscles, lip print patterns, 3-D imaging of facial surfaces and more. Their previously published studies have shown that relatives of OFC patients are more likely to have subtle defects in the orbicularis oris muscle around the mouth, and facial differences such as mid-face retrusion and wider faces. OFC patients also report a family history of cancer more often than unaffected individuals, noted Dr. Marazita.

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Pitt team searches for genetic roots of cleft lip, palate

Pittsburgh, Pennsylvania (PRWEB) September 30, 2014

Researchers at the University of Pittsburgh School of Dental Medicine have been awarded a $11.8 million, five-year grant from the National Institute of Dental and Craniofacial Research, part of the National Institutes of Health, to continue their exploration of the genetic roots of cleft lip and cleft palate and to expand the effort to include populations in Colombia, Nigeria, the Philippines and Pennsylvania.

Orofacial clefts (OFCs), which are small gaps in the lip or palate that can form when a babys mouth doesnt develop properly during pregnancy, occurs in 1 out of 700 live births worldwide, said Mary L. Marazita, Ph.D., professor and vice chair, Department of Oral Biology, and director of the Center for Craniofacial and Dental Genetics (CCDG).

Orofacial clefts present a significant public health challenge as these patients typically require surgical, nutritional, dental, speech and behavioral treatments for years, Dr. Marazita said. We hope to build on the progress weve made in our previous studies by identifying genetic susceptibility not only for the overt defects, but also for more subtle features such as changes in facial structure that we have found in relatives of participants with OFCs.

Dr. Marazita and Seth M. Weinberg, Ph.D., assistant professor of oral biology, and director of the CCDG Imaging and Morphometrics Lab, lead the coordinating center for the project, which includes researchers from the University of Iowa, the Newborn Screening Foundation in the Philippines, the Lancaster Cleft Palate Clinic, Nigerias University of Lagos, Colombias Foundation Clinica Noel, and KU Leuven University in Belgium.

For the works next phase, the team will recruit for genetic studies about 6,100 individuals from more than 1,500 families with a history of cleft lip with or without cleft palate, or cleft palate alone, from a low-risk population in Nigeria; high-risk populations in the Philippines and Colombia; and mid-risk populations in Pittsburgh and Lancaster, Pa., as well as 2,000 unrelated individuals with no history of OFC.

Recent studies indicate different genes seem to be involved in different ethnic groups, so we must broaden our perspective to understand the factors that lead to clefts, Dr. Weinberg said. We have limited information about the development of cleft palate alone, for example. This research effort will greatly add to our knowledge.

The team also will assess participants for subclinical manifestations of genetic predisposition for OFCs with high-resolution ultrasound scanning of mouth muscles, lip print patterns, 3-D imaging of facial surfaces and more. Their previously published studies have shown that relatives of OFC patients are more likely to have subtle defects in the orbicularis oris muscle around the mouth, and facial differences such as mid-face retrusion and wider faces. OFC patients also report a family history of cancer more often than unaffected individuals, noted Dr. Marazita.

Minor dental abnormalities, facial shape differences, altered speech patterns and other less obvious changes in the mouth could all be part of a spectrum of defects that have the same genetic causes as cleft lip and palate, she said. If we can unravel those relationships and identify the biological pathways that cause them, we will gain insights that may lead to better treatments and better long-term outcomes for affected individuals.

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Pitt Researchers Search for Genetic Roots of Cleft Lip, Palate with Help from NIH Grant

PUBLIC RELEASE DATE:

30-Sep-2014

Contact: Chris Jones jonesc83@cardiff.ac.uk Cardiff University @cardiffuni

Screening families of patients with bowel cancer for a genetic condition would cut their risk of developing bowel, womb, and ovarian cancers, new research has found.

In a major study, Dr Ian Frayling from Cardiff University's School of Medicine and researchers from the University of Exeter's Medical School assessed the effectiveness of introducing a UK-wide screening programme for a genetic condition known as Lynch Syndrome.

Lynch syndrome is a caused by changes in genes which check the spelling in DNA. The condition increases the risk of people developing cancer, particularly bowel cancer and cancers of the womb and ovaries later in life. Without testing cancers, it is not obvious that they are caused by Lynch syndrome, and so it is often not diagnosed.

It is responsible for around one in 12 cases of people aged under 50 and around a third of people with the disease develop bowel cancer by the time they are 70, if no action is taken.

"If Lynch Syndrome is identified as the cause of bowel cancer, patients can be offered risk-reducing measures such as more intensive post-operative colonoscopy surveillance to spot recurrences and new cancers early," according to Cardiff University's Dr Ian Frayling, the clinical adviser to the study.

"As close relatives have a 50 per cent chance of sharing the gene, screening would provide a valuable opportunity to detect the condition in children, siblings, parents and more distant relatives.

"It would mean measures could be taken to reduce the risk of cancers developing," he added.

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Genetic test would help 'cut bowel cancer spread'

PUBLIC RELEASE DATE:

25-Sep-2014

Contact: Alison Trinidad alison.trinidad@usc.edu 323-442-3941 University of Southern California - Health Sciences

LOS ANGELES A multi-institutional team of researchers studying schizophrenia and bipolar disorder has been awarded a $16 million grant from the National Institute of Mental Health (NIMH) to create the most extensive genetic resource to date for these two devastating psychiatric disorders, using data assembled by the University of Southern California (USC).

The four-year award, shared by USC, the University of Michigan and the Broad Institute Inc., will help fund a project titled: "Whole Genome Sequencing of Schizophrenia and Bipolar Disorder in the Genomic Psychiatry Cohort (GPC)."

Keck School of Medicine of USC researchers Carlos N. Pato, M.D., Ph.D., Franz Alexander Professor and chair of the Department of Psychiatry and Behavioral Sciences and Michele Pato, M.D., professor and Della Martin Chair of Psychiatry, created the GPC, which includes more than 37,000 participants who have agreed to provide DNA samples for genomic, epidemiological and clinical studies.

"The GPC is a cohort of patients and controls who have agreed to partner with us in extensive genomic studies of human heredity, ranging from normal function to a variety of illnesses," said Carlos N. Pato, principal investigator of the new award. "This study will greatly increase the data available on the human genomic sequence. By design, it will help us study schizophrenia and bipolar disorder, but this resource should prove extremely important for understanding the role of the human genome in a broad set of disorders and in normal human functions."

Schizophrenia and bipolar disorder are chronic, disabling and often life-threatening. Despite estimated lifetime prevalence of just more than 1 percent worldwide and their burden on individuals, families and public health, little is known about the molecular basis of the disorders. The high heritability of these disorders which involve five- to 10-fold increased risk to first-degree relatives indicates that potential insights about their molecular basis may be found in the ways in which genome sequences vary from person to person. Better understanding of the genetic basis of schizophrenia and bipolar disorder could identify molecular mechanisms for novel drugs, therapies and preventive strategies.

"The failures and successes of genetic analyses over the past 15 years have shown that schizophrenia and bipolar disorder are highly polygenic illnesses, which means that making meaningful observations about the genetic basis of schizophrenia and bipolar disorder will require analyzing the largest possible number of genomes," said Michele Pato. "The important challenge is not only to find variants that affect the function or expression of a gene, but to find the subset of variants that truly matters to psychiatric illness."

The study will sequence total genomic DNA from 10,000 or more ethnically diverse individuals from the GPC, split evenly among schizophrenia cases, bipolar disorder cases and psychiatrically normal controls. The resulting genome sequence data will be processed to obtain the most informative view of the genomes for these individuals. The team will also conduct association analyses within these and other available sequence data, and through genotype imputation with the Psychiatric GWAS Consortium comprising approximately 100,000 additional genomes, to identify genetic variants associated with schizophrenia and bipolar disorder.

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National team awarded $16 million NIH grant to study genetics of schizophrenia and bipolar disorder