Category Archives: Gene Medicine

PUBLIC RELEASE DATE:

21-May-2014

Contact: Karen Warmkessel kwarmkessel@umm.edu 41-032-889-194-104-041-53 University of Maryland Medical Center

BALTIMORE May 21, 2014. Researchers at the University of Maryland School of Medicine have identified a mutation in a fat-storage gene that appears to increase the risk for type 2 diabetes and other metabolic disorders, according to a study published online today in the New England Journal of Medicine.

The researchers discovered the mutation in the hormone-sensitive lipase (HSL) gene by studying the DNA of more than 2,700 people in the Old Order Amish community in Lancaster County, Pa. HSL is a key enzyme involved in breaking down stored fat (triglycerides) into fatty acids, thereby releasing energy for use by other cells.

"We found that Amish people with this mutation have defects in fat storage, increased fat in the liver, high triglycerides, low "good" (HDL) cholesterol, insulin resistance and increased risk of developing type 2 diabetes," says the study's senior author, Coleen M. Damcott, Ph.D., an assistant professor of medicine in the Division of Endocrinology, Diabetes and Nutrition and member of the Program for Personalized and Genomic Medicine at the University of Maryland School of Medicine.

In this study, 5.1 percent of the Old Order Amish study participants had at least one copy of the mutation. Four people had two copies of the mutation and consequently produced no HSL enzyme, Dr. Damcott says. The mutation is less common in non-Amish Caucasians of European descent (0.2%), thus the higher prevalence of the mutation in the Amish makes it possible to characterize its full range of effects.

"Future studies of this gene will allow us to look more closely at the effects of its deficiency on human metabolism to better understand the function of the HSL protein and its impact on fat and glucose metabolism," Dr. Damcott says. "These studies will also examine the potential of using HSL as a drug target for treating type 2 diabetes and related complications."

She notes that type 2 diabetes is a complex disease whose susceptibility is often determined by interactions between genetics and lifestyle factors, such as overeating and physical inactivity. Susceptibility genes for diabetes may be involved in several different metabolic pathways in the body, including storage and release of fat for energy. "Discovery of this mutation adds to the growing list of insights gained from genomic studies that can be used to develop new treatments and customize existing treatments for type 2 diabetes and related metabolic disorders," Dr. Damcott says.

Co-author Alan R. Shuldiner, M.D., the John L. Whitehurst Endowed Professor of Medicine, associate dean for personalized medicine and director of the Program for Personalized and Genomic Medicine, and his colleagues at the University of Maryland School of Medicine have previously identified a number of susceptibility genes for diabetes as well as for obesity, high blood pressure and other complex diseases. In 2008, they discovered a novel gene mutation among the Old Order Amish population that significantly reduces the level of triglycerides in the blood and appears to help prevent cardiovascular disease. Dr. Shuldiner's team has been conducting genetic research with the Old Order Amish in Pennsylvania since the early 1990s.

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Univ. of MD researchers identify fat-storage gene mutation that may increase diabetes risk

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Newswise PHILADELPHIAWhile large genetic testing panels promise to uncover clues about patients DNA, a team of researchers from Penn Medicines Abramson Cancer Center (ACC) has found that those powerful tests tend to produce more questions than they answer. In a study of 278 women with early onset breast cancer who did not have the BRCA genes, the researchers found that only 2.5 percent of the patients had inherited mutations that were actually clinically actionable. Experts dont yet know how to interpret most of the mutations discovered by the testknown as massively parallel gene sequencing.

Results of the study, led by author Kara Maxwell, MD, PhD, a fellow in the division of Hematology-Oncology in the Perelman School of Medicine at the University of Pennsylvania, will be presented during the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago in early June (Abstract #1510).

Large genetic testing panels sometimes reveal mutations in genes that are associated with an increased risk in developing cancer. BRCA 1 and BRCA 2 genes are prime examples, where women can opt for mastectomies and ovary removal surgerywhich research shows slashes their risk of developing those cancers. However, there is not yet guidance for clinicians on how to care for patients who exhibit other types of mutations, such as CHEK2 and ATM. These are known as variants of unknown significance (VUS).

Were in a time where the testing technology has outpaced what we know from a clinical standpoint. Theres going to be a lot of unknown variants that were going to have to deal with as more patients undergo large genetic testing panels, said Maxwell. Its crucial that we figure out the right way to counsel women on these issues, because it can really provoke a lot of anxiety for a patient when you tell them, We found a change in your DNA and we dont know what it means.

The team, which includes Susan Domchek, MD, the Basser Professor in Oncology and director of the Basser Research Center for BRCA in Penns ACC, and Katherine Nathanson, MD, an associate professor in the division of Translational Medicine and Chief Oncogenomics Physician for the ACC, studied 278 patients who had been diagnosed with breast cancer under the age of 40, were not carriers of the BRCA1 or BRCA2 mutations, and had no family history of ovarian cancer.

The researchers performed massively parallel gene sequencing to detect 22 known or proposed breast cancer susceptibility genes in each woman. Though the testing did reveal multiple variants of genes that are known to confer increased risk of breast cancer in patients who develop the disease young, only 2.5 percent of patients tested were found to have mutations that are actionable under current treatment guidelines, including TP53, CDKN2A, MSH2, and MUTYH.

In all, the sequencing revealed reportable variants in over 30 percent of the patients.

Knowing there is a mutation may not help us any more than knowing that the person has a positive family history which we already know, Nathanson said. We dont know yet what to do with the information on an individual basis, and there certainly are no clinical standards.

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Large Panel Genetic Testing Produces More Questions than Answers in Breast Cancer

hide captionSex can matter, whether you're looking at drug side effects, the response to treatment, or the progression of a disease.

Many potential new drugs look like they could be big winners at least when judged by how well they work in mice or other lab animals. Over the years, there have been a number of promising cancer "cures," possible Alzheimer's treatments, and candidate drugs for holding back the ravages of various degenerative diseases.

But, time after time, these great promises fade away once the potential treatments are tried in people. There are lots of reasons for that. Humans aren't rodents, for starters.

But now the National Institutes of Health is targeting a more subtle problem in animal studies: Labs often don't consider that the sex of the animal could also influence research findings.

There are obvious sex differences in people when it comes to disease. Low-dose aspirin affects men and women differently. It appears that some of the gene variants that increase the risk of Alzheimer's are more potent in women than in men. And women are more likely than men to have bad reactions to drugs.

It should be no surprise, then, that mice and other lab animals also have sex differences in their response to drugs and diseases. Yet scientists often don't take that into account when planning their laboratory studies. In fact, sometimes they deliberately choose male mice, because scientists worry that the cycling reproductive hormones in female animals might make it harder to interpret the results. It also appears that males are sometimes favored because that's simply the conventional thing to do.

Enough! says Janine Clayton, director of the Office of Research on Women's Health at NIH, and NIH Director Francis Collins. They're starting to roll out new guidelines to make sure that research on animals as well as on tissue samples taken from animals takes into account potential differences between the sexes. Clayton and Collins laid out their plans this week in a Nature commentary.

These days, following an abysmal history of ignoring women in clinical trials in the late 20th century, a bit more than half of all participants in NIH-funded studies are women.

But "there has not been a corresponding revolution in experimental design and analyses in cell and animal research despite multiple calls to action," Clayton and Collins write.

Scientists who do the research often ignore the issue; so do colleagues who review the studies. And scientific journals also don't demand that scientists state the gender of animals used in the studies they publish.

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Medicine Needs More Research On Female Animals, NIH Says

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Newswise PHILADELPHIA Breastfeeding, tubal ligation also known as having ones tubes tied and oral contraceptives may lower the risk of ovarian cancer for some women with BRCA gene mutations, according to a comprehensive analysis from a team at the University of Pennsylvania's Basser Research Center for BRCA and the Abramson Cancer Center. The findings, a meta-analysis of 44 existing peer-reviewed studies, are published in the Journal of the National Cancer Institute.

The researchers, from Penn's Perelman School of Medicine, found that breastfeeding and tubal ligation are associated with reduced rates of ovarian cancer in BRCA1 mutation carriers, and the use of oral contraceptives is associated with a reduced risk of ovarian cancer in patients with BRCA1 or BRCA 2 mutations. The analysis also helped better define factors that may increase risk among this population: Smoking, for instance, may raise the risk of breast cancer for patients with a BRCA2 mutation. Though the team cautions that more data are required before definitive conclusions about these variables can be made, the findings help to shed light on non-surgical risk reduction options for women who may not be ready to undergo prophylactic removal of their ovaries to cut their cancer risk.

Our analysis reveals that heredity is not destiny, and that working with their physicians and counselors, women with BRCA mutations can take proactive steps that may reduce their risk of being diagnosed with ovarian cancer, says lead author Timothy R. Rebbeck, PhD, professor of Epidemiology and Cancer Epidemiology and Risk Reduction Program Leader at Penn Medicine's Abramson Cancer Center. The results of the analysis show that there is already sufficient information indicating how some variables might affect the risk of cancer for these patients."

BRCA1 and BRCA2 are human genes that produce tumor-suppressing proteins. A woman's risk of developing breast or ovarian cancer is notably increased if she inherits a harmful mutation in either the BRCA1 gene or the BRCA2 gene from either parent. Fifty-five to 65 percent of women who inherit a harmful BRCA1 mutation, and about 45 percent of women who inherit a harmful BRCA2 mutation will develop breast cancer by age 70, compared to approximately 12 percent of women in the general population. Thirty-nine percent of women who inherit a harmful BRCA1 mutation and up to 17 percent of women who inherit a harmful BRCA2 mutation will develop ovarian cancer by age 70, compared to only 1.4 percent of women in the general population. Both BRCA mutations have also been associated with increased risks of several other types of cancer.

Though the study's findings point to a helpful role for birth control pills in cutting ovarian cancer risk, the relationship between oral contraceptives and breast cancer risk was ambiguous. The authors say women and their health care providers should weigh the potential benefits of oral contraceptives (reduction in ovarian cancer risk, avoidance of unintended pregnancy, and regulation of menstrual cycles, for instance) against the potential risks (such as blood clots or the possible increased risk of breast cancer). There was also insufficient evidence to draw conclusions about the relationships between breastfeeding and tubal ligation, respectively, and breast cancer. Future research aims to examine these issues as well as how other variables, such as alcohol consumption, affect the risk of breast and ovarian cancer for BRCA mutation carriers. Since BRCA testing is relatively new, researchers have struggled to conduct large studies to examine these trends due to limited availability of large numbers of prospectively identified BRCA1/2 mutation carriers.

Patients deserve better cancer-risk reduction options than surgically removing their healthy breasts and ovaries, said Susan Domchek, MD, executive director of the Basser Research Center for BRCA and co-author on the new paper. Its imperative that we continue examining and building upon past research in this area so that we can provide BRCA mutation carriers with options at every age, and at every stage of their lives.

Penn's Tara M. Friebel, MPH, is also an author of the paper.

Funding for the study was supported by the National Institutes of Health (R01-CA102776 and P50-CA083638) and the Basser Research Center for BRCA, the nation's first and only comprehensive center focused on prevention and treatment of BRCA-related cancers. In 2012, University of Pennsylvania alumni Mindy and Jon Gray gave a $25 million gift to establish the Basser Center in honor of Mindys sister, Faith Basser, who passed away at the age of 44 of ovarian cancer. Recently, the Grays committed an additional $5 million gift to support BRCA-related pancreatic cancer research as well as launch an external grants program to help advance science around the globe focused on BRCA-related research.

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"Heredity is Not Destiny": Breastfeeding, Birth Control Pills May Reduce Ovarian Cancer Risk Among Women with BRCA ...

May 13, 2014

Image Caption: Albino Doberman pinschers share a similar gene with humans who also have the condition and display the same characteristics including sensitivity to sunlight. Credit: Michigan State University

Sarina Gleason / Joshua Bartoe, Michigan State University

Michigan State University researchers have identified a genetic mutation in Doberman pinschers that causes albinism in the breed, a discovery that has eluded veterinarians and breeders worldwide up until now.

Paige Winkler, a doctoral student in the College of Veterinary Medicine, co-led the study with Joshua Bartoe, an assistant professor in the Department of Small Animal Clinical Sciences, and discovered a mutated gene that is associated with a form of albinism in humans.

What we found was a gene mutation that results in a missing protein necessary for cells to be pigmented, said Winkler. Some defects in this same gene cause a condition called oculocutaneous albinism in humans.

This type of albinism has certain characteristics that are evident in both humans and dogs.

With an albino Doberman, you see a white or lighter-colored coat, pink noses and lips, along with pale irises in the eyes, said Winkler. These traits are very similar to the characteristics humans display with this particular condition causing light-pigmented skin and hair, along with eye discoloration and vision disturbances.

The canine breed and people also experience the same skin sensitivity to sunlight, which results in an increased risk of skin tumors.

We knew that the albino Dobermans typically developed these types of tumors, much like humans, but we wondered what the actual increase in prevalence was between a white dog and a regular-colored Doberman, said Bartoe. What we found was a significant increase in risk for development of melanoma-like tumors in the albino dogs.

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Humans And Dogs Share Similar 'Albino' Gene

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Newswise MANHATTAN, Kan. A collaborative study involving Kansas State University researchers has discovered a new gene expression mechanism in porcine reproductive and respiratory syndrome, or PRRS, virus an important swine pathogen that costs the U.S. pork industry more than $600 million a year. The discovery provides a new avenue for scientists to explore strategies to control and prevent the disease.

Ying Fang, Ph.D., associate professor of diagnostic medicine and pathobiology at Kansas State University, led a study that looked at the unique gene expression mechanism of the PRRS virus. She and colleagues found a new protein in the virus, nsp2TF, was generated through novel ribosomal frameshifting signals.

The research recently appeared in the Proceedings of the National Academy of Sciences, or PNAS, study, "Transactivation of programmed ribosomal frameshifting by a viral protein."

Fang conducted this study with her European collaborators, including Eric Snijder and his team members at Leiden University Medical Center in The Netherlands, and Andrew Firth, Ian Brierley and Brierley's lab members at the University of Cambridge. Yanhua Li, Fang's doctoral student in pathobiology, China, made important contributions to this study. Zhi Sun, Fang's former doctoral student, and Longchao Zhu, visiting scholars in diagnostic medicine and pathobiology in Fang's lab, also were involved in the study.

The study builds on a 2012 PNAS study Fang and her European collaborators conducted while she was at South Dakota State University. In it, researchers identified the nsp2TF protein in the PRRS virus. The protein is expressed through a new gene expression mechanism called -2 ribosomal frameshifting.

"Frameshifting occurs when a ribosome encounters a 'slippery' sequence and downstream signal in messenger RNA," Fang said. "This causes the ribosome to shift two nucleotides backward, which results in all the genetic codons downstream of the shifted site to be read differently and produce a new protein that has a different function."

With the most recent study, Fang and colleagues have shown that this -2 frameshifting requires a PRRS virus protein, nsp1beta. It is the first time a virus's genetic mechanism has been found to require the action of a transacting viral protein rather than a RNA structure to induce a ribosomal frameshifting, which is novel in the protein translation field.

The function of the nsp2TF protein is currently under investigation, Fang said. The protein contains a genetic element that may be responsible for suppressing the pig's immune system.

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Researchers Find a New Gene Expression Mechanism of PRRS Virus

Researchers identified a genetic mutation in Doberman pinschers Affected dogs have white or lighter-colored coat, pink noses and lips, along with pale irises in the eyes

By Mark Prigg

Published: 13:01 EST, 12 May 2014 | Updated: 16:41 EST, 12 May 2014

Researchers have pinpointed the genetic mutation is dogs that cause them to becopme albino.

The mutation, caused by a missing protein, causes albinism in Doberman pinschers.

Affected animals have a white or lighter-colored coat, pink noses and lips, along with pale irises in the eyes - similar to humans affected.

Albino Doberman pinschers: Affected animals have a white or lighter-colored coat, pink noses and lips, along with pale irises in the eyes - an researcher now know the genetic mutation that causes the effect.

Researchers studied 20 dogs of each color and discovered that more than half of the albino dogs had at least one tumor while only one of the regular-colored dogs possessed a tumor.

The results of their research could be of great importance to Doberman breeders around the world.

Currently, American Kennel Club registration restricts dogs with the condition.

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Researchers find Albino gene in DOGS and its related to human disorder

redOrbit Staff & Wire Reports Your Universe Online

People possessing a variant of the longevity gene KLOTHO have demonstrated enhanced brain skills, regardless of factors such as age, sex or risk of Alzheimers disease, according to research published in the journal Cell Reports.

The National Institutes of Health-funded study found that people with the variant had improved thinking, learning and memory. It also revealed that increasing levels of the KLOTHO gene in mice made the creatures smarter, possibly by increasing the strength of the brains nerve cell connections, the study authors explained.

This could be a major step toward helping millions around the world who are suffering from Alzheimers disease and other dementias, lead author Dr. Dena Dubal, the David A. Coulter Endowed Chair in Aging and Neurodegeneration at the University of California San Francisco School of Medicine, said in a statement. If we could boost the brains ability to function, we may be able to counter dementias.

According to the study authors, the effects that aging has on the brain will become a greater health issue as people live longer, especially when it comes to the set of brain disorders known as dementias. The symptoms of dementia include impaired language skills and memory issues, and the number of cases is expected to double every 20 years. By the year 2050, over 115 million people worldwide are expected to require treatment for one of these conditions.

People who have one copy of a variant of the KLOTHO gene known as KL-VS are more likely to live longer and are also less likely to suffer a stroke, the researchers said. On the other hand, people who have two copies of the gene are more likely to live shorter lives and have a higher risk of stroke.

As part of their new study, Dr. Dubal and her colleagues discovered that men and women who possessed one copy of the KL-VS variant performed better on a series of different cognitive examinations than those who lacked the gene regardless of how old they were, whether they were male or female, or whether or not they had the apolipoprotein 4 gene (the primary genetic risk factor for Alzheimers disease).

The investigative team recruited over 700 subjects between the ages of 52 and 85, none of whom demonstrated signs of dementia, and tested several different cognitive abilities during three studies. Between 20 and 25 percent of all subjects had one copy of the KL-VS variant, and those individuals outperformed those who had no copies on the various tests, according to the study authors.

This study shows the importance of genes that regulate the multiple aging processes involved in the maintenance of cognitive function, said Dr. Suzana Petanceska, of the National Institute on Aging (NIA) Division of Neuroscience. Understanding the factors that control the levels and activity of KLOTHO across multiple organ systems may open new therapeutic avenues for prevention of age-related cognitive decline and dementia.

The KLOTHO gene also provides the blueprint for the klotho protein, which is made by cells found in the kidney, placenta, small intestine, and prostate. The researchers found that performance on the cognitive tests decreased with age, regardless of whether a subject had one or no copies of the KL-VS gene variant, and they believe that an age-related decrease in circulating levels of this protein could be partially responsible.

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Variant Of Longevity Gene Could Enhance Cognitive Abilities

Short height and long life have a direct connection in Japanese men, according to new research based on the Kuakini Honolulu Heart Program (HHP) and the Kuakini Honolulu-Asia Aging Study (HAAS).

"We split people into two groups -- those that were 5-foot-2 and shorter, and 5-4 and taller," said Dr. Bradley Willcox, one of the investigators for the study and a Professor in the University of Hawai`i (UH) John A. Burns School of Medicine's Department of Geriatric Medicine. "The folks that were 5-2 and shorter lived the longest. The range was seen all the way across from being 5-foot tall to 6-foot tall. The taller you got, the shorter you lived."

Researchers at the Kuakini Medical Center, the UH John A. Burns School of Medicine and U.S. Veterans Affairs worked on the study, which was recently published in PLOS ONE, a peer-reviewed medical journal.

The researchers showed that shorter men were more likely to have a protective form of the longevity gene, FOXO3, leading to smaller body size during early development and a longer lifespan. Shorter men were also more likely to have lower blood insulin levels and less cancer.

"This study shows for the first time, that body size is linked to this gene," said Dr. Willcox. "We knew that in animal models of aging. We did not know that in humans. We have the same or a slightly different version in mice, roundworms, flies, even yeast has a version of this gene, and it's important in longevity across all these species."

Dr. Willcox noted that there is no specific height or age range that should be targeted as a cut-off in the study, in part because "no matter how tall you are, you can still live a healthy lifestyle" to offset having a typical FOXO3 genotype rather than the longevity-enhancing form of the FOXO3 gene.

The Kuakini HHP started in 1965 with 8,006 American men of Japanese ancestry born between the years 1900 and 1919. The lifestyles and health conditions of these men were closely followed and studied by the researchers through the years. The Kuakini HHP is the only longitudinal study of Japanese-American men that has included epidemiological and clinical data of the cohorts for almost 50 years. From a worldwide perspective, it is the only research program that maintains a comprehensive, longitudinal database of demographic, lifestyle and medical information, as well as biological specimens collected, from such a large cohort of aging men.

"One of the reasons why Honolulu is perfect for this kind of study is that we have the longest-lived state in the country, combined with a population that has remained, for the most part, in Hawaii. This has helped us maintain one of the longest-running, largest studies of aging men in the world, in the Kuakini Honolulu Heart Program," Dr. Willcox said.

Approximately 1,200 men from the study lived into their 90s and 100s, and approximately 250 of those men are still alive today.

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Shorter men live longer, study shows

by Andrea Lutz

KTVB.COM

Posted on May 4, 2014 at 9:41 PM

Updated yesterday at 11:04 PM

BOISE -- Modern medicine and early detection are helping women in the fight against breast cancer, but recently a decision in our nation's highest court has made it easier to afford the cost of genetic cancer testing.

The Saint Alphonsus Breast Cancer Center in Boise reports that one in 500 breast cancer cases women have what's called the BRCA gene mutation.

Saint Als Breast Surgeon Elizabeth Prier says knowledge of the BRCA gene has been around for the last decade, and identifying at-risk women has intesified in the last five years.

A lot of women with BRCA1 will end up with breast cancer in their 30s sometimes in their late 20s, said Dr. Prier.

That means women end up starting their fight with the disease earlier.

Annie Pierce, a wife and mother of two, ended her battle with breast cancer before it even started.

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Breast cancer test made famous by Angelina Jolie now more affordable