Post Traumatic Stress Disorder (PTSD) affects roughly 20% of all veterans from the Afghanistan and Iraq wars. The disorder’s unfortunate prominence among those who’ve served prompted Lisa James, Ph.D., and Apostolos Georgopoulos, M.D., Ph.D., to investigate a genetic predisposition for PTSD. James and Georgopoulos are researchers at the Brain Sciences Center, an interdisciplinary center between the University of Minnesota Medical School’s Department of Neuroscience and the Veterans Affairs Health Care System.
The study assessed self-reported symptoms of PTSD and blood samples from 343 U.S. veterans. Upon running genetic tests, James and Georgopoulos found a specific protein present in the brain partially determined whether an individual was more resilient or more susceptible to being diagnosed with PTSD.
That protein is called apolipoprotein E.
Georgopoulos explained, “Apolipoprotein E moves lipids across cells in the brain. It cleans up the damage and debris, so to speak.”
Within apolipoprotein E, there are three major forms: E2, E3 and E4. The E2 allele appears to make individuals more resilient to trauma while the E4 allele increases the likelihood an individual will experience PTSD following a trauma.
“Prior to this study, we didn’t know a lot about genetic contributions to resilience,” said James. “These findings identify a specific gene that explain why some develop PTSD and others don’t.”
The study was published in Experimental Brain Research.
Looking forward, there is a national push to research ways the E4 form of this protein can be structurally modified to look and act like the more desirable E2. This modification would not only make individuals more resistant to PTSD, but potentially also to Alzheimer’s disease.
James hopes to continue examining other genes contributing to resilience. She is currently following a group of women between ages of 25 and 102 to better understand why some experience cognitive decline during aging and others do not.
This effort has been tremendously boosted by a recent gift of 1 million dollars to establish the Kunin Professorship in Women’s Healthy Brain Aging under the Department of Neuroscience, a professorship which James holds.
While these studies are in the early stages, the team is hopeful they will lead to breakthroughs in understanding the mechanisms in the brain that promote resilience.
“Resilience goes beyond PTSD. It includes Alzheimer’s, aging, and general cognitive function,” James said. “We’re interested in applying these findings toward identifying similar proteins or mechanisms related to many types of brain resilience or decline.”
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Imagine if an individual’s DNA could be matched to the most effective medication to treat his or her case specifically. Using pharmacogenomics, researchers and providers are getting closer to achieving this goal.
A form of precision medicine, which involves matching individual characteristics to treatment, pharmacogenomics focuses on how pharmacology and genetics work together.
Utilizing this method, researchers look at the genes of a person to understand how they might react to a treatment. For example, the presence of a certain gene might lead to a heightened chance of developing certain side effects from a drug.
Because drug regimens were developed to work for the average person, drugs are not 100 percent effective; some people have a great response to a drug while others have no response or a bad response to the same drug. Experts need to discern who might react negatively to a certain treatment regimen so they can prescribe an effective treatment program.
Jacobson studies how to effectively use immunosuppressant’s for kidney transplants that require certain genetic predictors, such as how fast a person can metabolize a drug.
“If the drug is metabolized quickly, it will leave the blood system quickly,” Jacobson said. “Those metabolizing quickly will be at risk for therapy failure.”
Jacobson also researches certain genetic predictors in relation to chemotherapy and bone marrow transplants. Certain predictors show if someone needs high versus low exposure to chemotherapy.
Jacobson developed a model aiming to help clinicians identify the best treatment options. She wants to use this model to decrease the risk of treatment related mortality.
“Right now everyone gets the same dose,” Jacobson said. “We want to use models and individual characteristics to predict the optimal dose for each person.”
The large amount of genetic data each person carries makes pharmacogenomics challenging. It’s difficult for experts to identify what each gene represents in relation to pharmacology.
“Our entire genome is billions of base pairs and we all differ,” Jacobson said. “How do you even begin to start interpreting all of those base pairs?”
According to Jacobson, some genetic variants are meaningless while others can result in serious harm, so it’s important to identify which ones might be relevant or not.
“In the long run, we need to find therapies that are highly effective and 100 percent safe,” Jacobson said. “To be 100 percent effective and safe may not be realistic but that’s what precision medicine is about.”
There will be a Precision Medicine Conference on June 20th that will bring precision medicine experts from across the Midwest together to discuss this growing field.
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In a new study from the University of Minnesota, researchers found there are numerous areas of the genome where obese and non-obese individuals differ in terms of their “methylome.”
Essentially, the researchers found that the level of DNA methylation (addition or subtraction of a methyl group on the DNA molecule) was related to level of body mass index (BMI), a marker of obesity. These differences in methylome are a type of “epigenetic” variation, which does not involve the genetic sequence itself, but rather is thought to alter which genes are turned “on” and “off” at a given point in time in a given tissue. Typical genetic sequences do differ but data shows these differences go beyond that.
Lead author, Ellen Demerath, Ph.D., associate professor of epidemiology and community health at University of Minnesota’s School of Public Health conducted the study in collaboration with other U of M researchers and researchers at three other United States institutions all of whom are working on the large on-going Atherosclerosis Risk in Communities (ARIC) Study. This is a 30-year prospective study of coronary heart disease risks in both white and African American adults ages 45-55 when the study started in 1985.
“Study participants are tracked annually and also brought in for blood draws and detailed examinations. This includes the measurement of body mass index (BMI) and waist circumference, typical markers of obesity,” said Demerath.
Researchers found these differences were not only noted in the blood but in fat tissue DNA as well. This could provide useful information about methylation in other disease-relevant tissues that are typically difficult to collect in large-scale community based studies.
When comparing their results for over 2,000 African American individuals with 3,000 white individuals in other studies, researchers were interested to learn signatures of obesity were largely similar across race/ethnic groups.
“This has not been shown before. It supports the idea that many of the same molecular pathways disrupted in obesity probably operating in both African Americans and Whites,” said Demerath.
The team’s goal of this research and other epigenetic research is to get a more exact understanding of how the behavioral factors including obesity, exercise, and cigarette smoking, as well as environmental exposures such as air pollution and dietary factors can change the DNA over our lifetime, and lead to disease.
“The results will hopefully be followed up with longitudinal data to assess whether these DNA methylation changes in obese individuals are permanent, or are changed if they lose weight,” said Demerath. “The work is exciting because it might be possible to design pharmaceutical or dietary or other behavioral interventions that specifically target these epigenetic signatures to avert diabetes and coronary heart disease.”
Demerath and her colleagues are submitting a number of NIH grant proposals this year to continue their research and expand its scope to look at methylation changes over time, race differences and genetic determinants of methylation variation related to obesity and diabetes.
“We want to achieve a very comprehensive understanding of the role of epigenetics in chronic disease in African Americans, and the ARIC study is fortunate to have one of the larger samples of African Americans of any epigenetic study in the United States,” said Demerath.
The post Research Snapshot: Obesity can lead to the alteration of specific genes appeared first on Health Talk.
Tylenol should relieve pain, cough suppressants should ease cough and serious ailments should reliably respond to vital medication. But when a prescribed medicine doesn’t do its intended job, it can be difficult to decide who or what is to blame.
It doesn’t help that sometimes the problem doesn’t lie within the medicine or the doctor; it can lie within your genes.
Take the blood thinner Plavix, used in the treatment of individuals who have had a stroke, heart attack or have angina, for example. Known generically as clopidogrel, this anticoagulant functions poorly for 25 percent of the Caucasian patients to whom it’s prescribed. That’s because those 25 percent carry a variant in their genome that prevents the medicine from thinning blood as expected. For these people, an enzyme named CYP2C19 doesn’t activate the medicine well enough for the patient at risk of a heart attack or stroke to get the desired effect. And that can be dangerous.
But thanks to the burgeoning field of pharmacogenetics (think “pharmacy” and “genetics” combined), genetic hurdles preventing a drug’s success can be identified.
And once you know what the problem is…
“You can match patient genes to their drug prescriptions,” said Pamala Jacobson, Pharm.D., director of the Institute of Personalized Medicine at the University of Minnesota College of Pharmacy and member of the Masonic Cancer Center, University of Minnesota. “The implications can be seen in so many places. Physicians offices, dental clinics and even community pharmacies can and are beginning to embrace the potential of matching drugs to the patients they work with.”Matching the right drug to the right person takes on an especially important role in life-threatening illness and disease. Institute of Personalized Medicine and Masonic Cancer Center, University of Minnesota, researchers discovered a key genetic variation influencing drug response in acute myeloid leukemia treatment in Feb. 2014. The discovery enables better patient-drug matching.
Of course, many drugs on the market today don’t necessitate matching a genome. Some drugs play on enzymes without much genetic variation or exhibit clinically irrelevant variations. For these drugs, genetics do not affect care decisions.
For the drugs and diseases where it does play a role, pharmacogenetics is a big part of today’s trend toward personalized medicine. A new lung cancer study that began last month will sequence patients’ tumor genomes to match the best drug possible.
“We know genetic variation can influence response to some medications,” said Jacobson. “Every month we’re learning about new pharmacogenetic effects, and people are starting to take an interest. The potential is huge.”
And it’s not just tumor genomes being sequenced. Researchers know the U of M developed HIV/AIDS drug Ziagen has a pharmacogenetic effects that, if identified in a patient, can be addressed. Patients who have the HLA-B*57:01 genetic variant should not receive the drug because they are at high risk of toxicity.
At the U of M Institute of Personalized Medicine scientists are genotyping the kidney transplant recipients to examine how it could impact kidney transplantation. They hope to one day prevent some of the undesirable immunologic reactions that can occur between donor and recipient genomes. Researchers are also trying to match a patient’s immunosuppressive drugs to their genome to reduce toxic effects and improve how well the drug works. Currently all patients receive the same drugs.
Pharmacogenetics, too, holds great potential in the area of liver transplantation. Planning around the way a new liver might metabolize drugs could one day play a role in improving transplantation success and recovery.
Students attending the College of Pharmacy, now leave the college with a strong background in pharmacogenomics – something that wasn’t the case just a few years ago.
Practitioner guidelines developed for the first time in 2009 outline how today’s available genetic tests can be used to improve drug therapy. Students focus heavily on this list of gene-influenced medications ranging from clopidegral to codeine. According to Jacobson, it’s incredibly important to teach pharmacogenomics to pharmacists, because the future is now.
Cost is no longer as prohibitive as it once was. Remember clopidegral (Plavix) and its genetic variability? For $250 or so, genotyping can be performed today to determine if an individual is likely to benefit from Plavix.
That understanding in hand, your genome might just decide your final Rx.
Gene partnership may be fueling cancer spread in as much as 20 percent of cancers
A key cancer-causing gene, responsible for up to 20 percent of cancers, may have a weak spot in its armor, according to new research from the Masonic Cancer Center, University of Minnesota.
The partnership of MYC, a gene long linked to cancer, and a non-coding RNA, PVT1, could be the key to understanding how MYC fuels cancer cells. The research is published in the latest issue of the journal Nature.
“We knew MYC amplifications cause cancer. But we also know that MYC does not amplify alone. It often pairs with adjacent chromosomal regions. We wanted to know if the neighboring genes played a role,” said lead author Anindya Bagchi, Ph.D., assistant professor in the University of Minnesota Medical School, the College of Biological Sciences and member of the Masonic Cancer Center. “We took a chance and were surprised to find this unexpected and counter-intuitive partnership between MYC and its neighbor, PVT1. Not only do these genes amplify together, PVT1 helps boost the MYC protein’s ability to carry out its dangerous activities in the cell.”
Contributors to this research include Yuen-Yi Tseng, graduate student with Anindya Bagchi, David Largaespada, Ph.D., professor in the College of Biological Sciences, Yasuhiko Kawakami, Ph.D., assistant professor in the College of Biological Sciences, York Marahrens, Ph.D., associate professor in the College of Biological Sciences and Kathryn Schwertfeger, Ph.D., assistant professor in the University of Minnesota’s Medical School.
Bagchi and his team focused on a region of the genome, 8q24, which contains the MYC gene and is commonly expressed in cancer. The team separated MYC from the neighboring region containing the non-coding RNA PVT1. Using a specialized gene manipulation technique called chromosome engineering, researchers developed genetically engineered mouse strains in three separate iterations: MYC only, the rest of the region containing PVT1 but without MYC and the pairing of MYC with the regional genes.
The expected outcome, if MYC was the sole driver of the cancer, was tumor growth on the MYC line as well as the paired line. However, researchers found growth only on the paired line. This indicates MYC is not acting alone and needs help from adjacent genes.
“The discovery of this partnership gives us a stronger understanding of how MYC amplification is fueled. When cancer promotes a cell to make more MYC, it also increases the PVT1 in the cell, which in turn boosts the amount of MYC. It’s a cycle, and now we’ve identified it, we can look for ways to uncouple this dangerous partnership,” said Largaespada.
Testing this theory of uncoupling, researchers looked closely at several breast and colorectal cancers which are driven by MYC. For example, in colorectal cancer lab models, where a mutation in the beta-catenin gene drives MYC to cancerous levels, eliminating PVT1 from these cells made the tumors nearly disappear.
“Finding the cooperation between MYC and PVT1 could be a game changer. We used to think MYC amplification is the major issue, but ignored that other co-amplified genes, such as PVT1, can be significant,” said Tseng, the paper’s first author. “In this study, we show that PVT1 can be a key regulator of MYC protein, which can shift the paradigm in our understanding of MYC amplified cancers.”
MYC has been notoriously elusive as a drug target. By uncoupling MYC and PVT1, researchers suspect they could disable the cancer growth and limit MYC to pre-cancerous levels. This would make PVT1 an ideal drug target to potentially control a major cancer gene.
“This is a thrilling discovery, but there are more questions that follow,” said Bagchi. “Two major areas present themselves now for research: will breaking the nexus between MYC and PVT1 perform the same in any MYC-driven cancer, even those not driven by this specific genetic location? And how is PVT1 stabilizing or boosting MYC within the cells? This relationship will be a key to developing any drugs to target this mechanism.”
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If you’re a dog lover, we have some good news. It turns out that a better understanding of the mechanisms behind aging and cancer could reduce the number of canines over the age of 10 that die from cancer each year. A better understanding of those same mechanisms may even yield big news for humans down the road.
Recently, University of Minnesota researchers made a surprising discovery about one gene implicated in aging.
And it all centered around a gene known as the telomerase (TOO-low-mears) reverse transcriptase gene, or “TERT.” The protein is part of a complex, “telomerase”, that was previously thought to be responsible for differing cancer risks between dog breeds.
But when Camille McAloney, a dual-degree D.V.M./Ph.D. student, investigated TERT in the University of Minnesota’s Modiano Lab alongside Kevin Silverstein, Ph.D., of the Minnesota Supercomputing Institute; Jaime Modiano, V.M.D., Ph.D., professor in the College of Veterinary Medicine and Masonic Cancer Center member; and Anindya Bagchi, Ph.D., she found otherwise.
“We found there is virtually no correlation in TERT genetic differences between the dog breeds we studied,” said McAloney. “That implies the TERT gene is less responsible for cancer risk than previously thought.”
In the four dog breeds McAloney studied – some very prone to cancer, others not – there wasn’t a significant difference in this one gene thought to be key to cancer risk.
While the Shih Tzus, Dachshunds, Irish Wolfhounds, and Newfoundlands in the study were different in many respects, any changes or mutations to TERT weren’t segregated by dog size or breed. That means no breed-specific polymorphisms, or genetic variations, have occurred in TERT since dog breeds were first established.
Any changes to TERT would have occurred in the domesticated dog’s wild predecessor: the wolf. And a gene barely changed since different dog breeds first emerged is unlikely to be responsible for such major variations in cancer risk from one dog breed to another today.
“Even more interesting than gene mutations not being affected by breeding,” said Anindya Bagchi, Ph.D., assistant professor with the U of M Masonic Cancer Center and Department of Genetics, Cell Biology and Development, “is that many of the mutations discovered were heterozygous.”
But let’s take a step back. If the TERT gene doesn’t equate to canine cancer, there’s another hypothesis.
There are two types of changes that can occur in genes: heterozygous and homozygous. (Remember Punnett Squares from science class?) We have two copies of each gene, but heterozygous changes, or mutations, occur in just one of those two. Homozygous mutations occur in both.
If not a single dog studied by McAloney had the homozygous mutation of the TERT gene that means this kind of genetic change likely isn’t tolerated. A dog that inherited two copies of the TERT mutation would die.
That’s the part Bagchi calls interesting because it leads to the question of why wolves underwent the original genetic mutation leading to only heterozygous mutations today. What was the health benefit?
The answer could lead to a better understanding of canine and human cancer alike.
Chances are, you know someone who’s had a kidney stone. The rock-like masses of calcium oxalate can be painful – and worse, can come back time and time again. As many as one in 10 people will develop a kidney stone during their lifetime.
Today, scientists know the biggest risk factor for kidney stones is genetics. However, just which genes passed from parent to child can claim responsibility for yielding the stones down the road isn’t yet known.
According to Eva Furrow, V.M.D., a post-doctoral fellow in veterinary population medicine at the University of Minnesota, this limitation is a problem. “Drugs and other preventative measures used to keep stones from recurring have limited success,” she said.
Current treatment options include diet change, increased water consumption, or taking medicine designed to bring urinary calcium levels down. While reducing the risk of stone formation, none of these options offer a lasting, across-the-board treatment.
To find a better way to prevent and treat kidney stone formation, the University of Minnesota and Mayo Clinic teamed up in 2012.
By taking a look at dogs – animals that share our kidney stone problem – scientists have been able to examine genes that could be key to the inherited disease.
“We’re starting at the beginning, following the disease path back to its genetic source to uncover information that can be used to invent potential new treatments,” said Furrow, who is leading investigations set to wrap this summer.
So far Furrow and colleagues at the Minnesota Urolith Center at the University of Minnesota and Mayo Clinic O’Brien Urology Research Center have narrowed the potentially responsible genes to 18 candidates.
Their analysis of Miniature Schnauzers, Bichons and Shih Tzus, both with and without kidney stones, has turned up a specific pattern on one chromosome of dogs with kidney stones. Now, Furrow expects to find a genetic mutation in the milieu responsible for stone risk.
Identifying the high-risk gene behind kidney stones could signify a big step toward better and alternative treatments, for canines and humans alike.
“The top gene we’re looking at now is a metal transporter,” said Furrow. “Our big question is really ‘is it responsible for susceptibility to kidney stones?’”
The investigations continue.
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Health Talk took a break from Thanksgiving meal preparation yesterday to talk turkey with University of Minnesota expert Kent Reed, Ph.D. Reed is an evolutionary biologist and animal geneticist with the university’s College of Veterinary Medicine. He’s helped sequence upwards of 90 percent of the turkey genome with the Turkey Genome Mapping Project and is now working to characterize the turkey genome’s precursor: the turkey transcriptome. Here’s what he has to say about your holiday centerpiece: Health Talk: Where did the turkey and its genome first start? Reed: Earliest domestication of the turkey was likely by indigenous peoples in southwest North America. Most domesticated turkeys today, however, are linked to the Spaniards who brought turkeys from Mexico to Europe where they were domesticated and then later returned to America. That means today’s domestic turkeys are probably most closely related to the subspecies that existed in Mexico. Jump ahead a few hundred years and Minnesota is one of the nation’s top turkey-producing states. Health Talk: Why sequence the turkey genome? Reed: We want to know what’s happened in the turkey genome during the process of domestication for faster growth and more meat. How is the domestic bird cialis 20 mg filmtabl preisvergleichviagra rezeptfrei günstig online bestellenhere
different from the wild bird and how can we use that information to raise birds that are healthy and grow well? Ultimately, we want to better understand turkey health, so when we take the turkey genome and turn it into a Thanksgiving dinner, it’s done in a way that promotes everyone’s health. HT: What kinds of genes are you looking for? Reed: We’re looking for genes that influence muscle development and the immune system. It also turns out domesticated turkeys are really sensitive to mycotoxins, or chemical products produced by fungi that colonize crops. Wild turkeys are less sensitive. So we’re also investigating the genes responsible for the health problems caused by mycotoxins in collaboration with Utah State University. We want to know how domestic turkeys lost the ability to process fungal toxins in their foods and if there’s a way to restore that natural ability again.HT: Genome in-hand, is the turkey’s health forecast optimistic? Reed: We haven’t seen too many genome-related changes yet, but we will. Historically, much of the turkey industry has been focused around “How do you grow more turkeys, faster, bigger?” but there are problems related to fast growth and big birds. It’s not just about making more meat. It’s about the bird’s overall health. We never know the next pathogen on the horizon. Having access to the turkey genome gives us tools to address future challenges.
Sexual differentiation is a major part of development for nearly all organisms, and scientists have long known the transformer 1 (TRA-1) gene controls all difference between the sexes in the nematode C. elegans, a simple animal that has provided an important model of how other more complicated animals develop. Though TRA-1 does not regulate sex in humans, it is related to the GLI, the family of genes that are important in human development and cancer. Still, nearly four decades after the discovery of the TRA-1 gene, scientists do not know much about what genes it controls to actually accomplish that task.
Now, new research from the University of Minnesota, in collaboration with the lab of Jason Lieb, Ph.D., at University of North Carolina, may shed some light on the topic.
Published this week in the Proceedings of National Academy of Sciences of the United States of America (PNAS), new research by Matthew Berkseth, a graduate student in the lab of David Zarkower, Ph.D., identified new genes controlled by tra-1 that are involved in sexual differentiation.
“In our study, we asked where in the genome the TRA-1 protein binds,” said Zarkower, a professor in the University of Minnesota Medical School and the Department of Genetics, Cell Biology and Development. “It turns out TRA-1 regulates a suite of several hundred genes whose combined action causes anatomy, physiology and behavior to be sex-specific.”
By looking at the spots in the genome where TRA-1 binds, researchers were able to find several things:
- TRA-1 promotes female development by preventing expression of male development genes.
- Timing of some developmental events is sex specific. “Nevertheless, we were surprised to find several genes controlled by TRA-1 were ones functioning in the timing of development. This suggests TRA-1 directly imposes sex specificity on developmental timing,” said Zarkower.
- The suite of TRA-1 targets uncovered in this research will offer resources to inform future investigation into sex differentiation.
“The work we’ve done here has laid out a path for identifying and functionally defining genes controlling sexual differentiation in nematodes,” said Zarkower of future work. His lab is looking into evaluating fully the roles these candidate target genes may play in sexual development.
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New research from the University of Minnesota College of Veterinary Medicine (CVM) has uncovered the role gene ORMDL3 plays in the disease asthma. ORMDL3, a gene recently linked to asthma susceptibility, has now been linked to the body’s ability to recruit inflammatory cells during an airway allergic reaction. Study findings appear today in the journal Nature Communications.
U of M researchers including Srirama Rao, Ph.D., (P. Sriramarao), CVM professor in the Department of Veterinary and Biomedical Sciences and associate dean for research, as well as professor in the U of M Medical School’s Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, has identified a function of how ORMDL3 regulates the recruitment of inflammatory cells to airways, thus causing airway inflammation, in a mouse model.
Sung Gil Ha, Ph.D., a CVM post-doctoral fellow and the study’s lead author, and colleagues have identified factors that up-regulate the ORMDL3 gene in specific white blood cells such as eosinophils during allergic asthma. Eosinophils are white blood cells intended to help protect the body from parasites; however, in the case of certain types of inflammation including exposure to allergens, instead of providing protection, they can cause tissue damage leading to asthma or other allergic disorders.
Not much is known about the function of ORMDL3 in asthma. By silencing or over-expressing ORMDL3 in eosinophils, the group has identified molecules regulated by the gene. These molecules enable eosinophils to congregate in airways where they cause allergic inflammation.
When turning the ORMDL3 gene off, researchers found lower levels of integrins expressed on the surface of eosinophils, meaning a decreased ability of eosinophils to migrate and cause inflammation in the airways.
“While exciting, our finding is just one piece of the puzzle,” said Rao. “The more we understand about various asthma susceptibility genes including ORMDL3, the better positioned we will be to strategize new treatment options.”
The discovery provides momentum for future understanding of the pathogenesis of asthma and role of genetics in inflammatory allergic reactions. This research is not only relevant for asthma but potentially other allergic disorders such as those of the GI tract and skin. The American Academy of Allergy, Asthma & Immunology estimates the number of asthma suffers internationally at 300 million with 250,000 annual deaths attributed to the disease.
Genetic disposition can influence the severity or susceptibility to an asthmatic reaction to allergens or environmental factors such as stress and cold.
The ORMDL3 gene studied by U of M researchers has been linked to asthma in various ethnic groups worldwide.
Research funding was provided by the National Institutes of Health grant nos. HL108000 and AI35796.
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U of M collaborates with more than 20 research institutions to identify new genes associated with fatal lung disease
University of Minnesota Genomics Center (UMGC) researchers collaborated with more than 20 national and international research institutions to identify a number of genetic markers associated with idiopathic interstitial pneumonia (IIP), a serious and often fatal lung disease with a poorly understood cause. Although there are several variants of IIP, the preponderance of patients in the current study suffered from interstitial pulmonary fibrosis (IPF), the most common and severe IIP.
These genetic locations (loci) led to the identification of neighboring genes proposed to be involved in the cause and/or progression of the disease. Researchers believe these discoveries will move them closer to more effective treatments.
These findings were recently published in Nature Genetics.
In the laboratory of lead author, David A. Schwartz, M.D., from the University of Colorado-Denver School of Medicine, researchers were able to localize regions of the genome that were more frequently found in individuals with the disease.
The UMGC was called upon by Schwartz for a very specific skill set.
“The UMGC provided high-throughput replication genotyping of the genetic hits identified in their genome-wide association study,” said Kenneth Beckman, Ph.D., director of the University of Minnesota Genomics Center. “The UMGC specializes in very high-throughput population genotyping, and helped to get the work done quickly.”
There are very few drugs that effectively slow down IPF which has a median survival time of 3-5 years after diagnosis. By illuminating the genes and gene products that are likely to be involved in IPF, this study will be a boon to pulmonologists and pharmacologists.
Craig Henke, M.D., is a professor of medicine in the Pulmonary and Critical Care Division at the University of Minnesota and sees patients with IPF at his clinic. Although Henke was not affiliated with this particular study, he does research on IPF and notes the importance of trying to better understand this deadly disease.
“IPF was once considered an uncommon disease but the prevalence of IPF has been increasing as the population ages, now afflicting an estimated 1 million people worldwide and 200,000 individuals in the U.S.,” said Henke. “Studies that provide insight into the development of this deadly disease may help in the development of new medicines or therapies for IPF.”
“The discoveries highlighted by Dr. Schwartz’s research –in which we were fortunate enough to play a role—represent only the beginning of a period of intense work that lies ahead. Nevertheless, with this study, researchers now have a framework on which to base the work that lies ahead,” concluded Beckman.
After one of the largest examinations of genetic data ever conducted, researchers from Harvard Medical School and Massachusetts General Hospital have found a genetic link between five types of mental disorders: schizophrenia, bipolar disorder, autism, major depression and attention deficit hyperactivity disorder.
While researchers acknowledge hundreds of genes may ultimately determine psychiatric illness, the study’s significance lies in its demonstration that the five psychiatric conditions may actually represent a disease spectrum rather than five distinct, unrelated conditions.
The latest findings, published in The Lancet, stem from a genetic examination of more than 60,000 people from across the globe.
According to University of Minnesota Physicians psychiatrist S. Charles Schulz, M.D., the head of the University of Minnesota Medical School’s Department of Psychiatry, the latest research is significant in how it might lead to a breakdown in the silos of psychiatric illness.
“This is the largest study to ever examine the genetics of multiple illnesses, and it has the ability to describe that there are genes that go across five mental disorders,” said Schulz. “What they’re talking about is defining illness across a spectrum. Historically this area of psychosis had been broken down into disease categories. What we’re finding is that the underlying biology demonstrates similarities across these five conditions.”
Schulz added that it’s actually not surprising that there would be overlapping gene abnormalities within the spectrum of psychotic illness. In fact, 12 years ago he and his colleagues completed a study showing similarities in the brain images of both schizophrenic and bipolar patients at the outset of their illness.
By examining genes, researchers may be able to redesign the way medications are sought, developed and tested. The hope is that psychiatry may ultimately be able to head down a road of targeted therapy. In breast cancer for example, physicians can determine which type of breast cancer some patients are battling, tailoring therapies and treatment approaches for a more effective outcome. Taking the same approach for psychiatric patients could result in profound patient benefit.
According to Schulz, work within the field of genetics may arm future clinicians with tools to better assess or measure gene characteristics related to symptoms across the spectrum of psychotic illness. Confronted with a schizophrenic patient battling cognitive abnormalities, for example, a doctor might use genetic profiles to determine which medication would work best for that particular patient.
“What we might find is that within general conditions, there are underlying genes that, if we could identify them, would help us provide the best treatment for particular patients,” said Schulz. “For the field of psychiatry, the prospects of aiding our patients in this way is really very exciting, and an area of research we at the University are excited to contribute to in the coming years.”
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Masonic Cancer Center researchers identify genetic variation which may predict acute myeloid leukemia treatment success
Researchers from the College of Pharmacy and Medical School working within the Masonic Cancer Center, University of Minnesota, have partnered to identify genetic variations that may help signal which acute myeloid leukemia (AML) patients will benefit or not benefit from one of the newest antileukemic agents.
Their study is published today in Clinical Cancer Research.
In the latest study, U of M researchers evaluated how inherited genetic polymorphisms in CD33, a protein that naturally occurs in most leukemia cells, could affect clinical outcomes of patients treated with an existing chemotherapy drug, gemtuzumab ozogamicin (GO), an immuno-conjugate between anti-CD33 antibody and a cytotoxin known as calicheamicin, which binds to CD33 on leukemic cells. As GO is internalized by leukemia cells, the cytotoxin is released, causing DNA damage and generating leukemic cell death.
In recent clinical trials GO has been shown to induce remission and improve survival in subset of patients with AML, however there is wide inter-patient variation in response.
Jatinder Lamba, Ph.D., and colleagues identified and evaluated three genetic variations of CD33 in two groups of patients with pediatric AML – one group that received the drug GO, and one group that did not. They found that specific genetic variation in CD33 that significantly affected the clinical outcome of AML patients who received GO based chemotherapy.
“Understanding how genetics play a role in how drugs work is extremely useful, particularly for a drug like GO which has shown a very heterogeneous response in AML patients,” said Jatinder Lamba, Ph.D., the study’s lead author and a researcher who holds appointments in both the College of Pharmacy and the Masonic Cancer Center, University of Minnesota. “Our latest findings lead us to believe that genetic variation in CD33 influences how AML patients’ leukemic cell responds to GO.”
AML is a cancer of the blood and bone marrow, and is the second most common form of leukemia in children. Though the most common type of treatment for AML is chemotherapy, Lamba says the disease remains hard to treat and newer, more effective therapies are needed.
“The overall goal of our study was to use genetic data to predict beneficial or adverse response to a specific drug, thus opening up opportunities to use this information for drug optimization to achieve maximum therapeutic efficacy and minimum toxicity. Our hope is that our research could serve as a marker of prognostic significance for clinicians to select the therapy that has the greatest odds of being effective for individual patients based on their CD33 genotype.”
Other University of Minnesota researchers involved in the study include Amit Kumar Mitra, Ph.D, University of Minnesota College of Biological Sciences, Leslie Mortland, M.D., from the University of Minnesota Medical School and Betsy Hirsch, Ph.D., from the Medical School and the Masonic Cancer Center, University of Minnesota.
A team funded by the Minnesota Partnership for Biotechnology and Medical Genomics has uncovered clues to possible drugs for two rare cancers through research involving baker’s yeast and a library of chemical compounds. The team from Mayo Clinic and the University of Minnesota published the findings in the journal PLoS ONE.
Mayo Clinic molecular biologist Jim Maher, Ph.D., and University of Minnesota medicinal chemist Gunda Georg, Ph.D., led the research. These scientists and their teams operated as a collaborative unit, one of the dozens that the Minnesota Partnership has funded over the past 10 years to answer basic questions about disease.
The two rare cancers, paraganglioma and pheochromocytoma, are caused by errors in the DNA of families and have been difficult to study in the laboratory. The researchers devised a way to make the yeast cells mimic the cancer cells and then compared their growth against more than 200,000 potential drugs to ultimately find a handful of promising leads — potential drugs that would selectively slow the growth of the mimic cells.
“Many patients travel to Minnesota for treatment of these conditions, because we have the clinical experience to help them,” Dr. Maher says. “Hopefully this work will lead to future treatments.”
Dr. Maher speaks from experience, as a 35-year paraganglioma patient himself.
The findings suggest that drugs might work by blocking the yeast cells’ sugar digestion, essentially starving them. The researchers think that the same approach might one day be used to treat patients with the two rare cancers, and they are planning studies to pursue that idea.
Co-lead authors are Mayo endocrinologist Irina Bancos, M.D., and John Paul Bida, Ph.D., a former Mayo Graduate School doctoral student. Other authors include Mary Bundrick, Molly Nelson Holte, Eric Poeschla, M.D., and Dyana Saenz, Ph.D., all of Mayo Clinic; Yeng Her and Debra Evans, also from Mayo Graduate School; and Defeng Tian, Kristen John and Derek Hook, Ph.D., all of the University of Minnesota.
In addition to the Minnesota Partnership grant, the research was supported by Mayo Clinic, the Fraternal Order of Eagles, Mayo Graduate School, and a grant from the Ann and George M. Fisher Endowed Research Fund for Individualized Medicine. About the Minnesota Partnership: The Minnesota Partnership for Biotechnology and Medical Genomics is a collaboration among the University of Minnesota, Mayo Clinic and the state of Minnesota. To learn more about the Partnership, go to www.minnesotapartnership.info.
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If you missed it, Amanda Schaffer, a science and medical columnist for Slate recently wrote a compelling piece for Newsweek about genetic material found only on the Y chromosome making its way into the brains of women.
According to researchers at the Fred Hutchinson Cancer Research Center in Seattle, the concept, known as “microchimerism,” has opened up questions around a) just how the material got there, since it’s absent in a woman’s genome at birth outside of rare genetic defects, and b) the effect of the phenomenon once the material arrives in the female brain.
“While microchimerism has been found in other parts of the body, the discovery extends the phenomenon to the human brain. And it energizes many questions about how this curious mix of self and other functions in our bodies—and how its presence in such a crucial and sensitive organ might differ.”
Now, researchers are trying to determine what the impact might be. Could microchimerism of the brain cause problems down the road? Could the misplaced genetic material actually offer some potential benefit? According to Schaffer’s piece:
“The question,” explains Diana Bianchi, a reproductive geneticist and professor at Tufts University School of Medicine, “is whether it is helping or hurting.” And as the burgeoning literature on autoimmune diseases, cancer, and tissue injury and repair suggests, the answer is probably some of both.
Check out Schaffer’s article, “How Male DNA Gets in a Woman’s Brain” over at Newsweek’s site The Daily Beast.
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