Category Archives: Gene Medicine

PITTSBURGH, January 8, 2015 - Genetic mutations may link smoking and alcohol consumption to destruction of the pancreas observed in chronic pancreatitis, according to a 12-year study led by researchers at the University of Pittsburgh School of Medicine. The findings, published today in Nature Publishing Group's online, open-access journal Clinical and Translational Gastroenterology, provides insight into why some people develop this painful and debilitating inflammatory condition while most heavy smokers or drinkers do not appear to suffer any problems with it.

The process appears to begin with acute pancreatitis, which is the sudden onset of inflammation causing nausea, vomiting and severe pain in the upper abdomen that may radiate to the back, and is typically triggered by excessive drinking or gallbladder problems, explained senior investigator David Whitcomb, M.D., Ph.D., chief of gastroenterology, hepatology and nutrition, Pitt School of Medicine. Up to a third of those patients will have recurrent episodes of acute pancreatitis, and up to a third of that group develops chronic disease, in which the organ becomes scarred from inflammation.

"Smoking and drinking are known to be strong risk factors for chronic pancreatitis, but not everyone who smokes or drinks damages their pancreas," Dr. Whitcomb said. "Our new study identifies gene variants that when combined with these lifestyle factors make people susceptible to chronic pancreatitis and may be useful to prevent patients from developing it."

In the North American Pancreatitis Study II consortium, researchers evaluated gene profiles and alcohol and smoking habits of more than 1,000 people with either chronic pancreatitis or recurrent acute pancreatitis and an equivalent number of healthy volunteers. The researchers took a closer look at a gene called CTRC, which can protect pancreatic cells from injury caused by premature activation of trypsin, a digestive enzyme inside the pancreas instead of the intestine, a problem that has already been associated with pancreatitis.

They found that a certain variant of the CTRC gene, which is thought to be carried by about 10 percent of Caucasians, was a strong risk factor for alcohol- or smoking-associated chronic pancreatitis. It's possible that the variant fails to protect the pancreas from trypsin, leaving the carrier vulnerable to ongoing pancreatic inflammation and scarring.

"This finding presents us with a window of opportunity to intervene in the diseases process," Dr. Whitcomb said. "When people come to the hospital with acute pancreatitis, we could screen for this gene variant and do everything possible to help those who have it quit smoking and drinking alcohol, as well as test new treatments, because they have the greatest risk of progressing to end-stage chronic pancreatitis."

Whitcomb's team has been implementing more personalized approaches to pancreatic diseases in the Pancreas Center of Excellence within the Digestive Disorders Center at UPMC and hopes to learn whether use of genetic information can, in fact, reduce the chances of chronic disease in high-risk patients.

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The study team includes Jessica LaRusch, Ph.D., Antonio Lozano-Leon, Ph.D., Kimberly Stello, Amanda Moore, Venkata Muddana, M.D., Michael O'Connell, Ph.D., Brenda Diergaarde, Ph.D., and Dhiraj Yadav, M.D., all of the University of Pittsburgh.

The project was funded by National Institutes of Health grants DK061451, DK077906 and DK063922, and the Conselleria de Industria e Innovacin, Xunta de Galicia, Spain.

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Smoking, alcohol, gene variant interact to increase risk of chronic pancreatitis

Wednesday, January 07 11:43:20

Novartis is diving deeper into the world of gene-based medicine by signing deals with two U.S. biotech companies, giving it access to a powerful new genome editing technology.

The tie-ups with unlisted Intellia Therapeutics and Caribou Biosciences show the Swiss drugmaker's confidence in the potential of so-called CRISPR technology, both for making new medicines and as a research tool.

CRISPR, which stands for clustered regularly interspaced short palindromic repeats, allows scientists to edit the genes of selected cells accurately and efficiently. It has created great excitement since emerging two years ago and is being tipped for a Nobel Prize.

While current gene therapy approaches involve adding genes to affected cells, CRISPR opens up the possibility of correcting those cells' faulty genes in the lab before returning them to the patient.

Translating that promise into new treatments will take many years but Novartis' decision to apply the technology in its research labs is an important endorsement, since the company is the world's largest drugmaker by sales.

It is also a sign the Swiss group intends to be at the forefront of the nascent field, after recently establishing a new cell and gene therapies unit within the company.

Mark Fishman, head of the Novartis Institutes for BioMedical Research (NIBR), said genome editing could open a new branch of medicine, leading to cures for diseases caused by faulty genes.

"We have glimpsed the power of CRISPR tools in our scientific programmes in NIBR and it is now time to explore how to safely extend this powerful technology to the clinic," he said.

The deal with Intellia gives Novartis exclusive rights to develop programmes focused on engineered chimeric antigen receptor T-cells (CARTs) and the right to develop a certain number of targets for editing hematopoietic stem cells.

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Novartis: Gene editing is new frontier

By looking at the expression levels of downstream genes of the regulators in breast cancer, investigators at Dartmouth Hitchcock's Norris Cotton Cancer Center (NCCC), led by Chao Cheng, PhD, have identified a gene signature in E2F4 that is predictive of estrogen receptor positive (ER+) breast cancer. The findings, published in Breast Cancer Research, define a new opportunity for personalizing medicine for women whose Oncotype DX assay results classify them as of "intermediate-risk for recurrence." Until now, there has been no standard of care for those with intermediate risk. Results at NCCC support reclassifying 20-30% of those patients as "high-risk for recurrence," indicating they should receive aggressive follow-up treatment.

"Our data-driven approach to designing an effective prognostic genomic signature for E2F4 activity in ER+ breast cancer patients gave us the essential information to develop what will be a simple clinical test to aid physicians in selecting the most effective treatment regimens for each patient," reported Cheng. "Furthermore, our approach is highly flexible, and because of the widespread essentiality of E2F4 in many types of cancer, it will be of great utility in solving many biomedical questions."

With the goal to design an accurate and quick genomic test to measure the activity levels of the regulators associated with E2F4, Cheng's team looked to the aberrant behavior of transcription factors as a way to track and predict the root cause of all cancers - dysregulated gene expression that leads to uncontrollable cell proliferation, tumor genesis, and ultimately metastases.

The target genes were identified by chromatin immunoprecipitation sequencing (ChIP-seq) and researchers compared the regulatory activity score (RAS) of E2F4 in cancer tissues to determine the correlation with activity and patient survival. The prognostic signature for E2F4 was significantly predictive of patient outcome in breast cancer regardless of treatment status and the states of many other clinical and pathological variables.

Cheng explained the translational use of the E2F4 signature, "By developing a flexible, reproducible, and predictive test, we are providing physicians working in many areas of cancer with the information they need to tailor treatment regimens to specific individual patients. This is the essence of personalized medicine: the right treatment for the right patient at the right time."

The team's next steps include evaluating the prognostic potential of E2F4 in additional breast cancer datasets to validate its broad effectiveness, and improving the signature by reducing it to its core component genes.

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The collaborators are all from the Geisel School of Medicine at Dartmouth College and affiliated with Dartmouth's Norris Cotton Cancer Center in Lebanon, NH, USA.

This work was supported by the American Cancer Society Research grant IRG-82-003-270, the Centers of Biomedical Research Excellence (COBRE) grant GM103534, and the Geisel School of Medicine at Dartmouth College.

About Norris Cotton Cancer Center at Dartmouth-Hitchcock

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Dartmouth develops prognostic test for E2F4 in breast cancer

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History explains why people with the malady, and their physicians, are cautious to believe that a cure is in sight

HEATHER VAN UXEM LEWIS

In 2011, a remarkable study in the New England Journal of Medicine detailed the successful treatment of six adults with haemophilia B, which is caused by a deficiency in the coagulation protein known as factor IX. All of the participants were able to eliminate or reduce the frequency of clotting-factor-replacement injectionsthe current standard treatment for the diseaseafter their livers began producing functional levels of factor IX. The experimental therapy came in the form of an adeno-associated virus (AAV) carrying a gene that encodes instructions for production of normal levels of human factor IX. Three trials of AAV-mediated gene transfer in patients with haemophilia B are ongoing, with high expectations.

After more than 20 years of research on gene transfer, it is a promising time for haemophilia therapies. It now seems likely that a single-dose treatment for haemophilia B using an AAV or another gene-transfer technique will be a viable option for many people in the next decade or two.

Yet haemophilia researchers are not inclined to speak enthusiastically of a cure. Part of that caution comes from recognition that there are still problems to solve. For example, some 40% of people with haemophilia B would find no refuge in an AAV treatment because they produce antibodies that attack and neutralize this virus.

And even if that problem were solved, the treatment would apply only to those with haemophilia B. The more common form of the condition, haemophilia A, stems from a deficit in another proteinfactor VIIIand the gene for that protein is a more difficult target. Regardless of the type of haemophilia, researchers remain hesitant about gene therapy owing to the unresolved ethical issues that arose decades ago.

The unfettered optimism that characterized the early years of gene-therapy research came to a screeching halt in 1999, when 18-year-old Jesse Gelsinger died in a phase I clinical trial at the University of Pennsylvania in Philadelphia. Gelsinger had undergone an experimental gene transfer for his otherwise treatable metabolic disorder. His death, along with a series of other harmful events in early gene-therapy trials for a variety of diseases, threatened the whole field.

Haemophilia specialists who were engaged in gene-transfer studies were more guarded than most of that era's self-proclaimed gene doctors. The source of their reserve goes beyond the cautious optimism that characterized such research after 1999; it is grounded instead in the long and troubled experience that the haemophilia community has had with technological fixes.

By the late 1970s, a therapeutic revolution had transformed haemophilia from an obscure hereditary malady into a manageable disease. But the glory of this achievement was tragically short-lived. The same clotting-factor-replacement therapies that delivered a degree of normality to the lives of people with haemophilia brought unexpected and fatal results: tens of thousands of people with haemophilia were diagnosed with transfusion-related HIV/AIDS in the 1980s and with hepatitis C virus (HCV) in the 1990s.

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Gene Therapys Haemophilia Promise Is Tempered by Memories of Past Tragedies

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History explains why people with the malady, and their physicians, are cautious to believe that a cure is in sight

HEATHER VAN UXEM LEWIS

In 2011, a remarkable study in the New England Journal of Medicine detailed the successful treatment of six adults with haemophilia B, which is caused by a deficiency in the coagulation protein known as factor IX. All of the participants were able to eliminate or reduce the frequency of clotting-factor-replacement injectionsthe current standard treatment for the diseaseafter their livers began producing functional levels of factor IX. The experimental therapy came in the form of an adeno-associated virus (AAV) carrying a gene that encodes instructions for production of normal levels of human factor IX. Three trials of AAV-mediated gene transfer in patients with haemophilia B are ongoing, with high expectations.

After more than 20 years of research on gene transfer, it is a promising time for haemophilia therapies. It now seems likely that a single-dose treatment for haemophilia B using an AAV or another gene-transfer technique will be a viable option for many people in the next decade or two.

Yet haemophilia researchers are not inclined to speak enthusiastically of a cure. Part of that caution comes from recognition that there are still problems to solve. For example, some 40% of people with haemophilia B would find no refuge in an AAV treatment because they produce antibodies that attack and neutralize this virus.

And even if that problem were solved, the treatment would apply only to those with haemophilia B. The more common form of the condition, haemophilia A, stems from a deficit in another proteinfactor VIIIand the gene for that protein is a more difficult target. Regardless of the type of haemophilia, researchers remain hesitant about gene therapy owing to the unresolved ethical issues that arose decades ago.

The unfettered optimism that characterized the early years of gene-therapy research came to a screeching halt in 1999, when 18-year-old Jesse Gelsinger died in a phase I clinical trial at the University of Pennsylvania in Philadelphia. Gelsinger had undergone an experimental gene transfer for his otherwise treatable metabolic disorder. His death, along with a series of other harmful events in early gene-therapy trials for a variety of diseases, threatened the whole field.

Haemophilia specialists who were engaged in gene-transfer studies were more guarded than most of that era's self-proclaimed gene doctors. The source of their reserve goes beyond the cautious optimism that characterized such research after 1999; it is grounded instead in the long and troubled experience that the haemophilia community has had with technological fixes.

By the late 1970s, a therapeutic revolution had transformed haemophilia from an obscure hereditary malady into a manageable disease. But the glory of this achievement was tragically short-lived. The same clotting-factor-replacement therapies that delivered a degree of normality to the lives of people with haemophilia brought unexpected and fatal results: tens of thousands of people with haemophilia were diagnosed with transfusion-related HIV/AIDS in the 1980s and with hepatitis C virus (HCV) in the 1990s.

Continued here:
Gene Therapys Hemophilia Promise Is Tempered by Memories of Past Tragedies

(PRWEB) January 06, 2015

Sequencing the genomes, or entire DNA codes, of individuals to better diagnose and treat disease is a burgeoning area of research. From identifying specific genetic mistakes highly associated with certain cancers to applying effective treatments to mitigate a wayward genes effects, personalized genomic medicine is increasingly finding its way into patient care.

Harnessing the power of whole genome analysis and further defining the role of pathologists in this new era of medicine is the topic of the 2015 Benjamin Highman Lecture, sponsored by the Department of Pathology and Laboratory Medicine at UC Davis Health System.

The lecture, entitled Moving to Genomic Medicine, will be held from 5 p.m. to 6 p.m. on Thursday, Jan. 22 at the Education Building, 4610 X Street in auditorium #2222 in Sacramento. A reception will follow the presentation. Participants can register at Eventbrite.

The lecture will be presented by Debra G. B. Leonard, a leading expert in molecular pathology and genomic medicine and in applying genomic information for diagnosis and treatment of human diseases, including inherited disorders, cancers and infectious diseases.

During her presentation, Leonard will highlight the current applications for genomics and describe the various online genomic medicine resources for testing and for making patient-care decisions. She has spoken widely on various molecular pathology testing services, the future of molecular pathology and the impact of gene patents on molecular pathology practice. Leonard is professor and chair of pathology and laboratory medicine at the University of Vermont Medical Center and Physician Leader of Pathology and Laboratory Medicine at Fletcher Allen Health Care.

Making use of the massive amount of data that results from whole genome testing is an ongoing challenge for practicing physicians across disciplines, said Lydia Howell, professor and chair of pathology and laboratory medicine at UC Davis Health System. While we have the technology to quickly identify an individuals entire genetic code, which includes some three million genetic sequences, its less easy to know which genetic mistakes actually cause disease. Pathologists, with their expertise in molecular diagnostic testing, are in a unique position to lead the current movement of genomic medicine from the research bench to applications in the clinic.

The Highman Symposium is an annual lectureship in honor of Benjamin Highman, who spent almost 40 years in the U.S. Public Health Service as medical director and as chief of Pathologic Anatomy at the National Institutes of Health. He was awarded the Willey Medallion and a special citation by the U.S. Food and Drug Administration. In 1985, Highman retired and joined the volunteer faculty at the UC Davis School of Medicine.

The Department of Pathology and Laboratory Medicine includes 40 faculty and 400 academic and clinical staff who develop and deliver comprehensive diagnostic services in the fields of pathology and laboratory medicine through established and novel diagnostic modalities. Its Clinical Laboratory is home to one of the most technologically advanced testing facilities in California, providing many unique diagnostic tests unavailable elsewhere. The department processes 5 million clinical tests and 20,000 surgical pathology and 20,000 cytology specimens each year.

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UC Davis presents 2015 Benjamin Highman Lecture on genomic medicine

Insight into regulation of the genes that allow the immune system to recognize pathogens will help scientists rationally design new vaccines and prevent autoimmunity

WORCESTER, MA - UMass Medical School scientists Jeremy Luban, MD, and Manuel Garber, PhD, will be principal investigators on a 3-year, $6.1 million grant to develop a model for predicting whether a given gene will be turned on or off under specific conditions. Funding for the grant comes from the recently launched Genomics of Gene Regulation (GGR) program at the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health. In total, $28 million in new grants aimed at deciphering the language of gene expression were awarded.

"Why a certain gene is expressed in a specific cell at a given time is an essential biological question that is fundamental to our understanding of life and disease," said Dr. Luban, MD, the David J. Freelander Professor in AIDS Research and professor of molecular medicine. "This grant will help us decipher the rules that govern gene expression. Ultimately, such information will help explain why one person survives a viral infection and another person does not."

Dr. Garber, PhD, director of the Bioinformatics Core and associate professor of molecular medicine said "Understanding of the regulatory code network - the DNA elements that control when and for how long a gene is expressed - has been elusive. The work we'll carry out in this project will allow us to model and test the regulatory code of dendritic cells. As a result, we would be able to predict the impact of mutations that do not directly affect the gene product but that affect how and when the gene is made."

Over the past decade, new scientific evidence suggests that genomic regions outside of the primary protein-coding regions of our DNA harbor variations that play an important role in disease. These regions contain elements that control gene expression and, when altered, can increase the risk for a disease.

The GGR grants will allow researchers to study complex gene networks and pathways in different cells types and systems. The resulting insight into the mechanisms controlling gene expression may ultimately lead to new avenues for developing treatments for diseases affected by faulty gene regulation, such as cancer, diabetes and Parkinson's disease.

"There is a growing realization that the ways genes are regulated to work together can be important for understanding disease," said Mike Pazin, PhD, a program director in the Functional Analysis Program in NHGRI's Division of Genome Sciences. "The Genomics of Gene Regulation program aims to develop new ways for understanding how the genes and switches in the genome fit together as networks. Such knowledge is important for defining the role of genomic differences in human health and disease."

Luban and Garber will be working with UMMS colleagues Job Dekker, PhD, co-director of the Program in Systems Biology and professor of biochemistry & molecular pharmacology; Oliver Rando, PhD, MD, professor of biochemistry & molecular pharmacology, and Scot Wolfe, associate professor of biochemistry & molecular pharmacology, to develop a model system for exploring gene regulation using human dendritic cells.

The dendritic cell is a key part of the innate immune system that distinguishes self from non-self and, when appropriate, directs the body to attack invading pathogens. In its immature state dendritic cells help prevent autoimmunity by keeping the immune system's T-cells from attacking the body's own cells. When an immature dendritic cell encounters a pathogen, though, a developmental switch is activated and the cell undergoes profound changes in gene expression as it matures. In contrast to immature dendritic cells, these mature cells elicit a potent immune response from T-cells that targets the pathogen.

Luban, Garber and colleagues will examine the changes that the dendritic cell undergoes when it encounters a pathogen and moves from the immature to the mature state. Among the factors they will look at are the genes that are turned on and off during this process. They will examine changes in transcription factors, chromatin modifying enzymes and the cis-acting DNA elements. Linking these elements to specific changes in gene expression should provide a model for predicting the expression of specific genes in dendritic and other cells.

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UMMS to develop a model for predicting gene expression in dendritic cells

(CNN)-- Ever marvel at someone who smoked and still lived to be 90? Just plain good luck, researchers say. And those who live like Puritans and get cancer anyway?

That's bad luck -- and it's the primary cause of most cancer cases, says a Johns Hopkins Medicine research study.

Roughly two-thirds of cancers in adults can be attributed to random mutations in genes capable of driving cancer growth, said two scientists who ran statistics on cancer cases.

That may sound jaw-dropping. And Johns Hopkins anticipates that the study will change the way people think about cancer risk factors.

They also believe it could lead to changes in the funding of cancer studies, with a greater focus on finding ways to detect those cancers attributed to random mutations in genes at early, curable stages.

Smoking can still kill you

But, no, that's not permission to smoke or to not use sunblock.

Some forms of cancer are exceptions, where lifestyle and environment play a big role. Lung cancer is one of them. So is skin cancer.

And, if cancer runs in your family, this unfortunately doesn't mean you're in the clear. Some cancers are more strongly influenced by genetic heritage than others.

"The remaining third (of cancer cases) are due to environmental factors and inherited genes," the Kimmel Cancer Center said in a statement on the study published Friday in the magazine Science.

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Random Gene Mutations Primary Cause Of Most Cancer

Johns Hopkins study could advance use of stem cells for treatment and disease research

A powerful "genome editing" technology known as CRISPR has been used by researchers since 2012 to trim, disrupt, replace or add to sequences of an organism's DNA. Now, scientists at Johns Hopkins Medicine have shown that the system also precisely and efficiently alters human stem cells.

In a recent online report on the work in Molecular Therapy, the Johns Hopkins team says the findings could streamline and speed efforts to modify and tailor human-induced pluripotent stem cells (iPSCs) for use as treatments or in the development of model systems to study diseases and test drugs.

"Stem cell technology is quickly advancing, and we think that the days when we can use iPSCs for human therapy aren't that far away," says Zhaohui Ye, Ph.D., an instructor of medicine at the Johns Hopkins University School of Medicine. "This is one of the first studies to detail the use of CRISPR in human iPSCs, showcasing its potential in these cells."

CRISPR originated from a microbial immune system that contains DNA segments known as clustered regularly interspaced short palindromic repeats. The engineered editing system makes use of an enzyme that nicks together DNA with a piece of small RNA that guides the tool to where researchers want to introduce cuts or other changes in the genome.

Previous research has shown that CRISPR can generate genomic changes or mutations through these interventions far more efficiently than other gene editing techniques, such as TALEN, short for transcription activator-like effector nuclease.

Despite CRISPR's advantages, a recent study suggested that it might also produce a large number of "off-target" effects in human cancer cell lines, specifically modification of genes that researchers didn't mean to change.

To see if this unwanted effect occurred in other human cell types, Ye; Linzhao Cheng, Ph.D., a professor of medicine and oncology in the Johns Hopkins University School of Medicine; and their colleagues pitted CRISPR against TALEN in human iPSCs, adult cells reprogrammed to act like embryonic stem cells. Human iPSCs have already shown enormous promise for treating and studying disease.

The researchers compared the ability of both genome editing systems to either cut out pieces of known genes in iPSCs or cut out a piece of these genes and replace it with another. As model genes, the researchers used JAK2, a gene that when mutated causes a bone marrow disorder known as polycythemia vera; SERPINA1, a gene that when mutated causes alpha1-antitrypsin deficiency, an inherited disorder that may cause lung and liver disease; and AAVS1, a gene that's been recently discovered to be a "safe harbor" in the human genome for inserting foreign genes.

Their comparison found that when simply cutting out portions of genes, the CRISPR system was significantly more efficient than TALEN in all three gene systems, inducing up to 100 times more cuts. However, when using these genome editing tools for replacing portions of the genes, such as the disease-causing mutations in JAK2 and SERPINA1 genes, CRISPR and TALEN showed about the same efficiency in patient-derived iPSCs, the researchers report.

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'CRISPR' science: Newer genome editing tool shows promise in engineering human stem cells

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Newswise MAYWOOD, Ill. As many as 500,000 people in the United States have a heritable and potentially fatal heart disease called hypertrophic cardiomyopathy.

The disease can cause irregular heartbeats, heart valve problems, heart failure and, in rare cases, sudden cardiac death in young people. But some people who carry gene mutations that cause hypertrophic cardiomyopathy never experience symptoms.

A new study helps explain why. For the first time, researchers have found that, in addition to gene mutations, environmental stress plays a key role in development of the disease.

The study, led by senior author Sakthivel Sadayappan, PhD, MBA, of Loyola University Chicago Stritch School of Medicine, is published in the Journal of Molecular and Cellular Cardiology.

In hypertrophic cardiomyopathy, the heart muscle becomes abnormally thick, making it harder for the heart to pump blood. The disease can cause irregular heartbeats such as atrial fibrillation; obstructed blood flow that can cause shortness of breath, chest pain, dizziness and fainting spells; problems with the mitral valve; an enlarged ventricle (pumping chamber) that reduces the hearts ability to pump blood; heart failure; and sudden cardiac death. Its the leading cause of heart-related sudden death in people under age 30, including many athletes. For example, Boston Celtics basketball star Reggie Lewis died at age 27 after collapsing during a practice session.

More than 1,400 gene mutations have been linked to hypertrophic cardiomyopathy. An individual will have a 50 percent chance of inheriting the condition if one parent has the disease. About 1 in 500 people has hypertrophic cardiomyopathy, but the risk is much higher among people from India and other south Asian countries.

Dr. Sadayappans study involved mice that carried mutations that cause hypertrophic cardiomyopathy. To study the effect of environmental stress, researchers performed a procedure that mimics high blood pressure. This environmental stress significantly increased three measures of hypertrophic cardiomyopathy: The hearts became heavier, the pumping ability decreased and there were lower levels of a protein that is critical for the normal functioning of the heart. The protein is called cardiac myosin binding protein-C, or cMyBP-C.

The findings suggest that carriers of hypertrophic cardiomyopathy mutations who do not yet have symptoms may be at greater risk of developing cardiomyopathy from a variety of environmental stressors, such as high blood pressure, diabetes and alcohol use. This is due to the compounding effects of stress and insufficient levels of cMyBP-C, Dr. Sadayappan and colleagues wrote.

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Why Do Only Some People with Hereditary Heart Disease Experience Symptoms?