Genetic Clues For Finding And Treating Cardiovascular Disease (CVD)

The status of research identifying CVD genes, testing to predict CVD, and developing genetically-based medication is the focus of the spring conference of the American Physiological Society (APS)

February 19, 2002 – San Francisco – One in four Americans are affected by cardiovascular disease (CVD). Accordingly, it is the nation’s leading killer of Americans, striking without regard to sex or race. Nearly a dozen of the nation’s top research investigators from the fields of genetics, genetic testing, gene transfer, gene therapy and gene-based medicines are presenting the status of their work along with new insights and forecasts of the future. Discussions about the research now underway at the Mayo Clinic, Harvard Medical School, the University of Pennsylvania and other leading research sites are part of the three-day spring conference of the American Physiological Society (APS). The conference, entitled “Physiological Genomics of Cardiovascular Disease,” is being held February 20-23, 2002, in San Francisco.

Background

The mutations of human genes have been found to be responsible for more than 4,000 diseases. Some disorders are caused by the mutation (defect) of a single gene, as is the case of sickle cell anemia, cystic fibrosis (CF) and Alzheimer’s disease (AD).  By contrast, the family of disorders that constitute CVD typically result from more than one mutated gene. For example:

• More than 300 genes have so far been associated with cardiac hypertrophy.

• Genetic factors are believed to be responsible for approximately two-thirds of the cases of high blood pressure (hypertension).

• “Responsibility genes” have been identified as the specific cause of dilated cardiomyopathy and another six “susceptibility genes” have been noted.

CVD may also result form the interaction between genetics and their interaction with the environment, defined as smoking, obesity and the like.

Program Highlights

Physiological genomics is the study of how healthy and disease genes function. The highlights of this conference thus include:

GENETIC IDENTIFICATION

• America’s Top Gene Hunter is Francis S. Collins, MD, Ph.D.  As director of the National Human Genome Research Institute at the National Institutes of Health, he oversees the identification, mapping and understanding of human genes, including those responsible for disease. Identifying disease genes is the biological equivalent of looking for a needle in a haystack. The human haystack is comprised of 3 billion “base-pairs,” the equivalent of the number of seconds in 95 years.  Between 30,000-100,000 human “needles” or genes need to be found inside the stack, and simply finding them is not enough. “Junk DNA” genes must be set aside and susceptibility genes distinguished from responsibility genes. Dr. Collins sets the stage for the three-day discussion of disease gene hunting and cardiovascular disease.

• Genetic Mapping for Cardiovascular Disease: Hypertension is a common, complex disease involving as many as 20 genes. It affects 50 million Americans and plays a significant role in CVD. Eric Boerwinkle, Ph.D., is the center director of the Human Genetics Center at the University of Texas (Houston) Health Science Center and leads the research team that recently located a susceptibility gene for hypertension (on chromosome 5). Dr. Boerwinkle and his colleagues are involved in large-scale studies involving families and blood pressure. He will discuss the status of this work and his work on pharmacogenetics; i.e., the use of the patient’s own DNA for creating individualized medication aimed at a specific disease.

TESTING FOR GENETIC SUSCEPTIBILITY

• Genetic Testing: The Ultimate Form of Preventive Medicine?: Do you carry a gene that predisposes you to high blood pressure? If so, will your son or daughter carry it too? Genetic testing reveals whether an individual has a disease gene or is susceptible to it. Predictive testing identifies individuals at risk for certain disease years before symptoms appear. The ability to test for the presence of the genes associated with coronary artery disease is underway. Testing for the presence of genes such as LDLA (which removes “bad” cholesterol” from the blood), APOA1 (associated with heart attack and stroke when levels are low), CETP (responsible for the break down of HDL, the “good” cholesterol), and APOE (its 30 variations are involved in high levels of “bad” cholesterol) are expected to be developed. Curt D. Sigmund, Ph.D., of the University of Iowa’s Department of Internal Medicine, Molecular Biology Program, and the conference chair, will be available to talk about the trend.

• Gene Transfer and Gene Therapy:  Gene transfer is being tested in the treatment of cardiovascular disease. Its great promise lies in the fact that acquired conditions as well as genetic disorders may be treated using genetic material. Robert D. Simari, MD, is the Director of the Cardiovascular Molecular Biology laboratory at the Mayo Clinic and is involved in the development of interventions and treatments of CVD through modulation of gene expression. He provides an update of his approach.

• Gene Therapy vs. Cell Therapy for Therapeutic Angiogenesis: Traditional therapies to reverse CVD have used either angioplasty (to essentially blow out the blockages in the arteries) or coronary artery bypass grafts (which obviate the clogged passageways). The latest generation involves the application of “therapeutic angiogenesis.” In this process a  unique DNA cocktail (comprised of “naked plasmid DNA” and a growth-factor medicine) is injected directly into the muscle of the patient’s heart in order to produce new blood vessels that supplement or replace the diseased pathways. Douglas W. Losordo, MD, Associate Professor of Medicine at the Tufts University School of Medicine, is the world’s leading researcher for gene/cell therapy therapeutic angiogenesis and is currently overseeing clinical trials involving this procedure.

• Gene Therapy for Coronary Heart Disease:  Dr. Michael Mann is a pioneer in CVD gene therapy. His most recent work uses chemically modified DNA, which is injected into a patient’s veins. Using a pressurized pump to force the chemical into the veins the procedure also expands the normal arterial pressure by 200 percent. Since the chemical is friendly to the human immune system the procedure is believed to be well tolerated by the patient.  The technique is undergoing clinical trials in heart by-pass patients. Dr. Mann, of the University of California, San Francisco Medical Center, is also widely known for his earlier work using genes to prevent new blockage of coronary bypass grafts (“re-stenosis”).

GENE-BASED MEDICINES

• Pharmacogenetics: Why do some patients respond to drugs while others do not? Why does one feel no toxic effect while another has a life-threatening reaction? The difference is due to their genetic makeup. The genes of the first person may be coded to tell the body to quickly and efficiently absorb drugs and eliminate them as soon as possible. By contrast, the genetic commands of the other may instruct the body to slowly absorb and release its ingestibles, thus causing lingering and toxic effects. Allen Roses, MD, the Worldwide Director of Genetics at GlaxoSmithKline, Inc., is responsible for the company’s development of “pharmacogenetics,” the utilization of a person’s DNA to create medications that best respond to their genetic makeup. Pharmacogenetics is expected to replace the current “one size fits all” approach to medications. Many predict that medications will soon be prescribed based on the unique combination of safety, toxicity and efficacy most compatible with the patient’s genetic uniqueness.

NEW MODELS FOR INVESTIGATION

• The Mouse, the Rat and the Glow-In-The-Dark Zebrafish: A number of important similarities exist between the formative stages of the human heart and that of the tropical, freshwater Zebrafish (Danio Rerio). Marc Fishman, Ph.D., of the Massachusetts General Hospital, has determined that this common aquarium occupant may be as important to identifying CVD as the mouse and rat have been to understanding the human genome. The Zebrafish has already proven its value by pinpointing a variety of heart mutations that may eventually explain congenital human heart disease. The florescent, see-through Zebrafish is comprised of bright-green organs. This colorful workhorse may someday lead researchers to uncover the dark mysteries of the human heart.

100 SCIENTIFIC PRESENTATIONS FROM

INVESTIGATORS AROUND THE WORLD

The conference also includes 100 scientific presentations, among them:

• A Study of 700 Healthy Venezuelan Males For Hypertension:  In earlier research Juan C. Mendible, Ph.D., and his colleagues examined the genetics of the Venezuelan aborigines, a population that has lived in the remote southeastern part of that country for 25,000 years. The investigators discovered that although more than 85 percent of the aborigines carried a gene that is associated with salt-sensitive hypertension the population did not develop this disorder. These findings are especially noteworthy as they stand in stark contrast to other data. Namely, that cardiovascular disease – which includes hypertension (also known as high blood pressure) – is the leading cause of death among Venezuelans age 35 and older. Thus, other factors must play a role in the development of the disease, but what are they? Dr. Mendible is the head of the Laboratory of Molecular Cardiology at the Institute of Experimental Medicine at the Unviversidad Central de Venezuela and will discuss his findings and theories.

Conference Co-Sponsors

The American Physiological Society (APS) was founded in 1887 to foster basic and applied science, much of it relating to human health. The Bethesda, MD-based Society is one of the world’s most prestigious organizations, totaling more than 10,000 members, including physiological researchers and academicians. Clinical physiologists investigate the function of the human body, including the effects of genes, diseases, exercise and metabolism. Their primary professional commitment is to understand these processes and functions so that promising new cures can be developed.  The APS publishes 3,800 articles in its 14 peer-reviewed journals every year. Physiological Genomics, APS’ newest journal and the conference co-sponsor, is among the Society’s flagship publications.

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