Geneticists Form New Frontier In Cardiovascular Studies

Research into the links between genes and heart disease is attracting more attention from both cardiologists and granting agencies. Both groups are coming to accept what cell biologists have suspected for some time--that dissecting the genetic causes of extremely rare diseases will yield important clues to the pathogenesis of more common maladies. Since 1989, the genes behind a handful of inherited cardio-vascular conditions have been identified, shifting the focus of the field to genetic studies, researchers say. "These discoveries will usher in a new age of research, with a great impact on diagnosis, reversal of conditions, prognoses, treatment, even cure," says Stephen Mockrin, a cardiologist and chief of the hypertension and kidney diseases branch of the National Heart, Lung and Blood Institute (NHLBI) in Bethesda, Md. For now, though, the number of grants being funded for inherited cardiovascular disease reflects the rarity of these conditions. For example, in fiscal year 1992, out of a total grant budget of $95 million, the Dallas-based American Heart Association is supplying $3.6 million in funding for 118 research projects for noninherited cardiomyopathies (defects in the heart muscle). A separate category, for the familial (inherited) cardiomyopathies, which afflict only about 5 in 10,000 people, funds only 13 projects, for a total of $392,359. Amid the millions of people with environmentally triggered heart disease are a few with disorders caused by single genes. Funding to better understand these conditions is diverse, coming from the National Institutes of Health, the American Heart Association, the Howard Hughes Medical Institute, the British Heart Foundation, the Robert A. Welch Foundation, the Perot Family Foundation, and state health agencies. Some studies are partially supported by private funds honoring people who died of particular illnesses. Big-industry interest in inherited cardiovascular disease will build, predicts Mark Keating, a cardiologist who is studying long QT syndrome at the University of Utah Health Science Center. "There's not much interest yet; it's still pretty new to them. The large pharmaceutical companies will probably buy companies that are doing the genetics; that seems to be the pattern." The funding picture at the federal level is poised to grow, reports Stephen Mockrin, a cardiologist and chief of the hypertension and kidney diseases branch of the National Heart, Lung, and Blood Institute. Mockrin heads an expert panel that will recommend funding strategies for inherited disease research over the next decade. The report will be out by year's end. "Our director, Claude Lenfant, recognizes the potential that would result from dissecting the genetic underpinnings of diseases that are studied by the institute," Mockrin says. "He has identified the area as one of extreme importance and is trying to foster and facilitate it."--R.L. But the interest in this area is poised to change, experts say (see accompanying story), because genetic research into rare disorders has already spawned broader-based knowledge of other, more widespread diseases. For example, genetic studies on the few families who have been found to have hereditary cancers have identified genes involved in more common cancers. For example, a mutant p53 gene has been found in every cell of a person with the Li-Fraumeni family cancer syndrome, which afflicts only about 100 families worldwide. The same gene is mutated by environmental agents, such as cigarette smoke, inducing the far more common lung cancer. Now it appears that studies under way on rare cardiovascular diseases may yield similar findings of relevance to a wide range of more common diseases. Genetic research in cardiovascular disease may be particularly valuable for people without risk factors. For example, a research team at the Institut National de la Sante et de la Recherche Medicale (INSERM) in Paris, led by Francoise Cambien, recently identified a genetic variant of the angiotensin-converting enzyme that is associated with coronary heart disease in people lacking other risk factors (Nature, 359:641-44, 1992). The search for a gene responsible for an illness often begins with epidemiology. Does an ethnic group have an unusual preponderance of a certain condition--and a particular gene variant? Is a disorder more common in both members of identical twin pairs, where heredity is held constant, than in fraternal twin pairs, where it is not? "The way I look at disease is that there are two factors--genetic and environmental," says Mark Keating, a University of Utah cardiologist with appointments in both the medicine and human genetics departments. "We know a fair amount about environmental factors from epidemiological studies. But we've gone as far as we can go with these studies without learning more about genetic factors." The next step in heart disease research will have to come down to the molecular biology level, says Jonathan Seidman, a geneticist at Harvard Medical School. "Cardiology research has seen dramatic technological advances in the last several years--heart transplants are better, pacemakers are improved, angioplasty is more effective. But in terms of figuring out the real root causes, there hasn't been much progress. So a number of people are pinning their hopes on a genetic-biochemical approach," he says. Seidman and his team recently identified the mutant muscle protein behind familial hypertrophic cardiomyopathy, or FHC (H. Watkins, et al., New England Journal of Medicine, 326:1108-14, 1992). Virginia Michel, a cardiologist at the Mayo Clinic in Rochester, Minn., whose team of cardiologists and geneticists is closing in on the gene behind another inherited heart overgrowth--familial dilated cardio-myopathy--has found the molecular biology approach is valuable. "Once we identify familial patients, we can start to look for underlying genetic defects and predispositions," she says. "When we've identified those, we can gain insight into basic mechanisms." The granddaddy of all gene-heart disease linkages was deciphered between 1979 and 1985, when cardiologists Michael Brown and Joseph Goldstein at the University of Texas Southwestern Medical Center in Dallas identified and described the low-density lipoprotein (LDL) receptor. The receptor dots cells lining arteries, binding and drawing into the cells cholesterol- containing low-density lipoproteins. Inside the cells, cholesterol is liberated and metabolized. In 1985, Brown and Goldstein received the Nobel Prize in physiology or medicine for their work (M.S. Brown and J.L. Goldstein, Science, 232:34-47, 1986). Brown and Goldstein deciphered the cholesterol utilization pathway in vitro, using a human skin fibroblast system. In vivo, people with two mutant genes completely lack LDL receptors on liver cells. As a result, they suffer from familial hypercholesterolemia (FH), with a blood cholesterol that's an extremely high 600-1,200 mg/dl, and they suffer fatal heart attacks by age 20. In the milder cases, patients have one mutant LDL receptor gene and one normal one, have cholesterol levels of 300-600 mg/dl, and suffer heart attacks in early adulthood. Only 1 in 500 people has mild FH, accounting for just 5 percent of heart attacks in people under age 60. But the FH work was critical in understanding the complex feedback loop that cells use to regulate production of LDL receptors, which led to the development of drugs for people with cholesterol levels above 240 mg/dl, whether caused by genes or more controllable factors. Identifying the abnormal protein behind an inherited disorder is intellectually satisfying, because it explains often disparate symptoms. This was the case for Marfan syndrome, the disorder that Abraham Lincoln may have had. Marfan syndrome produces very long limbs; a sunken, enlarged rib- cage; and a weakened aorta that can burst. It was identified as a disorder of connective tissue in 1956. Thirty years later, the late David Hollister of the University of Nebraska Medical Center in Omaha hypothesized that the responsible protein was fibrillin, because it is abundant in precisely those tissues affected by the syndrome. On July 25, 1991, a trio of papers in Nature installed fibrillin solidly in the realm of modern genetics. In one paper, researchers linked the Marfan gene to the long arm of chromosome 15 in many affected families; in the second, a fibrillin gene probe was used to home in on chromosome 15; and the third paper reported that variants in the gene were found only in Marfan patients, and mutations in the gene were found in those patients lacking a family history (B. Lee, et al.; C.L. Maslen, et al.; H.C. Dietz, et al., Nature, 352:330-9). FHC is a major cause of sudden death of people in their teens and 20s. In 1989, the Harvard Medical School group and others tracked FHC to a part of chromosome 14 known to contain a gene for myosin. This protein is abundant in muscle in the heart's ventricles, which become overgrown and disorganized in FHC. FHC research has been boosted by the study of a French Canadian family, tracing back to the man who brought the mutant gene from France in the 1600s. Nailing down the FHC gene and protein has already helped clinical practice. "Patients don't like to provide samples of heart muscle," says Seidman, and now diagnosis can be made on amplified RNA from circulating white blood cells. Different mutations correlate to varying degrees of illness, and the type of genetic variant is turning out to be a better predictor of lifespan than the degree to which the heart is overgrown. "For example, the French Canadian family has an average life expectancy of 33 years, but a family we are studying in Philadelphia lives much longer," Seidman says. Although FHC is rare, cardiac hypertrophy can be part of any cardiovascular disease. The size of the heart increases in response to many types of stress--athletes in perfect health may have hearts twice the normal size. Seeing how the heart overgrowth in FHC differs from that in similar conditions is a major goal of his research, Seidman says. For 95 percent of the 56 million people in the United States with hypertension, the cause is unknown. This is why the October 2 paper in Cell reporting a genetic link between this essential hypertension and a variant of a protein called angiotensinogen is being called a breakthrough (X. Jeunemaitre, Cell, 71:169-80, 1992). "The [Jeunemaitre paper] is the first reported case of linkage of a genetic variant with essential hypertension," says Claude Lenfant, director of the National Heart, Lung and Blood Institute, which funded the study. "Identifying the genes involved in hypertension has been difficult because the disease is caused by multiple environmental and genetic factors," says Lenfant. Like the myosin defect explaining FHC, angiotensinogen is a logical cause of hypertension, since it normally regulates fluid and electrolyte balance and maintains the tone of blood vessel walls and because it is elevated in the blood of people with high blood pressure. A team led by Jean-Marc Lalouel, a medical geneticist at the University of Utah in Salt Lake City, and Pierre Corvol, a medical geneticist at INSERM, looked at 15 variants of the angiotensinogen gene in 379 pairs of siblings who had hypertension before age 60 and were taking antihypertensive drugs. The researchers found that the hypertensive siblings were much more likely to have two particular genetic variants than could be accounted for by chance. These same two alleles were also overrepresented in a group of unrelated people with essential hypertension. The researchers caution that the angiotensinogen link is more of a susceptibility than a cause, because blood pressure is affected by many factors. Some geneticists suspect that dozens of genes may be involved in regulating blood pressure. "Ultimately, the finding may lead to new diagnostic tools to identify persons at risk of developing hypertension or to help physicians make treatment decisions," says Lenfant. Utah cardiologist Keating is probing long QT syndrome, an inherited cardiac arrhythmia that causes collapse and sudden death in young people. Deafness is often part of the syndrome. An 1856 reference to the illness described a young deaf girl, who, upon being called in to face the school principal for a minor infraction, dropped dead. Her two siblings, also deaf, likewise died suddenly when badly frightened. Long QT syndrome is treatable with drugs; but the trick is identifying affected individuals, because the first symptom can be sudden death. Using the classic tool of the geneticist--a large family-- Keating's team screened more than 60 percent of the human genome to find a piece of DNA to act as a marker that always accompanies long QT, and is never seen in nonaffected relatives. They have narrowed the gene's location down to a million-base-pair stretch of chromosome 11, and suspect an abnormal potassium channel may underlie the condition. Keating is also working on Williams syndrome, in which the aorta is blocked, and "figuring out genetic factors in the common, garden-variety diseases like hypertension," he says. Because circulatory diseases are influenced by the environment and by other genes, there is plenty of work left to do in the genetics-cardiology realm. "Many of the diseases of the vascular system, such as hypertension and atherosclerosis, are continuous traits, as opposed to discrete traits such as cystic fibrosis," says NHLBI's Mockrin. "With CF, you either have it or you don't; there's no in between. But with blood pressure, there is a bell curve of values, and above a certain point, risk of stroke and heart attack goes up. Genetics is much more difficult when you're dealing with a quantitative trait. It's a completely different ball game." And, embracing that challenge, Keating predicts: "The next 20 years will be a really exciting time for all human disease, but especially for cardiovascular diseases that have genetic factors." Ricki Lewis is a freelance science writer based in Scotia, N.Y.

Geneticists Form New Frontier In Cardiovascular Studies

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