Cardiovascular Disease

Cardiovascular disease is a set of diseases affecting the heart and blood vessels. As with most chronic diseases whose incidence increases with age, it involves both inherited and environmental contributors and is therefore classified as a complex genetic disease. Most researchers believe that all major risk factors for cardiovascular disease have been identified. It is estimated that cigarette smoking, hypertension, abnormal serum cholesterol (low-density lipoprotein cholesterol or high-density lipoprotein cholesterol), obesity, lack of physical exercise, and diabetes account for 50 percent of the variability of risk in high-risk populations. The remaining risk is likely composed of a large number of yet-to-be identified minor risk factors or genetic influences that account for the development of disease in most individuals. Investigators who have attempted to estimate the overall contribution of genetics to the development of cardiovascular disease have proposed numbers ranging from 20 to 60 percent, based upon the analysis of large epidemiologic studies.

Finding Genes for Cardiovascular Disease

Genetics studies of cardiovascular disease involve searches for genes in two general classes: causative genes and disease-susceptibility (or disease-modifying) genes. These are sought through gene-linkage analysis or candidate-gene studies, respectively. Identifying causative genes for this disease is likely several years away at best. Before that time, however, a new understanding will have been reached regarding the relationship between inherited risks and outcomes in cardiovascular disease. With the development of new technology, we also have the promise of a detailed catalogue of disease-modifying genes that may open the door to therapeutic advances.

Gene-linkage analyses involve the study of families that express the cardiovascular trait of interest. In such studies, it is important also to establish the relative risk. Relative risk is defined as the probability of developing a condition (such as cardiovascular disease) if a risk factor (such as a gene) is present, divided by the probability of developing the condition if the risk factor is absent. A relative risk greater than 4.0 (that is, a four-fold greater risk due to presence of a gene or genes) will be associated with a reasonable likelihood of success in finding associated genes, given a study of 200 sibling pairs demonstrating the condition.

One of the best-studied types of cardiovascular disease is early-onset (or premature) coronary artery disease, which has a particularly strong genetic or inherited component. The coronary arteries are those around the heart that supply it with blood. Early-onset is defined as disease presentation (as reversible heart pain, heart attack, or cardiovascular surgery) before the age of 50. Approximately 8 to 10 percent of the U.S. population with cardiovascular disease presents before age 50, according to most surveys. Based upon a number of relatively small epidemiologic studies and several genetics studies in twins, a conservative estimate of the relative risk ratio contributed by genetics to the development of early-onset cardiovascular disease is between 4.0 and 8.0. Despite the fact that it has an inherited component, the actual genes responsible for familial predisposition to early-onset coronary artery disease have been incompletely investigated and remain obscure.

While population-level relative risk for developing cardiovascular disease can be known with a great deal of accuracy, therefore, this knowledge cannot be used to counsel or direct therapy for an individual in any given family. In fact, it has become clear to most practicing cardiologists that even when we know which cardiovascular risk factors are present, we have a very limited ability to predict the development of disease in most individuals.

Ongoing Studies

The ongoing studies of the genetics of cardiovascular disease consist of two general types: those that accumulate individual cases with the goal of performing association candidate-gene studies, and those that collect data from families (sibling pairs or extended families) with the idea of performing gene-linkage studies. Candidate-gene studies examine variations in genes that code for proteins that are likely to be involved in a disease or its prevention, such as genes controlling cholesterol metabolism or blood pressure. Linkage studies look for chromosome regions that are co-inherited with risk for disease, and then look carefully at the region to determine what genes are present.

Patients for both types of studies may be located in similar ways. Disease registry databases contain information on patients with particular conditions, which may have been collected by hospitals, charitable organizations, or research organizations. Clinical trials databases are generated during the testing of a new drug or other treatment. Population-based longitudinal studies collect data on a large number of randomly selected people (not just those with disease) and follow them over many years, to determine what factors lead to development of disease. Each study has its own contribution to make, and only through the combined efforts of multiple studies and approaches will we discover and understand the genetic contributions to the development of cardiovascular disease.

Goals of Genetic Studies

Many of the promises of genetics investigations have probably been grossly overstated. The immediate potential of the ongoing and planned investigations into the genetics of cardiovascular disease is more promising for gene-directed therapy (the use of genetic information to guide the judicious use of medical interventions) than for somatic gene therapy (the use of a gene or gene product which, when introduced into a human organ, changes the function of the organ).

The realistic promises of current genetics studies include the elucidation of disease mechanisms; the identification of new targets for the development of therapeutic pharmacologic agents; and the use of genetic markers to identify individuals for whom a particular agent is either effective or unusually hazardous. This approach, called pharmacogenomics, improves the safety and efficacy of treatments, and enhances the ability to preferentially select subjects for clinical trials based upon genetic predispostion and for gene-directed therapy. In the latter case, for example, a genetic contributor to the development of early-onset cardiovascular disease might be used as an additional risk factor whose identification could focus the allocation of preventive resources, whether educational, behavioral, or pharmacologic, to populations at particularly high risk for the disease.

Bill Kraus

Bibliography

Lander, E. S., and N. J. Schork. "Genetic Dissection of Complex Traits." Science 265 (1994): 2035-2048.