Assessment of cardiovascular risk: time to apply genetic risk factors?

It has been common knowledge for centuries that certain diseases run in families. Also in cardiovascular medicine, many prospective studies indicate that a family history of coronary heart disease doubles the cardiovascular risk. Given this information, it would appear to be straightforward to search for genetic variations, which may mediate the risk. In monogenetic diseases such as the long QT syndrome or hypertrophic cardiomyopathy, the situation could be resolved by identifying single mutations that fully account for the presence of the respective disease. Polygenic diseases such as atherosclerosis are much more complex. Within the same individual, several polymorphisms may increase the risk to a different extent. Moreover, some genetic polymorphisms may only increase the risk in the presence of other genetic variations, i.e. there may be an interaction between different polymorphisms. Therefore, several potential candidate polymorphisms should probably be tested simultaneously, which requires large patient populations. One polymorphism reported to increase the risk for myocardial infarction was the insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene. This polymorphism consists of either the presence or absence of a DNA fragment inside intron 16. Carriers of the D allele tend to have higher ACE levels in blood, and hence may have an activated ACE system. The renin-angiotensin system is known to regulate blood pressure and may be involved in the pathogenesis of certain forms of hypertension. Within the blood vessel wall, the reninangiotensin system plays a role in endothelial function and vascular structure. The concept is supported by the clinical effectiveness of ACE inhibitors in the treatment of hypertension and heart failure and in their ability to reduce the incidence of myocardial infarction and stroke in patients with coronary heart disease. After the first report of a risk increase among carriers of the D allele, subsequent studies reported conflicting results. While some found a several-fold increase in the risk for coronary heart disease, in other studies the presence of a D allele was not associated with coronary heart disease. A recent meta-analysis found a significant 30% increase in risk for coronary heart disease in the pooled risk estimate, but there was a significant heterogeneity among the different studies. Moreover, there was evidence of See page 633 for the article to which this Editorial refers