Genetic markers: progress and potential for cardiovascular disease.

The recent completion of the Human Genome Project has provided an unprecedented opportunity for researchers to identify high-risk patients and improve human health through the use of technologies that integrate the entire genome. In the past, disorders that yielded their secrets to genetic investigations tended to be rare, single-gene conditions (eg, Brugada syndrome, Liddle syndrome). Today, attention is increasingly focused on elucidating genetic susceptibility to the common multifactorial diseases that clinicians encounter on a daily basis.1 A significant portion of current medical research is devoted to the pursuit of genetic variants that can be used to identify disease. These variants are not necessarily the cause of the illness, but markers that will help improve diagnosis and risk assessment. The level of expression of certain genes (ie, the amount of corresponding RNA or proteins produced) may signify a disease state. If these genes are consistently overexpressed or suppressed in a certain clinical context, they also may be considered biomarkers. Two approaches are used when pursuing genetic markers: researchers can conduct candidate gene studies (which focus on single genes) or genomic studies (which examine the entire genome.) Some diseases are monogenic (ie, caused by defects in only one gene). In such cases, genetic studies make clinical diagnosis straightforward. Mutations can be assessed by patient genotyping, and the expression of single genes can be assessed using techniques such as real-time reversetranscription polymerized chain reaction (RT-PCR) or Northern blot. However, for more common diseases, it has been more difficult to identify genetic markers, because most common diseases are polygenic. This genetic “web” of multiple genes may be very large and act in complex ways to induce a disease state. In addition, these conditions are often triggered by an interaction of genetic, environmental, and physiological factors, making it difficult for researchers to narrow their focus to a single gene. This is particularly true for many common cardiovascular disorders such as heart failure. In these cases, a “genomic” approach that examines the entire genome may be valuable. To expedite the search for genes associated with polygenic diseases, researchers use the complementary approaches of whole genome scans and microarray gene profiling, in combination with real-time RT-PCR, to identify and validate clusters of relevant genes. These gene clusters or expression patterns may be used as markers to distinguish among different disease states. Thus, gene profiling can be performed on tissue biopsy samples or circulating blood cells. Some genetic markers associated with cardiovascular disease risk are listed in Table 1.2–99 This review focuses on biomarkers identified in human subjects; however, it is also noteworthy that genetic and genomic studies have made extensive use of animal models to further characterize the cardiovascular system.100 It has long been known that some cardiovascular disorders are more prevalent among families that share genetic and environmental factors. Genetic studies involving twins and well-characterized pedigrees have established that the cardiovascular risk profile includes a substantial heritable component. It is clear that genetic factors influence quantitative traits (eg, levels of low-density lipoprotein [LDL] cholesterol and high-density lipoprotein [HDL] cholesterol, blood pressure, adiposity, and left ventricular mass). It is therefore not surprising that the causative basis of complex cardiovascular disorders (eg, atherothrombosis) involves a dynamic interplay among multiple genes in addition to gene–environment interactions. Our present challenge is to determine whether the genomic variations uncovered by the Human Genome Project are a useful addition to the clinician’s traditional assessment of family history and the application of standard risk factor profiles such as the Framingham Risk Score. We propose that the continued analysis and characterization of genomic variations will identify genetic markers that enhance the ability of clinicians to identify high-risk individuals with increased susceptibility to atherothrombotic vascular complications, as well as those individuals who are most likely to benefit from targeted therapeutic intervention.