For coronary artery disease patients, it may help their physicians understand the prognosis and make decisions on the management of their ailment. By Michael Lim

WITH billions spent on research into understanding the human genome, expectations are running high as to the application of the enormous amount of knowledge that has been gleaned from these studies. The primary motivation for the understanding of the human genome is to help physicians predict the risk of developing a disease, understand the course of the disease and predict the response to treatment.

Coronary artery disease (CAD)

Much of the genetic research on heart disease is on the narrowing of the heart arteries or coronary artery disease (CAD) as CAD continues to be a major cause of death in most developed and affluent countries. The first reported study on the CAD related gene, published in 2007, identified a site (9p21) on chromosome 9, which even today remains the gene most consistently associated with CAD. Studies have also associated this gene with an increased risk of heart attack, heart artery calcification and blockage of the lower-limb arteries. Currently, there are 50 genes on the human chromosomes that have been identified as being associated with CAD.

New mechanisms that cause heart disease

With the identification of 50 sites where genetic variation is associated with increased likelihood of CAD, we would have thought that we would have discovered most of the genes that could account for CAD. In reality, the CAD genes that scientists have identified are estimated to account for only about 10 per cent of the inherited CAD. Furthermore, the increased susceptibility for CAD for most of these genes are not accounted for by the current known risk factors for heart disease, such as blood pressure, diabetes mellitus and high cholesterol levels. This means that these genetic studies have the potential to identify other genetic pathways or mechanisms which increase the risk of developing CAD.

Genetic studies are beginning to help us understand new mechanisms that increase the likelihood of CAD. In a 2010 publication in Nature journal, researchers were able to demonstrate how a variation on a genetic site on chromosome 1 caused an increased risk of CAD. The study showed that the variation on the specific genetic site reduced the production of a gene called SORT1 gene in the liver. In the human gene pool, the SORT1 gene has the strongest impact on cholesterol particles. The SORT1 gene regulates the production of a protein called sortilin, which affects the uptake of bad cholesterol or low-density lipoprotein cholesterol (LDL-C) by cells. Therefore, when this genetic variation is present, there is decreased production of SORT1 gene, causing a decreased production of the protein sortilin, which then results in decreased LDL-C uptake by cells from the blood circulation and hence culminates in higher LDL-C levels left in the blood circulation, increasing cholesterol deposition into the walls of arteries and increasing the likelihood of CAD.

Simply put, the genetic variation triggers a chain reaction which ultimately leaves more bad cholesterol in the blood circulation and increases the likelihood that the arteries will get clogged. Understanding the existence of this new sortilin pathway could mean that scientists can develop drugs that can target this mechanism and thereby decrease CAD risk in those with this genetic variation.

These new mechanisms and other undiscovered pathways may eventually help us to understand why certain patients continue to get progressive narrowing of their heart arteries despite living a healthy lifestyle and having optimal control of risk factors for CAD. As we learn more about these new mechanisms, scientists will be able to develop new treatment strategies to prevent the development or progression of CAD.

CAD genes and prognosis

For those with pre-existing CAD, genetic data may help physicians understand the prognosis and potentially help physicians use the information to make decisions on the management of the CAD.

A good example is the thrombomodulin gene which regulates the production of thrombomodulin, a protein on the inner lining of blood vessels that reduces blood clotting by converting a clot forming protein, thrombin, to clot preventing protein. A genetic variation in the thrombomodulin gene has been shown to be associated with increased long-term survival in those undergoing bypass heart surgery, presumably by mechanisms that are able to reduce the likelihood of clotting of the blood vessels and grafts.

Genetic variations can cause good effects but they can also cause adverse consequences. Genetic studies have also been able to demonstrate that there are genetic variants that are associated with an increased risk for sudden cardiac death in CAD patients.

Impact of CAD genes on treatment decisions

Beyond the traditional risk factors for CAD, such as smoking, high blood pressure, high cholesterol and diabetes mellitus, does the presence of CAD genes provide incremental benefit in treatment decisions? What is clear from the studies is that the presence of CAD genes independently increase the risk of CAD even after considering the conventional risk factors for CAD

In the Atherosclerosis Risk in Communities (ARIC) study published in Circulation Cardiovascular Genetics journal in 2009, the authors reported that the addition of genetic risk scoring using the chromosome 9p21 site resulted in a change in the classification of CAD risk category for about 13 per cent of the patients and these changes could have impacted the treatment decisions and target goals for the affected patients.

Genetic testing for CAD

Current data suggests that the identification of CAD genes may possibly impact treatment decisions beyond the conventional risk factors, by equipping physicians with more information to enable them to make better management decisions. In certain situations, it may also help physicians to assess the prognosis in patients. From the patient’s perspective, CAD genetic testing can also have potential benefits. Patients whose genetic profiles are associated with an increased likelihood of CAD may be more likely to be compliant with treatment. Despite the potential benefits of genetic screening, mass screening for the asymptomatic patient is not recommended as there is a lack of certainty as to whether gene-driven therapeutic decisions will change clinical outcomes and the impact of the currently known CAD genes account for only a small fraction of the inherited CAD disease.