People can develop significant coronary artery disease despite having good risk-factor control. By Michael Lim

MR A was very careful with his food and ate only fish and vegetables for his meals. He exercised regularly in the belief that exercise would raise the high density lipoprotein cholesterol (HDL-C) or “good” cholesterol, and protect him from heart disease. His low density lipoprotein cholesterol (LDL-C) or “bad” cholesterol was mildly elevated. Hence, he was surprised to learn that he had a severe narrowing of one of his major heart arteries. While this may seem rather unusual, advances in genetic studies are helping us to understand this better.

Although 99.5 per cent of humans’ DNA sequence in their chromosomes is identical, it is the 0.5 per cent that is not that makes one individual so different from another.

Advances in genetic studies have enabled physicians to identify heart disorders related to abnormalities in single genes affecting heart muscles (for example, arrhythmogenic right ventricular dysplasia, hypertrophic cardiomyopathy and dilated cardiomyopathy), heart rhythms (long QT syndrome, Brugada syndrome, atrial fibrillation, Wolff-Parkinson-White syndrome), and cholesterol (familial hypercholesterolemia).

However, narrowing of the heart arteries, (coronary artery disease or CAD), which accounts for most heart-related deaths, is not a single-gene disorder.

Genetic risk of narrowed arteries

Studies have claimed that 40-60 per cent of susceptibility to CAD is inherited. Data from the Framingham Study and the Interheart studies have shown that a family history of CAD is associated with a 11/2 to more than two times increased risk of CAD.

The Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (Cardiogram) group and other genomic investigators have identified at least 50 genetic variants associated with an increased risk of CAD, with 50 per cent present in more than 50 per cent and 25 per cent present in more than 75 per cent of the population. Some of these genes may have a detrimental impact on a certain racial group but not on others. The incremental impact on CAD risk of these genetic variants is usually modest.

What is interesting is that 35 of the 50 genetic-risk variants increase the risk of CAD by different mechanisms which are independent of traditional risk factors such as high cholesterol, high blood pressure, or diabetes mellitus. The earliest identifiable genetic variant associated with CAD was 9p21 on chromosome 9. About a quarter of the population have one copy of 9p21 in each paired chromosome (chromosomes in our cells come in pairs except for sex chromosomes); in half, it is present in only one of the paired chromosomes. The increased relative risk for CAD was 25 per cent for one copy and 50 per cent for two copies. However, this risk is not seen in blacks. These findings help to explain why a person such as Mr A can develop significant CAD despite having good risk-factor control. It also means that when physicians understand these genetic mechanisms better, new treatment modalities targeted at these genetic pathways can be developed to further reduce the risk of CAD.

ABO blood and heart attacks

The only genetic risk variant identified so far which is associated with increased risk of heart attacks is among those in the ABO blood group. In the Nurses’ Health Study on more than 90,000 patients followed up for 20 years, the presence of blood group A or B was each associated with a 10 per cent increased frequency of heart attacks and the risk was increased about 20 per cent for those with both A and B blood groups. Those with A and B blood groups produce a protein that modifies the blood clotting factor, called the von Willebrand Factor (vWF), prolonging its circulation in the blood stream; hence, the level of vWF is about 25 per cent higher in those with blood groups A, B and AB, compared to those with blood group O.

As the main mechanism of heart attack is the formation of a blood clot obstructing the lumen of the narrowed heart artery, increased levels of blood clotting factor will increase the likelihood of blood clot formation, thereby increasing the likelihood of a heart attack.

Cholesterol – genes or diet?

While a healthy diet remains an important part of controlling cholesterol levels in our body, one must be cognisant that about three quarters of the production of HDL-C and LDL-C by the liver are determined by the genes in our body.

Hence, those like Mr A who have been extremely careful with diet and yet have elevated LDL-C are likely to have genetic variations which result in higher levels of LDL-C. In some, the genetic variation may make the patient less responsive to cholesterol-lowering drugs (statins); hence the LDL-C cannot be significantly lowered even with high-dose statins.

A promising, safe and effective way of lowering LDL-C without statins is being evaluated. LDL-C in the blood binds to LDL-C binding proteins (LDL-C receptors) in the liver and upon this binding process, the LDL-C is removed from the blood circulation and enters the liver to be broken down.

In 2003, a protein enzyme, PCSK9, was discovered to have the ability to bind to LDL-C receptors, causing the receptor to degrade. Fewer LDL-C receptors means less LDL-C is removed by the liver, leading to increased LDL-C in the blood circulation and hence, increased likelihood of heart attacks.

A beneficial genetic mutation which impaired the PCSK9 function showed a modest 28 per cent reduction in LDL-C, but a significant 88 per cent reduction in the risk of CAD. This has led scientists to develop an antibody which is able to block the action of PCSK9, resulting in significant reduction in LDL-C – even for those who were already on high-dose statins.

It therefore presents a novel, safe and complementary option for those on statins who are unable to achieve optimal results and is an example of how an understanding of new genetic pathways can lead to new and effective ways of reducing CAD.

Learning from our genes

If your parents have heart disease, you have AB blood and have elevated “bad” LDL cholesterol despite going to extreme lengths to have a healthy diet, from a genetic perspective, you are at higher risk of getting heart disease. While it has been estimated that up to 60 per cent of CAD is attributable to genetic factors, the 50 genetic risk variants that have so far been identified can account for only 20 per cent of the risk at best.

So there is currently a gap in our knowledge. What is clear is that CAD is a preventable disease. The genetic studies have enabled physicians to discover new pathways that cause CAD independent of traditional risk factors such as high blood pressure, diabetes and high cholesterol. Understanding these genetic pathways and developing novel tools to block the development of CAD should eventually lower the incidence of CAD.

The sequencing of an individual’s genome can be done for less than US$1,000 and in under a week. With the rapidly decreasing price of DNA sequencing, it will not be long before the public will demand the right to have their risk profiles analysed. Physicians have formed professional organisations to train their colleagues, in anticipation of the exciting new developments that await us in the coming decade. It will not be possible to stop the tide of genetically personalised medicine. More importantly, more physicians need to be educated to anticipate the preventive tide of genetic medicine that will gradually diminish the prevalence of CAD.