Your personal genetic sequence could lead to potential health benefits. By Michael Lim

THE day you can get an analysis of your entire genome sequence for US$1,000 is not too far off. While US$3 billion was spent on the human genome sequencing project, advances in technology have made it possible to have your entire genome sequence made available for US$15,000 presently, and in five years’ time, it is estimated that this cost will drop to as low as US$1,000.

For many, this may herald the era of personal genomic medicine. With knowledge of your entire personal genome sequence, the question is whether this will reduce the likelihood of you getting heart disease or will it alter outcomes? Despite the promise of personal genomic medicine, the answer is not so clear.

Surprisingly, individual genes have shown to have limited value in predicting disease. The genetic analysis of common disease, including heart disease, is turning out to be more complex than expected.

While multiple gene sites have been identified that are associated with increased risk of blockage of heart arteries (coronary heart disease) and risk factors for coronary heart disease, in practice, they are too complex, too many, and too varied to enable the use of these genetic markers to predict the development of coronary heart disease (CHD) in daily clinical practice.

In hypertrophic cardiomyopathy, which is a condition with abnormal thickening of the heart muscle and is the most common cause of sudden cardiac death in the young, at least 11 genes with more than 1,000 mutations have been identified.

However, as the disease is too heterogeneous and is associated with too many genetic mutations, genetic testing is of little use in predicting disease but its greatest benefit is to exclude the likelihood of a relative developing the disease if there are no genetic mutations detected.

Despite the challenges, some companies have tried to develop aggregate genetic biomarkers together to form a composite test, called a genomic signature, to predict disease.

A genomic signature is an assembly or aggregate of genetic biomarkers put together to increase the predictability of a disease. Currently, genomic signatures used in medicine today are used for the diagnosis and prognosis of cancer or cardiovascular disease, of which some have already obtained the approval of the US Food and Drug Administration.

One of the genetic signatures was developed to help doctors make better decisions on doing invasive procedures, which are both expensive and can cause complications.

In a large US study on close to 400,000 patients, it was found that 62 per cent of the patients who underwent an invasive test – coronary angiography – did not have any significant disease of the heart arteries; simply put, these tests were unnecessary. A genetic signature studied showed good correlation with the severity of the heart artery disease.

Hence, a genetic signature test of this nature may be helpful in identifying patients who are likely to benefit from an invasive coronary angiography and reduce the incidence of unnecessary angiograms.

Pharmacogenetics, which is the utilisation of genetic studies to predict why people respond differently to medication is one area in which genetics has been found to be useful in cardiovascular disease.

One example is the different response to widely used cholesterol lowering drugs called statins. One genetic variant, SLCO1B1*5 gene, is associated with an increased likelihood of getting muscle pain (myopathy) or destruction of muscle cells (rhabdomyolysis).

For those with one or two copies of this genetic variant, they are at risk for myopathy or rhabdomyolysis if they take the statins like simvastatin (Zocor) or atorvastatin (Lipitor), and hence, they should use other statins like rosuvastatin (Crestor) or pravastatin (Pravachol). Absence of this genetic variant means that the risk of muscle complications is low and any statin can be used.

Another example of the use of pharmacogenetics involves clopidogrel, a drug which prevents platelets from clumping together. This drug is commonly given to patients with heart attack or those who have metallic stents placed into the heart arteries to open blocked segments.

Those who have Cytochome P450 2C19 genotype have been found to have reduced clopidogrel efficacy and hence are at greater risk of getting clot formation in the stents.

In reality, while it helps doctors understand the different responses to medication, the use of pharmacogenetics in clinical practice is currently limited and it is used mainly in research.

Can the knowledge of the personal genome be harnessed to motivate patients to change their lifestyle for the better? In a study in which patients were divided into two groups where one group had disclosure of their risk of Alzheimer’s dementia (AD) and another group were informed that they were at risk of both Alzheimer’s dementia and coronary heart disease (AD + CHD), significantly more people in the second group (AD + CHD) went on a diet and regular exercise programme.

This meant that disclosure of genetic risks can motivate people to change their behaviour to prevent the disease, which in this case, the exercise and dieting will potentially reduce the risk of getting CHD.

While we cannot change the genes we are born with, changes in gene expression and genome function can occur that do not depend on the DNA code of our genes; these changes are called epigenetic changes. What it means is that external influences can cause the gene to be switched on or to be switched off.

A process called demethylation can cause the gene to be switched on and in contrast, methylation can cause the gene to be switched off or repressed. Lower blood DNA methylation is associated with increased incidence and death from stroke and CHD. Folic acid deficiency, ageing, inflammation, and chemotherapy can reduce DNA methylation.

Hence, environmental influences can affect our health by their impact on our genes. As doctors glean more clinical applications from this treasure trove of genetic information, it is not unforeseeable that in the near future, everyone may carry a genomic report card stating his entire genomic sequence with his susceptibility for disease; genomic signatures for diagnosis and prognosis for heart disease and cancer; pharmacogenetic profile for safety and efficacy of medication prescribed; and methylation status of his blood DNA.

This can potentially impact lifestyle behaviour to reduce the likelihood of getting the disease and motivate individuals to get their epigenomic status to a healthy state by modifying environmental influences.

Pharmacogenetics, which is the utilisation of genetic studies to predict why people respond differently to medication is one area in which genetics has been found to be useful in cardiovascular disease.