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GeneSpeak with the experts

Dr Ajit Mullasari,

Director of Cardiology at the Institute of Cardio-Vascular Diseases at Madras Medical Mission, Chennai, India.
Dr Ajit has been part of a recent study on Coronary Artery Disease based on the upcoming Polygenic Risk Score (PRS) Technique. This study received recognition and has been published in the Journal of the American College of Cardiology.
We had a candid chat with Dr Ajit on issues related to CAD in Indian context, latest technology in CAD diagnosis, relevance of this new technique in CAD management and many more. Some excerpts below:
Why is the Indian population so vulnerable to CAD- Is it our lifestyle, food, genetics, or any other factors?

We always considered that there is a genetic issue with Indians with respect to CAD as South Asians no matter where they stay – in India or any other country always had higher cases of CAD than any Caucasian. Even if our body structure is much leaner, smaller and thus comparatively lower food consumption than the Caucasian, still we end up showcasing higher accounts of CAD.

It can be said that the environmental issues such as blood pressure, diabetes, smoking, etc. affects every population and importance to that is paramount as these are lifestyle problems and affect our health irrespective of our genetic predisposition. And hence, a major focus has always been, very rightfully on keeping lower weight, quit smoking, keeping cholesterol down and other such environmental factors. But despite all these measures, it is evident that Indians have higher accounts of CAD and we often arbitrarily blame it on either lifestyle or genetics. We have found that certain cases of heart diseases such as high cholesterol also known as familial hypercholesterolemia runs in a family and is caused by a single gene i.e. it is a monogenic disorder. Thus, once identified, such groups of people can be given appropriate medication to manage this problem as they tend to suffer with severe diseases. However, these are very infrequent, around 1 in 200 as compared to the accounts of CAD we have in the country. So, it can be considered that South Asians have some genetic issue that is causing high CAD cases and hence, it is evident that a genetic factor is playing a major role apart from the monogenic factors, the genetic risk for South Asians was a bit abstract until now while all the focus was on the environmental factors.

Do you think it is critical to have a strong system to tackle Coronary Artery Disease in India?

Yes, and it can be done in two parts:

  • Follow primary preventive health programs such as exercise, eat healthy, eat less, manage blood sugar, fats, reduce stress, get the pollution level down, etc. and take appropriate medication if you already have been diagnosed with cholesterol or diabetes, etc. This is of primary importance.
  • Now with the scoring (PRS) available, we can identify a small population who are at a higher risk and in need of aggressive treatment and a stricter management of sugar and aggressively manage lifestyle factors- strictly no smoking, regular exercise, etc. As we cannot apply general or uniform treatment for all South Asian and hence, the scoring technique (Polygenic Risk Score technique) will help us to identify and give the much-needed focused treatment to those at high risk.

What role do you think that a genetic testing would play in treating CAD?

The moment we say South Asians are at higher risk than Caucasians or east Asians, we need to understand what are the factors behind it . No single gene is responsible for CAD. Most people suffer from a mixture of “bad” genes in various proportions. It is not one gene but a precise mix of the mutations together causing the phenotype /CAD.

Hence, it is important to know the genetic correct traits. Earlier, it was very difficult to get the genetic traits as getting the whole genome sequencing was extremely expensive 10 years back and people also lacked the understanding of what to do with the information obtained from this sequencing i.e. how to analyse the data and what to seek from it. Polygenic Risk Score technique is a way that will help us to use the data to stratify your risk and help in diagnosis and treatment.

How do you anticipate the acceptance of this approach by people and do you expect any scepticism in the community?

Scepticism is warranted. That is how science improves and that is why nothing in science is taken on a face value. People were sceptical when Down's syndrome was first considered to be a chromosomal disorder and there will be many more such examples. With PRS, we are now taking a grip on the issue and it may get improvised further as we move along. What we have now with us is a validated science that was published in a prestigious and well-known journal. Now our focus is its application on a larger population. With this, a patient with PRS can be given a personalised treatment depending on his risk even if he may not have any immediate symptoms or issues. Thus, it promises a better management and prevention of possible heart problems. However, acceptance will also be affected by affordability of the tests.

Talking about PRS, i.e. Polygenic Risk Score technique, you said that this technique is going to help in CAD diagnosis. But how exactly is it going to sync with the existing technique or system in place, what more can it add to the current diagnosis system?

This (PRS) is a completely new way of thinking. It is not like the other cases, where for example, a person is suffering from downs syndrome and you get the chromosomal analysis done or do one gene or one chromosome test and identify the root cause.

What we are proposing now is that we are looking at a person’s whole genome. To put it simply, no one gene determines that you will get a heart disease. It is always a result of the polygenic mix. More than 60 genes have been identified that seem to predispose heart disease at least in the European ancestry group. So, now we are taking a whole genome and looking at these 60 genes and analysing the frequency in which it comes out. Then, taking a set of diseased and healthy people, we see what is different in these 60 genes of these people. With a very sophisticated technology and based on the frequencies, it was clear that these 60 genes played a significant role in causing heart diseases in European population. This is also known as the GWAS (Genome Wide Association) study. With this result, we knew that these genes were important. But we did not have any information on the South Asian data. Hence, we targeted to analyse these genes among the South Asian population. Interestingly, it was the same 60 genes that showcased as predisposing to the heart problem, but the absolute risk was approx. 1.6 times more among the South Asians compared to Europeans in the same dataset. So, the same genes are not only the problem but also posing a higher risk to South Asians. This was validated in case control studies in South Asians from the UK Biobank, Bangladeshi cohort and MedGenome’s data set of Indians/South Asians.

PRS code is a number, just like a score- so those people in top 5% -high risk scores will have risk similar to monogenic risk - even if they may look normal, may not have any family history, could be a non-smoker, physically fit, etc. PRS- Is a polygenic risk score of an individual calculated by using blood to determine a person’s risk. Being a South Asian we already have a 1.6 times higher risk and for an individual the risk maybe 4 times higher. Hence, PRS can be a very important technique to diagnose a potential fatality and thus help in prevention by taking appropriate personalised treatment.

Where do you place this test in order of sequence for diagnosis and treatment- a preliminary or subsequent tests?

As someone with a significant background in the field of genetics of CAD, I would take it as a first step and consider PRS to be included within the very first few tests. So, along with the usual questions about one’s habits, family history, I would like to know the PRS as well during the initial consultation. But for this to happen,

  • we need to first educate the people. It is important for people to understand that we now have a way to evaluate your genetic risk and we can guide you better.
  • Another important deciding factor would be the cost. It needs to be affordable enough for people to go for it.
  • Availability and accessibility to this test is also an important factor for people.

However, It’s application should be validated in a large population, based on which the scores will be modified

Is the young onset of CAD seen more in India than other countries?

People suffering from heart disease in their 30s and 40s do not always have the traditional factors. A Caucasian getting a heart attack would mostly attribute it to his/her lifestyle or habits such as smoking and high cholesterol. In India, about one third of smokers under 40 years of age get a heart attack but about 67% of them will have no associated disorders such as high cholesterol, sugar, or BP. In such cases, people end up associating the cause of the heart attack to other external factors such as stress, pollution, etc.

However, it is a matter of thought why a healthy person falls prey to a sudden heart attack or an active, lean, physically fit person running a marathon suddenly drops dead.

If we analyse such cases, we may not find any classic family history or related to second degree relatives. In such a situation, one can assume that perhaps the entire family has the risk factor, but the disease has not been expressed due to low impact from any possible environmental trigger factors.

For example, if a parent has lived up to 80 years despite carrying the risk, it does not mean that their children will not get a heart attack in their 40s. As even with risks, perhaps the parents may have been a little more vigilant about their health as compared to the children and this would have been helpful in suppressing the trigger factors, which may not be the case for the children.

So, if we do a PRS test for these people, we will be able to guide them that though their parents had a high-risk score, but with certain lifestyle practices they were able to manage their health well. Hence, we can give proper guidance along with medication to manage their heart health and avoid potential damage.

At what age should one get tested?

This is a one-time test unlike many other tests that we do yearly or at a certain interval. However, the idea is not to make everyone go for this test and create a panic. Some situations where I would recommend this test would be

  • If a person has witnessed sudden deaths or angioplasty or bypass surgery in the family due to cardiac problem with no apparent history known or despite following a balanced lifestyle, then the genetic factor could be evaluated.
  • If there is a history of heart disease in a family and a person wants to take a precautionary step. Taking PRS, would help them understand their risk and manage their health better. Like the case of a known actress -Ms. Angelina Jolie, who has a family history of breast cancer, on testing found herself to be a carrier of the same BRCA gene which put her in 100% risk of developing cancer. The test gave her the choice to opt for double mastectomy, though an extreme but well informed and lifesaving decision. Likewise, PRS will also give people the choice to decide what they want to do for their well-being. Hence, a person showing a high-risk score, but no immediate symptoms of any disease can be guided to take required medication and precaution to avoid a severe illness in future.
  • Someone who had angioplasty or bypass in their 40s.

This is a future of personalised medication like administering lipid lowering therapies to bring down total cholesterol to lower than 50, as risk score may vary person to person and no fixed treatment can be applied to all. Based on risks, the treatment will be personalised to suit each case.

Is the young onset of CAD seen more in India than other countries?

Yes, it will surely be used in diseases such as diabetes, cancer, and so on. We need to understand one fact that even if environmental factors play a role in causing diseases, the issue often lies within our own system. Even generations back these diseases existed. In current times, it may have only got worse due to additional players like the environmental problems or lifestyle changes and cases are more visible as people are living longer, dying less due to other reasons such as infectious diseases.

Are there any limitations for this technique?

Currently it is still undergoing validation so I cannot announce it as the pinnacle of all solutions for CAD diagnosis. We need to fine-tune it as this is just the beginning. We need to validate it among a larger audience in India, especially younger folks with heart diseases. This will help us to refine the score.

This is a very important publication as we always suspected that SA are predisposed to heart disease. This is also the first time that the study on this topic, even if the group was small, has been commendable and that too getting published in a big journal- American Journal of Cardiology, one of the top three journals in cardiology. This assures that the study has a lot of value and scope. MedGenome has helped us with the research in India, and we hope this association continues.

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