Genome-wide polygenic scores (GPS) that integrate information from many common DNA variants of an individual into a single value for risk stratification for a wide range of diseases is one of the newest developments in genetic medicine.
Since the rates of non-communicable diseases, including coronary artery disease (CAD), are substantially higher among South Asians, polygenic risk scores (PRS) to identify high-risk individuals is particularly useful in this population. But there were challenges like prior genome-wide association studies, which is needed as input to GPS derivation to weight a given variant’s contribution to the risk of CAD, had been mostly performed in individuals of European ancestry; Lifestyle and environmental factors modulate the impact of genetic variation on the risk; and many more. But a pathbreaking study— first-ever on the South Asian population— initiated by MedGenome Labs, Asia’s leading genomics research-and clinical data-driven diagnostics company, in collaboration with experts from Broad Institute of MIT and others, validated a novel PRS method to predict the risk of developing coronary artery disease/myocardial infarction. MedGenome, as a pioneer in genetic testing in this region, has also now made available this test in the Indian market.
This polygenic risk score for coronary artery disease, if implemented at the population level, would help in better stratification of high-risk individuals. Such risk prediction and preventive interventions can have a huge impact on public health, and on the economy in general, in these countries, especially India, says Dr Vedam Ramprasad, CEO, MedGenome Labs, in Straight Talk with Editor C H Unnikrishnan. Edited excerpts:
Can you explain the principle of Genome-wide Polygenic Risk Score?
For long, we all know that every disease, whether communicable or noncommunicable, has genetics in their origin. As you know, monogenic diseases are purely attributed to a mutation or variation in the DNA or RNA in one particular gene and these diseases hardly have any external factors like environment or lifestyle etc that influence their outcome. But, other common diseases like coronary artery disease, diabetes, hypertension, stroke, inflammatory bowel disease, Alzheimer’s, schizophrenia and many more have some genetic component in their causes, though they are often influenced by other factors such as lifestyle, environment, diet etc. That’s why the onset, symptoms, severity and mortality of, and due to, these diseases typically vary from person to person. For example, smoking is one of the direct and serious causes for coronary artery disease, but at the same time it’s not necessary that every smoker will develop the disease and show the same level of severity. Since all these common diseases have their root cause governed by the small effects or variations in not just one, but thousands of genes in the human genome, analysing these large numbers of small or modest variations in the human genome to arrive at a single standardised value to predict that risk is called Polygenic Risk Score. Here, one very important fact that we need to remember is that these effects or variations in the genes cannot be modified later, as one gets them from the parents at the time of birth. However, all other external factors like lifestyle and environment can be altered or modified to protect us, and the severity of the disease can also be minimised through medical interventions. But, this is possible only if we know or quantify the risk.
In the last 15 years (at least), there has been a revolution in science called genome-wide association studies. A lot of global studies on this have been carried out, though mostly on Caucasian populations. Of late, there have been large studies on Asian populations, including in China and India. All these studies have found several variations associated with particular genotypes. But there has never been a robust method developed to summate all these variations and relate them to the onset or severity of a disease or diseases. So, that way, the current study that we have concluded is a powerful tool for the summation of these variations into one robust statistical value reflecting the risk analysis. In other words, genome-wide polygenic risk score is a value that gives you a general genetic risk estimation related to whether you will have a particular disease or not. This particular study was aimed at developing a polygenic risk score for coronary artery disease (PRS CAD) in the South Asian population.
What does your study say about the genetic risks of heart disease among Indians and the South Asian population in general? How is it different from European ancestry samples?
Well, it’s a known fact that we have developed different ethnicities and ancestries through evolution. At the same time, due to various geographical barriers and other bottlenecks, people haven’t intermingled much in terms of breeding. Rather, many of these groups remained isolated or secluded, leading to inbreeding. So, these ethnic groups have widely varying genetic profiles. Caucasians are distinctly different from South Asians in genetic structure and traits. Since polygenic risk scores need to be analysed with a baseline of the genetic data of the respective ethnicity or ancestry, what helped us in doing this study was the baseline data that we generated through a landmark study — GenomeAsia 100K — a large human genome sequencing study on South and Southeast Asian population. In this genome sequencing project, which was also led by MedGenome in partnership with several government institutions from India, Malaysia, Singapore, Indonesia and other countries, we found that there are 2 million genetic variants which were unique to the South Asian population. Also, we have seen very unique genetic signatures in certain islands of Indonesia, Andaman and Nicobar and even several isolated locations and close communities of India.
After deriving a genome-wide polygenic risk score for coronary artery disease (GPS-CAD) tuned to individuals of South Asian ancestry, our series of analyses confirmed robust associations of this score with CAD in South Asian individuals involved in the UK Biobank and in a separate case-control study based in Bangladesh. Furthermore, we validated a generalisable framework to assess polygenic scores— including the use of an ancestry-specific imputation panel and a static reference distribution—and validated this framework by confirming robust associations of GPS-CAD with coronary artery disease in an independent study of South Asians based in India.
These results indicate that the cumulative impact of common DNA variants—now possible to quantify using a GPS—is an important driver of the risk of heart disease, even among individuals of South Asian ancestry. By optimising a polygenic score for the disease in South Asians, we noted a 3.22- to 3.91-fold increase in risk when comparing the highest to lowest quintiles across 3 independent study samples. Moreover, the pattern of disease associations was strikingly concordant across individuals of South Asian ancestry living in the United Kingdom, Bangladesh and India.
How soon can one test and predict this risk value using CAD PRS?
As I said earlier, one’s DNA or genetic destiny is determined when he or she is born. So technically speaking, one can do the polygenic risk score, which is a one-time screening test any time between the birth and death and it will remain the same in normal circumstances. Generally speaking, there is no compelling need to do a PRS at birth or at a very young age and perhaps, there could even be ethical issues. So the ideal age to do this screening test is at the age of 18 to 21 to know your risk profile so that you have enough time to control or modify your lifestyle, diet or other factors to mitigate the disease risk according to your score. Anyway, it’s an evolving area and there will be guidelines and other regulatory recommendations emerging soon.
To what extent can your study findings be clinically implemented for other diseases?
Polygenic risk score is an independent risk value analysis based on an individual’s genetic variations and their effects. It can be applied to any disease. But we focused on coronary artery disease (CAD) because of two reasons. The main reason is the prevalence of heart disease in India and other Southeast Asian countries. Studies show the current prevalence of heart disease in India is about 10 to 13%, which is very high considering the sheer size of population, and much of that is in the early age group of 40 to 45 years. So, the life-saving potential of PRS screening and early interventions in a country like India is huge. Secondly, some of our affiliate research organisations are doing intense studies in the area of new-generation therapies for heart diseases. So, this enables the clinical collaboration that is needed for such studies. In fact, we are in the process of studying the possibility of a similar effort for other diseases like diabetes, hypertension and so on. But as a policy, we will neither make claims nor offer those tests unless we have convinced ourselves on their accuracy by involving credible clinical establishments and publishing the observations for review and further investigation.
What is the specificity and accuracy rates of PRS screening and disease prediction in a stricter clinical sense?
Well, PRS as a screening test, its sensitivity is around 50%. This is because, as I said earlier, there are still several aspects of biology to be understood and many other factors influence the ultimate disease outcome, the onset and severity. But going by our observations, one thing that we can very confidently say is that the chances of an individual with a high polygenic risk score for coronary artery disease developing the disease at a comparatively early age is as high as 90%. So, this can be considered a powerful predictive tool as far as cardiovascular diseases among the South Asian population are concerned.
How costly is this technology at present and how did you arrive at the price point at which it has been made available in the Indian market?
MedGenome is currently offering this one-time screening test—PRS CAD—at Rs 5,000 in India. Considering the significant amount of investment and resources used in the study, this is actually being offered at a highly subsidised price with a view towards achieving volumes. The technology platform, the test kit and the reagents used for the test too are on the costly side as they aren’t available in India. But we believe that our path breaking study and test would prove to be very rewarding in the long run not only for us but the country too.
As an effective screening tool for predicting diseases, do you see the possibility of this emerging as a government supported health check programme, given how fast NCDs are growing in this country?
Frankly speaking, as a mid-sized Indian company working on impactful healthcare research projects and tests in an emerging area like genetics, we always expect and look forward to government support. That’s the only way such new technologies could reach the common man. We are ready to take up any initiative that the government would suggest or recommend, to take this forward.