Breakthrough study captures polygenic risk scores for CAD in South Asians

September 5, 2020 0 By FM

MedGenome Labs, a leading genomics research and clinical data-driven diagnostics company, along with experts from Broad Institute of MIT and Harvard and others, conducted the first-ever study on the South Asian population that validates a coronary artery disease-polygenic risk score (CAD-PRS) to predict the risk of developing coronary artery disease or myocardial infarction using a person’s genetic makeup. The method of assessing an individual’s risk of developing a disease by summating thousands of small or modest variations in several thousands of genes in his or her genome was based on the principle of genome-wide polygenic risk score (GPS). 

The research capturing the PRS for coronary artery disease in South Asian populations, published in the Journal of the American College of Cardiology (JACC), is critically important due to the highest prevalence of cardiovascular diseases as well as a rapidly rising number of heart attacks among the young in this region, particularly in India. 

The participation of clinical researchers from reputed medical institutions such as Massachusetts General Hospital, Boston; Narayana Health, Bangalore; Eternal Hospital, Jaipur; Madras Medical Mission, Chennai; KMCH, Coimbatore and a few other large medical institutions in this first polygenic risk score study on South Asian population also signifies its value.

The JACC paper cites that individuals of South Asian ancestry represent 23% of the global population corresponding to 1.8 billion people—and experience substantially increased risk of coronary artery disease (CAD) compared with most other ethnicities. 

“The practice guidelines in the United States now recognize South Asian ancestry as an important “risk-enhancing” factor for CAD. Because CAD has a significant inherited component, genetic analyses to understand and predict CAD among South Asian populations are of particular interest,” JACC report cited. 

But there were challenges. First, prior genome-wide association studies specific to the South Asian population—needed as input to GPS derivation to weight a given variant’s contribution to the risk of CAD, were not available. Most of such studies conducted earlier were on European ancestry. Second, a GPS derived from individuals of European ancestry may have an attenuated effect when applied to other ethnicities, given that variant frequency and correlation patterns vary across ancestral groups. A recent study for a range of traits suggested that GPS derived from Europeans displayed a lower predictive power when applied to South Asians. Third, cultural and environmental factors unique to South Asian populations may modulate the importance of genetic variation on the risk of CAD. A GPS specifically tuned to a South Asian population may thus have enhanced predictive capacity compared with previously described scores validated in individuals of European ancestry, but this has not been adequately explored to date.

However, a unique dataset on the Asian population recently provided by a landmark genome sequencing study—GenomeAsia 100K, again led by MedGenome, helped overcome these challenges and supported the baseline data for the pathbreaking CAD PRS study on the South Asian population. Researchers from the GenomeAsia 100K project developed a reference dataset of genomes from individuals living in Asia, with the goal of boosting the representation of Asians in genomic research in 2019. The pilot paper of this not-for-profit project was published in Nature in December 2019.  

New Study 

The CAD PRS study was conducted on the South Asian population in 1,800 confirmed CAD cases and 1,163 control samples from five centres across the country with a median age between 54 and 55 years. The findings of this study have helped develop a CAD PRS that integrates information from millions of sites of common DNA variation into a single metric that can be calculated from birth and develop a scalable polygenic score framework in India. This finding lays the scientific and operational foundation for clinical implementation not just for CAD but for other diseases.

The authors of the research paper confirm that the newly derived GPS CAD for South Asians—which can be calculated as early as the time of birth—enables a striking stratification of disease risk during middle-age. It also validates a scalable polygenic score framework in India, laying the scientific and operational foundation for clinical implementation, they said in the paper.

“CAD PRS is a powerful genetic predictor that can be used to identify individuals at increased risk for CAD. It provides a quantified risk score based on one’s genetic makeup and predicts a patient’s risk for having an acute coronary event, such as a heart attack, before symptoms appear. CAD PRS is an important new risk factor to help physicians stratify high-risk patients and better guide treatment decisions and lifestyle interventions,” says Dr Sekar Kathiresan, CEO, Verve Therapeutics and Professor of Medicine, Harvard Medical School, Cardiology Division, and Massachusetts General Hospital.

The research paper, also published in the Journal of Genetics, states that the estimated prevalence of CAD disease in India is at about 10.5% of the population, which extrapolates to a burden of about 32 million affected individuals. Over and above, the incidence of cardiac disorders has increased from 2% to 10.5% of the urban population in the past few years, and the early age of onset is a new countrywide trend. 

“South Asians, no matter where they stay – in India or any other country, always have higher cases of CAD than Caucasians. Even if our body structure is much leaner, smaller and thus requires comparatively less food compared to Caucasians, we still end up with CAD. So, it can be considered that South Asians have some genetic issue that is causing high CAD cases and hence we need to identify these genetic factors so that we are able to manage the disease in our population,” said Dr Ajit Mullasari, Director Adult Cardiology, Madras Medical Mission.

Screening test in India 

According to senior Indian cardiologists, this breakthrough study opens up an important pool of data as well as a greatly useful screening methodology. The technology will certainly be a game-changer in increasing CAD predictability, especially among the younger population. 

“The South Asian population (Indian, Bangladeshi and Pakistani) has a very high prevalence of atherosclerotic cardiovascular disease and the risk is considered to be almost 3-4 times the risk for Caucasians. This CAD PRS, for the very first time, gives us the opportunity to apply the concept of precision medicine to a population of South Asian ethnicity by enabling us to apply this accurate and potent risk stratifying tool to delineate the quantum of cardiovascular risk and as a result, modulate therapy in such a manner as to mitigate that risk,” says Dr Hisham Ahmed, Consultant Interventional Cardiologist at Amrita Institute of Medical Sciences and Research, Kochi.

Knowing the polygenic risk is important to individuals with a family history of CAD, hypertension, diabetes, high cholesterol level, smoking habits, alcohol consumption or stressful lifestyle, as CAD results from a combination of these factors. A poor lifestyle and high polygenic risk could be a fatal combination and may result in early-onset CAD. Such findings and methods developed can be used to screen large populations and high-risk individuals. MedGenome, as a leading provider of genetic testing and screening services in India, is currently the only lab offering the CAD PRS screening in the country, costing around Rs 5,000.

“Looking at all the available scientific evidence and our study results, we are convinced that there exists a good opportunity to combine both clinical and genetic risks (polygenic risk score based) and significantly improve the primary prevention of coronary artery disease,” says Dr Vedam Ramprasad, CEO, MedGenome India.