- Researchers at Massachusetts General Hospital have developed a new genome-wide polygenic score for coronary artery disease (GPS-CAD) that is specific to individuals of South Asian ancestry
- The GPSCAD was robustly associated with CAD in 7,244 South Asian participants of the UK Biobank and 491 participants of a case-control study in Bangladesh
- There was a 3.22- to 3.91-fold increase in risk of CAD when comparing the highest to lowest quintiles of GPSCAD, and the risk conferred by a high GPSCAD was largely independent of traditional CAD risk factors
- The team also developed an ancestry-specific reference distribution from 1,522 individuals recruited in India and validated it in 2,963 separately recruited participants of a CAD case-control study in India
- There was striking concordance in the pattern of disease associations across individuals of South Asian ancestry living in the U.K., Bangladesh and India
In the vast majority of people who develop coronary artery disease (CAD), the risk is driven by not just one DNA variant but rather the cumulative effect of many common variants. In 2018, researchers at Massachusetts General Hospital reported the development of a genome-wide polygenic score for CAD (GPSCAD) that integrates information from over six million sites in the genome.
Building on that research, Amit V. Khera, MD, MSc, cardiologist and a medical director of the Preventive Genomics Clinic at Mass General, and colleagues have derived a new GPSCAD designed for assessment of people who have South Asian ancestry. They report on the process in the Journal of the American College of Cardiology.
Deriving the Score
Using data from a previously published genome-wide association study, the researchers tested eight candidate scores in 7,244 South Asian participants in the UK Biobank (398 CAD cases and 6,846 control subjects). For the best-performing GPSCAD:
- The odds ratio for CAD per standard deviation of GPSCAD (OR/SD) was 1.58 when adjusted for age, sex and the top five principal components of ancestry
- People in the top quintile of the GPSCAD distribution had 3.22-fold greater odds of CAD than those in the bottom quintile
- A high GPSCAD was clinically more important than a moderately elevated score:
- People in the top quintile had 2.16-fold greater odds of CAD than those in the middle quintile
- People in the top 5% had 4.16-fold greater odds (3.68 greater odds after adjustment for traditional CAD risk factors)
Testing the Score
The GPSCAD was tested in 247 cases and 244 controls who participated in the Bangladesh Risk of Acute Vascular Events study of people with first-time myocardial infarction. They found:
- The OR/SD was 1.60 (1.51 when adjusted for CAD risk factors)
- People in the top quintile of the GPSCAD distribution had 3.90-fold greater odds of CAD than those in the bottom
- People in the top 5% had 2.46-fold greater odds than those in the middle quintile
A Framework for GPS Assessment
The team then quantified the principal components of ancestry in each of 1,522 Indian individuals from the GenomeAsia 100K project and generated an ancestry-matched reference distribution for the GPSCAD.
They recruited 1,800 additional CAD cases and 1,163 controls in India (median age 55 and 54, respectively) who were part of a MedGenome study and projected their data onto the genetic ancestry and GPSCAD reference distribution. This confirmed expected associations with CAD:
- The OR/SD was 1.66 (1.59 when adjusted for CAD risk factors)
- People in the top quintile of the GPSCAD distribution had 3.91-fold greater odds of CAD than those in the bottom
- People in the top 5% had 3.22-fold greater odds than those in the middle quintile
Adding the GPSCAD led to an improvement of 35% for reclassifying people with CAD risk factors and 32% for reclassifying those without.
Implications for Prevention
The Indian validation cohort was middle-aged, but a GPS can be calculated at any point during an individual's lifetime. Previous research in Circulation suggests that knowledge of a high genetic risk score may boost people's motivation to initiate or adhere to risk-reducing interventions.
Successful generalization of the GPSCAD to South Asians may represent an important public health opportunity, particularly considering the increased rates of a sedentary lifestyle and reluctance to take medicines frequently encountered in South Asian individuals.
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