The Science Behind Polygenic Risk Scores - Coronary Artery Disease (CAD)

The Science Behind Polygenic Risk Scores - Coronary Artery Disease (CAD) 

This Behind the Science blog post features summaries* of a few promising studies researchers have completed in the field of Polygenic Risk Scores (PRS) and will provide our more clinical readers insight into some of the arenas in which PRS can provide utility that better stratifies patient risk for various diseases. For more general patient-focused knowledge regarding the diseases on our panel, please visit our “Deep Dives” blog series. (Stay tuned for our Deep Dive on CAD coming soon!)

*Please note that the following blog post includes information pulled directly from the referenced articles and may also include direct quotes from the research team or other experts. For more detailed study information, including additional methods, a discussion of study limitations, and more, please refer to the cited article(s) directly. 

Research Citation: “Reclassification of coronary artery disease risk using genetic risk score among subjects with borderline or intermediate clinical risk.” (2022). Ahmed, R.A., Shi, Z., Rifkin, A.S., Wei, J., Zheng, S.L., Helfand, B.T., Hulick, P.J., Woo, J.S.H., Qamar, A., Davidson, D.J., Billings, L.K., and Xu, J.  Int J Cardiol Heart Vasc. 2022 Dec; 43: 101136. Published online 2022 Oct 13. doi: 10.1016/j.ijcha.2022.101136 

Background

With cardiovascular diseases (including Coronary Artery Disease (CAD) topping the list of leading causes of death worldwide, identification of those at increased risk is paramount for early implementation of risk-reduction strategies. Adults are recommended to undergo a standard 10-year ASCVD (atherosclerotic cardiovascular disease) risk estimation, including family history (FH) assessment as one applicable risk factor. 

Study Objective

To demonstrate that Polygenic Risk Scores (PRS) are informative tools for clarifying ASCVD for individuals with borderline risk based on traditional risk assessment methods.

Methods and Findings

A CAD incident cohort (a group of individuals in which CAD onset occurred after the study’s baseline date) of 366,493 people was derived from the UK Biobank (UKB), a large population-based study. At recruitment, the following were completed:

• A 10-year ASCVD risk estimate uses pooled cohort equations, a widely-used risk calculator that estimates risk among individuals without pre-existing cardiovascular disease.
  
• Family history (FH) of heart disease among first-degree relatives of study participants.
• Polygenic risk score (PRS), including well-established odds ratio (OR)-weighted and population-standardized polygenic risk score for CAD that represents a person’s relative risk (RR) for CAD compared to the general population.

Individuals were categorized into the following four risk groups based on their relative risk to the general population:

• RR <0.5 (low risk)
• RR 0.5-1.49 (average risk)
• RR 1.5-2.99 (high risk)
• RR >/=3 (very high risk)

As of the last UKB accession date of 1/5/2022, 6.6% of the subjects (N=23,753) had been diagnosed with CAD during an average of 12.6 years of follow-up. Based on previously-obtained 10-year ASCVD risk analysis, 158,880 (44.12 %), 51,202 (14.22 %), 121,880 (33.85 %), and 28,136 (7.81 %) subjects were classified as low-, borderline-, intermediate-, and high- ASCVD risk, respectively, with incident CAD rate at 2.18%, 5.65%, 10.03%, and 18.41%, respectively. 

For the subjects with borderline/intermediate ASCVD risk, their CAD risk was further stratified by FH and PRS:

• Using FH, subjects were stratified into two risk groups: those with a family history of CAD (47%) and those without (53%). The incident CAD rate was moderately higher in those with FH, at 10.28%, than in those without, at 7.37% (p < 0.001).
• Importantly, PRS was able to stratify subjects into the four RR groups listed above (18% were low risk, 69% average risk, 12% high risk, and 1% very high risk), and the following percentage of individuals previously assigned to each respective RR group were diagnosed with CAD during the follow-up period (incident CAD rate): 
  • 5.93% of subjects in the low RR group 
  • 8.64% of those in the average RR group
  • 12.81% of those in the high RR group
  • 17.9% of those in the very-high RR group

Discussion

“This large, population-based study provided evidence that PRS can be used as a supplementary factor for considering statin use among subjects with clinically defined borderline-/intermediate-ASCVD risk. Considering that ~50% adult subjects are in this group, this more personalized refinement of CAD risk has a large public health impact on primary intervention” - Dr. Jianfeng Xu, VP of Translational Research at Endeavor Health and Co-author of this study

A novel finding of this study is the demonstration of better performance of PRS than FH for stratifying CAD risk among subjects with borderline/intermediate ASCVD risk. Approximately 13% and 18% of these subjects can be further reclassified into higher (PRS ≥1.5) or lower (PRS<0.5) risk groups, respectively. These results, derived from a large population-based prospective cohort, provide evidence to support PRS as a useful tool in clarifying CAD risk. 

To read the research in the October 2022 International Journal of Cardiology. Heart & Vasculature publication, please visit: https://pubmed.ncbi.nlm.nih.gov/36275420/

Series Overview: Behind the Science

Welcome to Behind the Science, a blog series dedicated to providing a peek behind the curtain of the cutting-edge work happening both here at GenomicMD and also in the greater field of polygenic research. This series will supply our readers with valuable insights via curated research articles and press releases, as well as interviews with key players at our laboratory and beyond. Each post will provide an in-depth look at the roles, aspirations, and contributions that collectively drive the success of GenomicMD and polygenics research as a whole. In this series you'll find:

• Conversations with our experts: Interviews that give insights into the meticulous processes that underpin our genetic testing services.
• Unique Medical Perspectives: Interviews with doctors who utilize polygenic screening to improve patient care via precision medicine.
• Personal journeys: Firsthand stories from patients about how polygenic testing has influenced their health decisions, lifestyle choices, and overall well-being.
• Curated Research Articles and Press Releases: Keep up to date with articles and other news that shed light on the latest advancements in polygenic research

Join us as we explore the world of genetic testing and the inspiring individuals who are shaping the future of healthcare, one discovery at a time. Welcome to GenomicMD’s "Behind the Science" – where understanding meets innovation.