Clinical utility of polygenic risk scores for coronary artery disease

Abstract Background There is growing evidence that polygenic risk scores (PRSs) can identify individuals with elevated lifetime risk of coronary artery disease (CAD). Whether they can also be used to stratify the risk of subsequent events among those surviving a first CAD event remain uncertain, with possible biological differences between CAD onset and progression, and the potential for index event bias. Methods Using two baseline subsamples of UK Biobank: prevalent CAD cases (N = 10 287) and individuals without CAD (N = 393 108), we evaluated associations between a CAD PRS and incident cardiovascular and fatal outcomes. Results A 1 SD higher PRS was associated with an increased risk of incident myocardial infarction (MI) in participants without CAD (OR 1.33; 95% CI 1.29, 1.38), but the effect estimate was markedly attenuated in those with prevalent CAD (OR 1.15; 95% CI 1.06, 1.25) and heterogeneity P = 0.0012. Additionally, among prevalent CAD cases, we found an evidence of an inverse association between the CAD PRS and risk of all-cause death (OR 0.91; 95% CI 0.85, 0.98) compared with those without CAD (OR 1.01; 95% CI 0.99, 1.03) and heterogeneity P = 0.0041. A similar inverse association was found for ischaemic stroke [prevalent CAD (OR 0.78; 95% CI 0.67, 0.90); without CAD (OR 1.09; 95% CI 1.04, 1.15), heterogeneity P < 0.001]. Conclusions Bias induced by case stratification and survival into UK Biobank may distort the associations of PRS derived from case-control studies or populations initially free of disease. Differentiating between effects of possible biases and genuine biological heterogeneity is a major challenge in disease progression research.

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A012 Clinical Applications of Polygenic Risk Scores in Coronary Artery Disease and Familial Hypercholesterolaemia

Heart Lung and Circulation ◽

10.1016/j.hlc.2020.05.017 ◽

2020 ◽

Vol 29 ◽

pp. S5-S6

Author(s):

H. Fahmi ◽

A. Laurie ◽

P. Shepherd ◽

C. Bhoothpur ◽

M. Legget ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Familial Hypercholesterolaemia ◽

Clinical Applications ◽

Risk Scores ◽

Polygenic Risk ◽

Artery Disease

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Validation of genome-wide polygenic risk scores for coronary artery disease in French Canadians

10.1101/538470 ◽

2019 ◽

Author(s):

Florian Wünnemann ◽

Ken Sin Lo ◽

Alexandra Langford-Avelar ◽

David Busseuil ◽

Marie-Pierre Dubé ◽

...

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Risk Scores ◽

French Canadian ◽

French Canadians ◽

Polygenic Risk ◽

Genome Wide ◽

Artery Disease ◽

The Impact ◽

Cad Risk

AbstractCoronary artery disease (CAD) represents one of the leading causes of morbidity and mortality worldwide. Given the healthcare risks and societal impacts associated with CAD, their clinical management would benefit from improved prevention and prediction tools. Polygenic risk scores (PRS) based on an individual’s genome sequence are emerging as potentially powerful biomarkers to predict the risk to develop CAD. Two recently derived genome-wide PRS have shown high specificity and sensitivity to identify CAD cases in European-ancestry participants from the UK Biobank. However, validation of the PRS predictive power and transferability in other populations is now required to support their clinical utility. We calculated both PRS (GPSCAD and metaGRSCAD) in French-Canadian individuals from three cohorts totaling 3639 prevalent CAD cases and 7382 controls, and tested their power to predict prevalent, incident and recurrent CAD. We also estimated the impact of the founder French-Canadian familial hypercholesterolemia deletion (LDLR delta > 15kb deletion) on CAD risk in one of these cohorts and used this estimate to calibrate the impact of the PRS. Our results confirm the ability of both PRS to predict prevalent CAD comparable to the original reports (area under the curve (AUC) = 0.72-0.84). Furthermore, the PRS identified about 6-7% of individuals at CAD risk similar to carriers of the LDLR delta > 15kb mutation, consistent with previous estimates. However, the PRS did not perform as well in predicting incident (AUC= 0.56 - 0.60) or recurrent (AUC= 0.56 - 0.60) CAD. This result suggests that additional work is warranted to better understand how ascertainment biases and study design impact PRS for CAD. Collectively, our results confirm that novel, genome-wide PRS are able to predict CAD in French-Canadians; with further improvements, this is likely to pave the way towards more targeted strategies to predict and prevent CAD-related adverse events.

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Polygenic Risk Scores in Coronary Artery Disease and Atrial Fibrillation

Heart Lung and Circulation ◽

10.1016/j.hlc.2019.12.004 ◽

2020 ◽

Vol 29 (4) ◽

pp. 634-640 ◽

Cited By ~ 2

Author(s):

Patrick A. Gladding ◽

Malcolm Legget ◽

Diane Fatkin ◽

Peter Larsen ◽

Robert Doughty

Keyword(s):

Atrial Fibrillation ◽

Coronary Artery Disease ◽

Coronary Artery ◽

Risk Scores ◽

Polygenic Risk ◽

Artery Disease

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Polygenic Scores to Assess Atherosclerotic Cardiovascular Disease Risk

Circulation Research ◽

10.1161/circresaha.120.315928 ◽

2020 ◽

Vol 126 (9) ◽

pp. 1159-1177 ◽

Cited By ~ 8

Author(s):

Krishna G. Aragam ◽

Pradeep Natarajan

Keyword(s):

Cardiovascular Disease ◽

Coronary Artery Disease ◽

Coronary Artery ◽

Clinical Utility ◽

Disease Risk ◽

Cardiovascular Disease Risk ◽

Risk Scores ◽

Atherosclerotic Cardiovascular Disease ◽

Artery Disease ◽

Atherosclerotic Cardiovascular Disease Risk

An individual’s susceptibility to atherosclerotic cardiovascular disease is influenced by numerous clinical and lifestyle factors, motivating the multifaceted approaches currently endorsed for primary and secondary cardiovascular disease prevention. With growing knowledge of the genetic basis of atherosclerotic cardiovascular disease—in particular, coronary artery disease—and its contribution to disease pathogenesis, there is increased interest in understanding the potential clinical utility of a genetic predictor that might further refine the assessment and management of atherosclerotic cardiovascular disease risk. Rapid scientific and technological advances have enabled widespread genotyping efforts and dynamic research in the field of coronary artery disease genetic risk prediction. In this review, we describe how genomic analyses of coronary artery disease have been leveraged to create polygenic risk scores. We then discuss evaluations of the clinical utility of these scores, pertinent mechanistic insights gleaned, and practical considerations relevant to the implementation of polygenic risk scores in the health care setting.

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Coronary artery disease and myocardial infarction

Inherited Cardiac Disease ◽

10.1093/med/9780198829126.003.0013 ◽

2020 ◽

pp. 349-354

Author(s):

Perry Elliott ◽

Pier D. Lambiase ◽

Dhavendra Kumar

Keyword(s):

Myocardial Infarction ◽

Coronary Artery Disease ◽

Coronary Artery ◽

Association Studies ◽

Risk Scores ◽

Candidate Gene Approach ◽

Polygenic Risk ◽

Mendelian Disorders ◽

Genomic Studies ◽

Artery Disease

This chapter covers coronary artery disease (CAD) and myocardial infarction, starting with an introduction to the main causal and treatable risk factors for CAD and myocardial infarction, then goes on to discuss the Mendelian disorders associated with CAD (e.g. Tangier disease, sitosterolaemia, etc.) Association studies based on the candidate gene approach are discussed along with genomic studies, e.g. polygenic risk scores.

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