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. 2025 Jul 1;5(1):264.
doi: 10.1038/s43856-025-00981-w.

Appraisal of multiple polygenic risk scores to estimate the risk of myocardial infarction and coronary artery lesions

Hasanga D Manikpurage  1 , Jérôme Bourgault  1 , Ursula Houessou  1 , Audrey Paulin  1 , Pardis Zamani  1 , Eloi Gagnon  1 , Zhonglin Li  1 , Dominique K Boudreau  1 , Aida Eslami  1   2 , Pierre Voisine  3 , Patrick Mathieu  1   3 , Yohan Bossé  1   4 , Benoit J Arsenault  1   5 , Sébastien Thériault  6   7
Affiliations

Appraisal of multiple polygenic risk scores to estimate the risk of myocardial infarction and coronary artery lesions

Hasanga D Manikpurage et al. Commun Med (Lond). .

Abstract

Background: Polygenic risk scores (PRS) could help to identify individuals with a high genetic risk profile for coronary artery disease (CAD). We aimed to evaluate the association between previously reported PRS and myocardial infarction (MI) as well as the extent and recurrence of coronary artery lesions.

Methods: We validated previously reported CAD-PRS and 6 cardiovascular (CV) risk factors PRS (systolic blood pressure [SBP], type 2 diabetes [T2D], body-mass index [BMI], low-density lipoprotein cholesterol [LDL], triglycerides [TG], and lipoprotein-[a][Lp(a)]) in individuals of European ancestry from two Canadian population-based cohorts, the Canadian Longitudinal Study on Aging (CLSA, N = 24,599) and CARTaGENE (N = 26,806). Using a stepwise model, we determined an optimal combination of PRS to identify MI. We tested the selected PRS for association with the severity and recurrence of atherosclerotic CAD evaluated by coronary angiography in patients undergoing cardiac surgery (QUEBEC-ANGIO, N = 4108).

Results: We show that the CAD-PRS most strongly associated with MI has odds ratios per standard deviation increment of 1.75 [1.64-1.86] (P = 1.57E-70) in CLSA and 1.87 [1.73-2.03] (P = 3.06E-53) in CARTaGENE. In CLSA, the optimal model includes CAD-PRS, SBP-PRS, BMI-PRS, LDL-PRS, TG-PRS and Lp(a)-PRS. Adding these PRS increases modestly yet significantly the discriminative capacity when compared to traditional risk factors (difference of AUC = 0.025 [0.019-0.031] in CLSA, 0.018 [0.012-0.024] in CARTaGENE). In QUEBEC-ANGIO, the CAD-PRS is gradually and significantly associated with the extent and recurrence of CAD.

Conclusions: Screening multiple validated PRS may significantly improve genetic risk estimation of MI as well as the extent and recurrence of coronary artery lesions.

Plain language summary

Scores using common genetic (DNA) variations that can be measured in a blood sample have been developed to predict the risk of many diseases, including coronary heart disease (leading to heart attacks). In this study, we combined many of these scores to identify individuals who had a heart attack. We show that adding scores to known risk factors significantly improves prediction. We also show that some of these scores are associated with the level of obstruction in heart vessels measured during a specialized procedure. The use of these scores may improve the prediction of the risk of heart attack and obstruction of heart vessels.

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Conflict of interest statement

Competing interests: The authors declare the following competing interests: B.J.A. is a consultant for Novartis and Silence Therapeutics and has received research funding from Pfizer and Ionis Pharmaceuticals. The other authors declare no competing interests. The opinions expressed in this manuscript are the authors’ own and do not reflect the views of the Canadian Longitudinal Study on Aging.

Figures

Fig. 1
Fig. 1. Systematic comparison of all CAD-PRS available in PGS Catalog for their association with prevalent MI in CLSA.
Each circle represents a published PRS. Odds ratios per 1-SD of each PRS for prevalent MI were obtained from multivariable logistic regression including age, sex and the first ten ancestry-based principal components as covariates. GWAS: Genome-Wide Association Study; PRS: Polygenic Risk Score; SNP: Single Nucleotide Polymorphism.
Fig. 2
Fig. 2. Correlation between all the selected CAD-PRS and CV-PRS calculated in CLSA participants.
Data are presented as Pearson’s coefficients of correlation (r). BMI Body Mass Index, CAD: Coronary Artery Disease, HDL-C High-Density Lipoprotein Cholesterol, LDL Low-Density Lipoprotein Cholesterol, Lp(a) Lipoprotein(a), MI Myocardial Infarctio, PRS Polygenic Risk Score, SBP Systolic Blood Pressure, T2D: Type 2 diabetes, TG Triglycerides.
Fig. 3
Fig. 3. Distribution of CAD-PRS according to CAD extent at coronary angiography.
Boxplots comparing CAD-PRS in 6 different groups defined as no stenosis (N = 436), non-obstructive CAD (N = 566), single vessel disease (N = 637), 2-vessel disease (N = 945), 3-vessel disease (N = 835) and recurrent obstructive CAD (N = 568). Center marks, box boundaries and whiskers represent the median, first and third quartiles, and the most extreme data point which is no more than 1.5 times the interquartile range, respectively. Additional round marks represent points that are below or above these values. T-test: *P < 0.05; **P < 0.01; ***P < 0.005; ****P < 0.001.
See this image and copyright information in PMC

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