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. 2025 Aug;4(8):101994.
doi: 10.1016/j.jacadv.2025.101994. Epub 2025 Jul 24.

Coronary Artery Disease-Based Polygenic Risk Score in Early-Onset Acute Myocardial Infarction Subtypes

Weilai Dong  1 , Yuan Lu  1 , Shu-Xia Li  1 , Mitsuaki Sawano  1 , Cesar Caraballo  1 , Yuntian Liu  2 , Amit Khera  3 , Anthony Philippakis  4 , Rachel Dreyer  5 , Judith Lichtman  6 , Gail D'Onofrio  7 , Erica S Spatz  1 , David Herrington  8 , Wendy S Post  9 , Stephen S Rich  10 , Jerome I Rotter  11 , Harlan M Krumholz  12
Affiliations

Coronary Artery Disease-Based Polygenic Risk Score in Early-Onset Acute Myocardial Infarction Subtypes

Weilai Dong et al. JACC Adv. 2025 Aug.

Abstract

Background: The coronary artery disease-based polygenic risk score (PRS-CAD) estimates risk of acute myocardial infarction (AMI), but its performance across AMI subtypes in younger individuals, especially women, remains uncertain.

Objectives: The authors assessed PRS-CAD's performance in AMI subtypes.

Methods: We included 2,079 AMI patients aged 18 to 55 years with a 2:1 female-to-male ratio from the VIRGO (Variation in Recovery: Role of Gender on Outcomes of Young Acute Myocardial Infarction Patients) study and 3,761 controls from the MESA (Multi-Ethnic Study of Atherosclerosis) study. AMI subtypes were classified using the VIRGO taxonomy. We evaluated PRS-CAD's association with AMI subtypes using multinomial logistic regression and with 1-year outcomes in AMI subtypes using Cox regression.

Results: PRS-CAD was significantly associated with MI due to coronary artery disease (N = 1,876; OR: 1.82 per 1-SD increase; 95% CI: 1.67-1.97; P < 0.001) but not with MI with nonobstructive coronary artery disease (N = 188; OR: 1.13 per 1-SD increase; 95% CI: 0.96-1.34; P = 0.14). PRS-CAD's performance did not differ by sex. A 1-SD increase in PRS-CAD was associated with higher risk of 1-year hospitalization or death in patients with MI with nonobstructive coronary artery disease (HR: 1.50; 95% CI: 1.08-2.10; P = 0.02) but not in patients with MI due to coronary artery disease (HR: 0.98; 95% CI: 0.91-1.07; P = 0.67).

Conclusions: PRS-CAD's association with AMI varied by subtype but not by sex in young adults, warranting caution in application.

Keywords: acute myocardial infarction; polygenic risk score; subtypes.

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Conflict of interest statement

Funding support and author disclosures The VIRGO study was supported by grant R01 HL081153 from the National Heart, Lung, and Blood Institute (NHLBI). Whole genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the NHLBI. WGS for “NHLBI TOPMed: Multi-Ethnic Study of Atherosclerosis (MESA)” (phs001416.v3.p1) was conducted at the Broad Institute of MIT and Harvard (3U54HG003067-13S1). Centralized read mapping and genotype calling, along with variant quality metrics and filtering, were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1). Phenotype harmonization, data management, sample identity quality control, and general study coordination were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1) and TOPMed MESA Multi-Omics (HHSN2682015000031/HSN26800004). The MESA projects are conducted and supported by the NHLBI in collaboration with MESA investigators. Funding support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1TR001881, DK063491, R01HL105756, and R01HL146860. In the past 3 years, Dr Sawano has been partially supported by research funding from Polybio, Pfizer, and Novartis through Yale University; he has also received lecture honoraria from Boehringer Ingelheim. Dr Krumholz has received options for Element Science and Identifeye and payments from F-Prime for advisory roles; and he is a co-founder of and holds equity in Hugo Health, Refactor Health, and ENSIGHT-AI. He is associated with research contracts through Yale University from Janssen, Kenvue, Novartis, and Pfizer. Dr Lu has received support from the Sentara Research Foundation, the National Heart, Lung, and Blood Institute of the National Institutes of Health (under awards R01HL69954 and R01HL169171), and the Patient-Centered Outcomes Research Institute (under award HM-2022C2-28354) outside of the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

None
Graphical abstract
Figure 1
Figure 1
Multinomial Logistic Regression of PRS With AMI Subtypes The association of PRS-CAD with class I-IV AMI subtypes, as well as with MI-CAD and MINOCA, were assessed as compared to controls using multinomial logistic regression. Both the unadjusted model (blue box) and the model adjusted for sex, age, and the first four principal components (red box) are shown. AMI = acute myocardial infarction; MI-CAD = myocardial infarction due to coronary artery disease; MINOCA = MI with nonobstructive coronary artery disease; PRS-CAD = coronary artery disease–based polygenic risk score.
Figure 2
Figure 2
PRS Percentile Distribution in MI-CAD, MINOCA, and Control PRS-CAD percentile relative to controls is shown as violin plot. AMI = acute myocardial infarction; MI-CAD = myocardial infarction due to coronary artery disease; MINOCA = MI with nonobstructive coronary artery disease; PRS-CAD = coronary artery disease–based polygenic risk score.
Figure 3
Figure 3
Cox Proportional-Hazards Regression of PRS With 12-Month Outcomes in MI-CAD and MINOCA Cases The association of PRS-CAD with 12-month rehospitalization or death was analyzed using Cox proportional-hazards regression in MI-CAD and MINOCA separately. Further analysis was conducted for subcategories including death, cardiovascular rehospitalization, and noncardiovascular rehospitalization. For MINOCA cases, the regression analysis was not performed for death as there was only one death event. MI-CAD = myocardial infarction due to coronary artery disease; MINOCA = MI with nonobstructive coronary artery disease; PRS-CAD = coronary artery disease–based polygenic risk score.
Central Illustration
Central Illustration
Association of Coronary Artery Disease-Based Polygenic Risk Score With Acute Myocardial Infarction Subtypes The association of a CAD-based PRS with AMI subtypes was evaluated in 2,079 VIRGO AMI cases and 3,761 MESA controls, revealing subtype-specific differences in PRS-CAD associations. AMI = acute myocardial infarction; MESA = Multi-Ethnic Study of Atherosclerosis; MI-CAD = myocardial infarction due to coronary artery disease; MINOCA = MI with nonobstructive coronary artery disease; PRS-CAD = coronary artery disease–based polygenic risk score.
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