Polygenic Prediction of Recurrent Events After Early-Onset Myocardial Infarction

Maddalena Ardissino^{1

2

3

4}, Elvezia Maria Paraboschi^{5

6}, Samuel A Lambert^{1

2

7

8}, Lois G Kim^{1

2

9}, Martin Kelemen^{1

2}, Giuseppe Maglietta¹⁰, Antonio Crocamo¹¹, Giulia Magnani¹¹, Serena Bricoli¹¹, Luigi Vignali¹¹, Giampaolo Niccoli¹¹, Marco Tubaro¹², Libor Pastika³, Arunashis Sau³, Fu Siong Ng³, Antonio de Marvao^{4

13

14}, Michael C Honigberg^{15

16}, Pradeep Natarajan^{15

16}, Adam J Nelson¹⁷, Michael Inouye^{1

2

7

8

18

19}, Emanuele Di Angelantonio^{1

2

8

9

14

20}, Rosanna Asselta^{5

6}, Diego Ardissino^#^{21

22}, Adam S Butterworth^#^{1

2

8

9

18}

Affiliations

¹ British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care (M.A.,S.A.L., L.G.K., M.K., M.I., E.D.A., A.S.B.).
² Victor Phillip Dahdaleh Heart and Lung Research Institute (M.A.,S.A.L., L.G.K., M.K., M.I., E.D.A., A.S.B.).
³ National Heart and Lung Research Institute (M.A.,L.P., A.S., F.S.N.).
⁴ Medical Research Council-London Institute of Medical Sciences, Imperial College London, United Kingdom (M.A.,A.M.).
⁵ Department of Biomedical Sciences, Humanitas University (E.M.P., R.A.).
⁶ IRCCS Humanitas Research Hospital, Milan, Italy (E.M.P., R.A.).
⁷ Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care (S.A.L., M.I.).
⁸ Health Data Research UK Cambridge, Wellcome Genome Campus (S.A.L., M.I., E.D.A., A.S.B.).
⁹ National Institute for Health and Care Research Blood and Transplant Research Unit in Donor Health and Behaviour (L.G.K., E.D.A., A.S.B.).
¹⁰ Clinical and Epidemiological Research Unit (G. Maglietta), University Hospital of Parma.
¹¹ Department of Cardiology (A.C., G. Magnani, S.B., L.V., G.N.), University Hospital of Parma.
¹² Division of Cardiology, San Filippo Neri Hospital, Rome, Italy (M.T.).
¹³ Department of Women and Children's Health (A.M.).
¹⁴ British Heart Foundation Center of Research Excellence, School of Cardiovascular Medicine and Sciences, King's College London, United Kingdom (A.M., E.D.A.).
¹⁵ Program in Medical and Population Genetics, Broad Institute of Harvard & MIT, Cambridge (M.C.H., P.N.).
¹⁶ Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston (M.C.H., P.N.).
¹⁷ Adelaide Medical School, University of Adelaide (A.J.N.).
¹⁸ British Heart Foundation Centre of Research Excellence, School of Clinical Medicine, University of Cambridge, United Kingdom (M.I., A.S.B.).
¹⁹ Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (M.I.).
²⁰ Health Data Science Centre, Human Technopole, Milan (E.D.A.).
²¹ Department of Medicine and Surgery, University of Parma (D.A.).
²² Associazione per lo Studio della Trombosi in Cardiologia, Pavia, Italy (D.A.).

^# Contributed equally.

PMID: 39611259
PMCID: PMC11651354
DOI: 10.1161/CIRCGEN.124.004687

Polygenic Prediction of Recurrent Events After Early-Onset Myocardial Infarction

Maddalena Ardissino et al. Circ Genom Precis Med. 2024 Dec.

. 2024 Dec;17(6):e004687.

doi: 10.1161/CIRCGEN.124.004687. Epub 2024 Nov 29.

Authors

Affiliations

¹ British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care (M.A.,S.A.L., L.G.K., M.K., M.I., E.D.A., A.S.B.).
² Victor Phillip Dahdaleh Heart and Lung Research Institute (M.A.,S.A.L., L.G.K., M.K., M.I., E.D.A., A.S.B.).
³ National Heart and Lung Research Institute (M.A.,L.P., A.S., F.S.N.).
⁴ Medical Research Council-London Institute of Medical Sciences, Imperial College London, United Kingdom (M.A.,A.M.).
⁵ Department of Biomedical Sciences, Humanitas University (E.M.P., R.A.).
⁶ IRCCS Humanitas Research Hospital, Milan, Italy (E.M.P., R.A.).
⁷ Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care (S.A.L., M.I.).
⁸ Health Data Research UK Cambridge, Wellcome Genome Campus (S.A.L., M.I., E.D.A., A.S.B.).
⁹ National Institute for Health and Care Research Blood and Transplant Research Unit in Donor Health and Behaviour (L.G.K., E.D.A., A.S.B.).
¹⁰ Clinical and Epidemiological Research Unit (G. Maglietta), University Hospital of Parma.
¹¹ Department of Cardiology (A.C., G. Magnani, S.B., L.V., G.N.), University Hospital of Parma.
¹² Division of Cardiology, San Filippo Neri Hospital, Rome, Italy (M.T.).
¹³ Department of Women and Children's Health (A.M.).
¹⁴ British Heart Foundation Center of Research Excellence, School of Cardiovascular Medicine and Sciences, King's College London, United Kingdom (A.M., E.D.A.).
¹⁵ Program in Medical and Population Genetics, Broad Institute of Harvard & MIT, Cambridge (M.C.H., P.N.).
¹⁶ Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston (M.C.H., P.N.).
¹⁷ Adelaide Medical School, University of Adelaide (A.J.N.).
¹⁸ British Heart Foundation Centre of Research Excellence, School of Clinical Medicine, University of Cambridge, United Kingdom (M.I., A.S.B.).
¹⁹ Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (M.I.).
²⁰ Health Data Science Centre, Human Technopole, Milan (E.D.A.).
²¹ Department of Medicine and Surgery, University of Parma (D.A.).
²² Associazione per lo Studio della Trombosi in Cardiologia, Pavia, Italy (D.A.).

^# Contributed equally.

PMID: 39611259
PMCID: PMC11651354
DOI: 10.1161/CIRCGEN.124.004687

Abstract

Background: Myocardial infarction (MI) is a complex disease caused by both lifestyle and genetic factors. This study aims to investigate the predictive value of genetic risk, in addition to traditional cardiovascular risk factors, for recurrent events following early-onset MI.

Methods: The Italian Genetic Study of Early-Onset Myocardial Infarction is a cohort study enrolling patients with MI before 45 years. Monogenic variants causing familial hypercholesterolemia were identified, and a coronary artery disease polygenic score (PGS) was calculated. Ten-fold cross-validated Cox proportional hazards models were fitted sequentially including all clinical variables, the PGS, and monogenic variants on the composite outcome of cardiovascular death, recurrent MI, stroke, or revascularization.

Results: During a 19.9-year follow-up, 847 (50.7%) patients experienced recurrent events. Each 1-SD higher PGS was associated with a 21% higher hazard of recurrent events (hazard ratio, 1.21 [95% CI, 1.13-1.31]; P=4.04×10^-6). Except for secondary prevention, PGS was the strongest determinant of recurrent event risk (C index, 0.56 [95% CI, 0.54-0.58]) compared with clinical risk factors. Overall, predictive performance of clinical risk factors (C index, 0.69 [95% CI, 0.67-0.71]) improved after adding the PGS (C index, 0.69 [95% CI, 0.68-0.71]; P=0.006). When dividing the population by PGS quintiles, the highest fifth had a 57% higher hazard of recurrent events than the lowest fifth (hazard ratio, 1.57 [95% CI, 1.26-1.96]; P=5.57×10^-5).

Conclusions: When compared with other clinical risk factors, PGS was the strongest predictor of event recurrence among patients with an early-onset MI. Though the discriminative power of recurrent event prediction in this cohort was modest, the addition of PGS significantly improved discrimination.

Keywords: cardiovascular diseases; coronary artery disease; genetic risk score; genetics; heart disease risk factors.

PubMed Disclaimer

Conflict of interest statement

Dr Natarajan reports research grants from Allelica, Amgen, Apple, Boston Scientific, Genentech/Roche, and Novartis; personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Creative Education Concepts, CRISPR Therapeutics, Eli Lilly & Co, Foresite Labs, Genentech/Roche, GV, HeartFlow, Magnet Biomedicine, Merck, and Novartis; scientific advisory board membership of Esperion Therapeutics, Preciseli, and TenSixteen Bio; scientific cofounder of TenSixteen Bio; equity in MyOme, Preciseli, and TenSixteen Bio; and spousal employment at Vertex Pharmaceuticals, all unrelated to the present work. Dr Honigberg reports consulting fees from CRISPR Therapeutics and Comanche Biopharma, advisory board service for Miga Health, and grant support from Genentech, all unrelated to the present work. Dr Inouye is a trustee of the Public Health Genomics Foundation, a member of the Scientific Advisory Board of Open Targets, and has a research collaboration with AstraZeneca PLC, which is unrelated to this study. Dr Butterworth reports institutional grants from AstraZeneca, Bayer, Biogen, BioMarin, Bioverativ, Novartis, Regeneron, and Sanofi. The other authors report no conflicts.

Figures

**Figure 1.**
**Study design and data processing.** metaGRS indicates polygenic risk score.

**Figure 2.**
Incidence of recurrent cardiovascular (CV) events during follow-up among patients with early-onset myocardial infarction with high (top fifth), medium (middle three fifths), and low (bottom fifth) polygenic risk based on metaGRS. PGS indicates polygenic score; metaGRS, polygenic risk score.

**Figure 3.**
Cumulative incidence of recurrent cardiovascular events among patients with early-onset myocardial infarction with high (top fifth), medium (middle three fifths), and low (bottom fifth) polygenic risk based on metaGRS. metaGRS indicates polygenic risk score.

**Figure 4.**
**Discrimination ability of conventional risk factors, secondary prevention, polygenic score (metaGRS), and monogenic variants for recurrent cardiovascular events.** All models include age, sex, and 10 genetic principal components as covariates. metaGRS indicates polygenic risk score.

See this image and copyright information in PMC

References

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Polygenic Prediction of Recurrent Events After Early-Onset Myocardial Infarction

Affiliations

Polygenic Prediction of Recurrent Events After Early-Onset Myocardial Infarction

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical