Modification of coronary artery disease clinical risk factors by coronary artery disease polygenic risk score

Buu Truong; Yunfeng Ruan; Sara Haidermota; Aniruddh Patel; Ida Surakka; Whitney Hornsby; Satoshi Koyama; S Hong Lee; Pradeep Natarajan

doi:10.1016/j.medj.2024.02.015

Modification of coronary artery disease clinical risk factors by coronary artery disease polygenic risk score

Med. 2024 May 10;5(5):459-468.e3. doi: 10.1016/j.medj.2024.02.015. Epub 2024 Apr 19.

Authors

Buu Truong¹, Yunfeng Ruan¹, Sara Haidermota¹, Aniruddh Patel¹, Ida Surakka², Whitney Hornsby¹, Satoshi Koyama¹, S Hong Lee³, Pradeep Natarajan⁴

Affiliations

¹ Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, MA, USA.
² Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, MA, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
³ Australian Centre for Precision Health, University of South Australia, Adelaide, SA 5000, Australia; UniSA Allied Health and Human Performance, University of South Australia, Adelaide, SA 5000, Australia.
⁴ Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics and the Cardiovascular Disease Initiative, Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA. Electronic address: pnatarajan@mgh.harvard.edu.

PMID: 38642556
PMCID: PMC11088498 (available on 2025-05-10)
DOI: 10.1016/j.medj.2024.02.015

Abstract

Background: The extent to which the relationships between clinical risk factors and coronary artery disease (CAD) are altered by CAD polygenic risk score (PRS) is not well understood. Here, we determine whether the interactions between clinical risk factors and CAD PRS further explain risk for incident CAD.

Methods: Participants were of European ancestry from the UK Biobank without prevalent CAD. An externally trained genome-wide CAD PRS was generated and then applied. Clinical risk factors were ascertained at baseline. Cox proportional hazards models were fitted to examine the incident CAD effects of CAD PRS, risk factors, and their interactions. Next, the PRS and risk factors were stratified to investigate the attributable risk of clinical risk factors.

Findings: A total of 357,144 individuals of European ancestry without prevalent CAD were included. During a median of 11.1 years of follow-up (interquartile range 10.4-14.1 years), CAD PRS was associated with 1.35-fold (95% confidence interval [CI] 1.332-1.368) risk per SD for incident CAD. The prognostic relevance of the following risk factors was relatively diminished for those with high CAD PRS on a continuous scale: type 2 diabetes (hazard ratio [HR]_interaction 0.91, 95% CI_interaction 0.88-0.94), increased body mass index (HR_interaction 0.97, 95% CI_interaction 0.96-0.98), and increased C-reactive protein (HR_interaction 0.98, 95% CI_interaction 0.96-0.99). However, a high CAD PRS yielded joint risk increases with low-density lipoprotein cholesterol (HR_interaction 1.05, 95% CI_interaction 1.04-1.06) and total cholesterol (HR_interaction 1.05, 95% CI_interaction 1.03-1.06).

Conclusion: The CAD PRS is associated with incident CAD, and its application improves the prognostic relevance of several clinical risk factors.

Funding: P.N. (R01HL127564, R01HL151152, and U01HG011719) is supported by the National Institutes of Health.

Keywords: PRS; Translation to population health; clinical utility; interaction; precision medicine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Coronary Artery Disease* / epidemiology
Coronary Artery Disease* / genetics
Diabetes Mellitus, Type 2 / epidemiology
Diabetes Mellitus, Type 2 / genetics
Female
Genetic Risk Score
Genome-Wide Association Study
Heart Disease Risk Factors
Humans
Incidence
Male
Middle Aged
Multifactorial Inheritance / genetics
Proportional Hazards Models
Risk Assessment
Risk Factors
United Kingdom / epidemiology
White People / genetics

Abstract

Publication types

MeSH terms

Grants and funding