Allison Bebo ,Jamie A. Jarmul ,Mark J. Pletcher, Natalie R. Hasbani, David Couper, Vijay Nambi, Christie M. Ballantyne, Myriam Fornage, Alanna C. Morrison, Christy L. Avery ,Paul S. de Vries
The predictive ability of coronary heart disease (CHD) and ischemic stroke (IS) polygenic risk scores (PRS) have been evaluated individually, but whether they predict the combined outcome of atherosclerotic cardiovascular disease (ASCVD) remains insufficiently researched. It is also unclear whether associations of the CHD and IS PRS with ASCVD are independent of subclinical atherosclerosis measures. 7,286 White and 2,016 Black participants from the population-based Atherosclerosis Risk in Communities study who were free of cardiovascular disease and type 2 diabetes at baseline were included.
We examined whether two previously validated PRS for CHD and IS predict ASCVD outcomes in White and Black participants aged 45 to 64 years over a ten-year risk prediction period within the prospective Atherosclerosis Risk in Communities (ARIC) Study cohort [12, 13]. Additionally, this study investigated whether the CHD and IS PRS can cross-predict for IS and CHD outcomes, respectively, and whether these PRS are associated with incident ASCVD independent of measures of subclinical atherosclerosis, including ABI, cIMT, and carotid plaque.
Materials and Methods
The ARIC study is a prospective, population-based cohort study conducted among mostly White and Black participants from four centers in the United States . In brief, 15,792 participants aged 45 to 64 years were enrolled from 1987 to 1989. Of those participants, 12,153 participants have genotype data available and consented to the study. After the baseline visit, three, triennial follow-up visits were conducted. A fifth visit occurred between 2011 to 2013, a sixth visit occurred between 2016 to 2017, and a seventh visit occurred between 2018 and 2019. The study participants were contacted annually (semi-annually from 2012) by telephone in order to ascertain their health status. All included participants provided written informed consent. The ARIC study was approved by the University of Mississippi Medical Center IRB, Wake Forest University Health Sciences IRB, University of Minnesota IRB, and John Hopkins University IRB.
When we examined the effects of the PRS in the context of markers of sub-clinical atherosclerosis in White participants, the HR for the CHD PRS was significant with an HR of 1.53 (95% CI: 1.36–1.73) and the HR for the IS PRS was significant with an HR of 1.37 (95% CI: 1.21–1.54) for risk of incident ASCVD, after adjusting for traditional risk factors as well as ABI, cIMT, and carotid plaque (S2 Table). cIMT and carotid plaque were significantly associated with a 2.70-fold and 1.75-fold increase in outcomes of ASCVD (95% CI: 1.17–6.24; 1.35–2.25) after adjusting for traditional risk factors, and the CHD and IS PRS (S3 Table).
The major strengths of this study are that it was conducted using a well-established, prospective, and diverse cohort study in which ASCVD outcomes were carefully documented. Additionally, previous studies have shown that the PRS used in this study were state of the art and perform better than other, less comprehensive types of genetic risk scores [12, 14, 17]. Finally, this was one of the first studies to use the composite outcome of ASCVD as the primary outcome [18, 19].
The authors thank the staff and participants of the ARIC study for their important contributions.
Citation: Bebo A, Jarmul JA, Pletcher MJ, Hasbani NR, Couper D, Nambi V, et al. (2023) Coronary heart disease and ischemic stroke polygenic risk scores and atherosclerotic cardiovascular disease in a diverse, population-based cohort study. PLoS ONE 18(6): e0285259. https://doi.org/10.1371/journal.pone.0285259
Editor: Heming Wang, Brigham and Women’s Hospital and Harvard Medical School, UNITED STATES
Received: August 5, 2022; Accepted: April 18, 2023; Published: June 16, 2023
This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Data Availability: The genotype and phenotype data of the ARIC study are available through the ARIC coordinating center upon request, as outlined here https://sites.cscc.unc.edu/aric/index.php?q=distribution-agreements. Furthermore, the genotype and phenotype data of the ARIC study are also available to approved investigators via dbGaP using study accession number phs000280. Data access through dbGaP is restricted to approved investigators to protect the confidentiality and privacy of study participants. Approval is granted by the NHLBI Data Access Committee, independent of the authors of this manuscript.
Funding: This study was supported by the National Heart, Lung, and Blood Institute in the form of a grant to PdV [HL146860] and by the American Heart Association in the form of a grant to PdV [18CDA34110116]. The Atherosclerosis Risk in Communities (ARIC) study was supported by the National Heart, Lung, and Blood Institute, National Institute in the form of funds [HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, R01HL087641, R01HL059367, R01HL086694]; by the National Human Genome Research Institute in the form of a contract [U01HG004402]; by the National Institutes of Health in the form of a contract [HHSN268200625226C]; and in part by the National Institutes of Health and NIH Roadmap for Medical Research in the form of a grant [UL1RR025005].
Competing interests: The authors have declared that no competing interests exist.