Association of polygenic risk scores with incident atherosclerotic cardiovascular disease events among individuals with coronary artery calcium score of zero: The multi-ethnic study of atherosclerosis
Introduction
The clinical approach to prevention of atherosclerotic cardiovascular disease (CVD;ASCVD) involves identifying high risk individuals who may benefit from pharmacotherapy.1 The Pooled Cohort Equations (PCE) form the recommended first step for estimating absolute ASCVD risk.2,3 Coronary artery calcium (CAC) offers superior risk discrimination and risk reclassification compared to other CVD risk markers and is considered the strongest negative risk marker.4, 5, 6 CAC = 0 is associated with low absolute ASCVD event rates.5 However, CVD risk factors remain associated with incident ASCVD events among individuals with CAC = 0.7, 8, 9, 10, 11 It is unclear whether this residual risk is due to genetic factors independent of traditional CVD risk factors.
Coronary heart disease (CHD) risk scores have been developed using single-nucleotide polymorphisms (SNPs) identified from genome-wide association studies (GWAS).12 A prior study found that individuals in the highest decile of a polygenic risk score (PRS) had an almost 4-fold higher likelihood of prevalent CHD compared with lower risk individuals.13 Among individuals who underwent coronary angiography, high PRS was independently associated with higher risk of all-cause mortality.14 A CHD PRS was also associated with incident myocardial infarction and mortality, particularly among men between the ages of 40 and 51 years.15
Less is known about the association of PRS (especially those combining both the CHD and stroke PRS) with ASCVD outcomes among those with CAC = 0. As imaging of atherosclerosis represents a “risk integrator” combining risk of ASCVD from both traditional and non-traditional CVD risk factors, it is possible that the utility of PRS may be low in those with CAC =0. In this study, we evaluated the association of genetic variants with incident ASCVD events among those with absent CAC at baseline. We leveraged the extensive information on CVD risk factors and genetic information and long-term follow-up for incident ASCVD events that are available in Multi-Ethnic Study of Atherosclerosis (MESA.).
Section snippets
Study design and population
Details of the MESA design have been reported elsewhere.16 Briefly, MESA is a prospective cohort study of 6814 U.S adults aged 45 to 84 years of White, Black, Hispanic, or Chinese American race/ethnicity. Participants were enrolled from 6 U.S. field centers (Baltimore, Maryland; Chicago, Illinois; Forsyth County, North Carolina; Los Angeles, California; New York, New York; and St. Paul, Minnesota) between 2000 and 2002. All participants were required to be free of clinical CVD at the time of
Baseline characteristics
The study population consisted of 3132 individuals with CAC = 0 (mean (SD) age 58 (9) years; 63% female; 33% White, 31% Black, 12% Chinese-American, and 24% Hispanic individuals). ASCVD PRS categories were: 1566 individuals in the bottom 50%; 940 in the middle 30%; and 626 in the top 20%. There were no statistically significant differences in baseline demographics, CVD risk factors, or 10-year ASCVD risks when comparing individuals in the top 20% of the ASCVD PRS distribution versus individuals
Discussion
In this study of middle-aged individuals with CAC = 0 at baseline, the incidence rates of ASCVD events were low regardless of the PRS groups. Nevertheless, within this group the ASCVD PRS was associated with incident ASCVD, which appeared to be driven by genetic variants related to stroke but not CHD, and only among women and non-Whites (Fig. 3). The PRS association was independent of traditional CVD risk factors that are represented by the pooled cohort equations and family history of
Additional contributions
We thank the staff and participants of MESA for their contributions.
Disclosures
Dr. Virani: Research support: Department of Veterans Affairs, National Institutes of Health, World Heart Federation, Tahir and Jooma Family.
Honorarium: American College of Cardiology (Associate Editor for Innovations, acc.org).
Dr. Greenland: Grants from the National Institutes of Health and the American Heart Association.
Dr. Ballantyne: Grant/Research Support- All significant. (All paid to institution, not individual): Abbott Diagnostic, Akcea, Amgen, Arrowhead, Esperion, Ionis, Novartis,
Acknowledgements
MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. 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,
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