Elsevier

Progress in Cardiovascular Diseases

Volume 74, September–October 2022, Pages 19-27
Progress in Cardiovascular Diseases

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

https://doi.org/10.1016/j.pcad.2022.08.003Get rights and content

Abstract

Background

Polygenic risk scores (PRS) are associated with atherosclerotic cardiovascular disease (ASCVD) events. We studied incident ASCVD among individuals with absent coronary artery calcium (CAC = 0), to investigate the association of PRS with incident ASCVD among such individuals.

Methods

Data was used from Multi-Ethnic Study of Atherosclerosis (MESA), a prospective cohort study of participants free of clinical CVD at baseline. PRS were developed based on a literature-derived list of single-nucleotide polymorphisms (SNPs) weighted by effect size. The coronary heart disease (CHD) PRS contained 180 SNPs, and the stroke PRS had 32 SNPs. These SNPs were combined to compute an ASCVD PRS. The PRS were calculated among 3132 participants with CAC = 0. Multivariable-adjusted Cox proportional hazards models evaluated the association between each PRS (top 20% vs bottom 50%) and ASCVD.

Results

The study population included 3132 individuals with CAC = 0 [mean (SD) age 58 (9) years; 63% female, 33% White, 31% Black, 12% Chinese-American, 24% Hispanic]. Over a median follow-up of 16 years, there were 108 incident CHD events and 93 stroke events. ASCVD event rates were generally <7.5 per 1000-person years for all ASCVD events regardless of PRS risk stratum. The ASCVD PRS was significantly associated with incident ASCVD: (HR; 95% CI) (1.63; 1.11, 2.39). The CHD PRS was not associated with any ASCVD outcome, whereas the stroke PRS was significantly associated with ASCVD (1.84; 1.27, 2.68), CHD (1.79; 1.05, 3.06), and stroke (1.96; 1.19, 3.23). The stroke PRS results were significant among women and non-Whites.

Conclusions

Among individuals with CAC = 0, the ASCVD PRS was associated with incident ASCVD events. This appears to be driven by genetic variants related to stroke but not CHD, and particularly among women and non-Whites. ASCVD event rates remained below the threshold recommended for consideration for initiation of statin therapy even in the high PRS groups.

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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