Background: It is unknown whether the impact of high diet-quality and physical activity (PA) depends on the level of polygenic risk score (PRS) in different ancestries. Objective: Determine the associations and interactions between high-risk PRSs, dietary patterns, and high PA with atherosclerotic cardiovascular disease (ASCVD) in European Americans (EAs) and African Americans (AAs). Another aim determined the molecular pathways of PRS-mapped genes and their relationships with dietary intake. Methods: Cross-sectional analyses utilized de-identified data from 1987-2010 from 7-National Heart, Lung, and Blood Institute Candidate Gene Association Resource studies from the Database of Genotypes and Phenotypes studies for EAs (n=6,575) and AAs (n=1,606). Results: The high-risk PRS increased ASCVD risk by 59% (Risk Ratio=1.59;95% Confidence Interval:1.16-2.17) in the highest tertile for AAs and by 15% (RR=1.15;1.13-1.30) and 18% (RR=1.18;1.04-1.35) in the second and highest tertiles compared to the lowest tertile in EAs. Within the highest PRS tertiles, high PA-diet combinations (Dietary Approaches to Stop High Blood Pressure (DASH), or Mediterranean, or Southern) reduced ASCVD risks by 9% (RR=0.91;0.85-0.96) to 15% (RR=0.85;0.80-0.90) in EAs; and by 13% (RR=0.87;0.78-0.97) and 18% (RR=0.82;0.72-0.95) for the DASH and Mediterranean diets, respectively in AAs. Top molecular pathways included fructose metabolism and catabolism linked to obesity, insulin resistance, and type 2 diabetes in both ancestries. Additional molecular pathways for AAs were Vitamin D linked to depression and aging acceleration; and death signaling associated with cancer. Conclusions: Effects of high diet-quality and high PA can counterbalance the influences of genetically high-risk PRSs on ASCVD risk, especially in AAs.

The authors have declared no competing interest.

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This work is supported by a K01 grant from the National Heart, Lung, and Blood Institute (NHLBI) grants: K01 HL127278 awarded to Dale Hardy, PhD. There was no additional external funding received for this study. The NHLBI had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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