| Summary: | It is unknown whether the impact of high diet quality and physical activity depends on the level of polygenic risk score (PRS) in different ancestries. Our cross-sectional study utilized de-identified data from 1987–2010 for self-reported European Americans (n = 6575) and African Americans (n = 1606). The high-risk PRS increased ASCVD risk by 59% (Risk Ratio (RR) = 1.59; 95% Confidence Interval:1.16–2.17) in the highest tertile for African Americans 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 European Americans. Within the highest PRS tertiles, high physical activity-diet combinations (Dietary Approaches to Stop High Blood Pressure (DASH), 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 European Americans; and by 13% (RR = 0.87; 0.78–0.97) and 18% (RR = 0.82; 0.72–0.95) for DASH and Mediterranean diets, respectively, in African Americans. Top molecular pathways included fructose metabolism and catabolism linked to obesity, insulin resistance, and type 2 diabetes. Additional molecular pathways for African Americans were Vitamin D linked to depression and aging acceleration and death signaling associated with cancer. Effects of high diet quality and high physical activity can counterbalance the influences of genetically high-risk PRSs on ASCVD risk, especially in African Americans.
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