BackgroundCarbohydrate and protein dietary proportions have been debated as to whether higher or lower levels are optimal for diabetes metabolic control.ObjectiveThe objective of this study was to investigate the associations, interactions, and mediational relationships between a polygenic risk score (PRS), carbohydrate and protein intake, and physical activity level on type 2 diabetes (T2DM) by genetic ancestry, in European Americans and African Americans. A secondary objective examined the biological pathways associated with the PRS-linked genes and their relationships to dietary intake.MethodsWe performed a cross-sectional study in 9,393 participants: 83.3% European Americans and 16.7% African Americans from 7-NHLBI Care studies obtained from the database of Genotypes and Phenotypes. The main outcome was T2DM. Carbohydrate and protein intake derived from food frequency questionnaires were calculated as percent calories. Data were analyzed using multivariable generalized estimation equation models to derive odds ratios (OR) and 95% confidence intervals (CI). Ancestry-specific PRSs were constructed using joint-effects Summary Best Linear Unbiased Estimation in the train dataset and replicated in the test dataset. Mediation analysis was performed using VanderWeele’s method.ResultsThe PRS in the highest tertile was associated with higher risk of T2DM in European Americans (OR = 1.25;CI = 1.03–1.51) and African Americans (OR = 1.54;1.14–2.09). High carbohydrate and low protein intake had lower risks of T2DM when combined with the PRS after adjusting for covariates. In African Americans, high physical activity combined with the high PRS and high protein diet was associated with a 28% lower incidence of T2DM when compared to low physical activity. In mediational models in African Americans, the PRS-T2DM association was mediated by protein intake in the highest tertile by 55%. The top PRS tertile had the highest magnitude of risks with metabolic factors that were significantly associated with T2DM, especially in European Americans. We found metabolic pathways associated with the PRS-linked genes that were related to insulin/IGF and ketogenesis/ketolysis that can be activated by moderate physical activity and intermittent fasting for better T2DM control.ConclusionsClinicians may want to consider diets with a higher portion of carbohydrates than protein, especially when the burden of high-risk alleles is great in patients with T2DM. In addition, clinicians and other medical professionals may want to emphasize the addition of physical activity as part of treatment regimen especially for African Americans. Given the metabolic pathways we identified, moderate physical activity and intermittent fasting should be explored. Researchers may want to consider longitudinal or randomized clinical trials to determine the predictive ability of different dietary patterns to inhibit T2DM in the presence of obesity and an elevated PRS.