Association of dietary carbohydrate ratio, caloric restriction, and genetic factors with breast cancer risk in a cohort study

The origin of breast cancer (BC) is widely considered to be a result of multiple factors, including both genetic and dietary influences. Dietary patterns shaped by calorie restriction-defined as reduced energy intake without inducing malnutrition, and varying ratios of the three major nutrients are thought to influence tumorigenesis. However, the complex interplay between caloric restriction, carbohydrate intake ratios, and genetic predisposition in influencing BC risk remains inadequately understood. This study aimed to explore these relationships in greater depth. A prospective cohort study which included 139,829 participants aged 40-72 years was conducted. We evaluated the association between dietary carbohydrate ratio under caloric restriction and the BC risk in a genetic risk group by using Cox proportional hazards regression models. The analysis also included a calculation of polygenic risk score (PRS) based on 304 breast cancer-associated genetic loci. A high dietary carbohydrate ratio pattern under caloric restriction was significantly associated with a 21% reduction in BC risk, respectively (HR_{G4 VS G1} = 0.80, 95% CI 0.66-0.97, P = 0.021), whereas a low PRS (lowest tertile) was associated with 0.84-fold decrease in risk (HR_{low VS high} = 0.84, 95%CI 0.72-0.98, P = 0.032). Compared with other participants, those at intermediate genetic risk with low carbohydrate ratio above caloric restriction showed a higher risk of BC (HR = 1.39, 95% CI 1.01-1.90, P = 0.041). In this cohort study, a diet pattern characterized by a high ratio of carbohydrates under conditions of caloric restriction may attenuate the impact of genetic factors on BC risk in individuals of European ancestry.