Analysis of data from the NHANES 1999-2018 and Mendelian randomization studies reveals the relationship between composite dietary antioxidant index and cardiovascular‑kidney‑metabolic syndrome

Background and purpose: Cardiovascular-kidney-metabolic (CKM) syndrome emphasized the key role of abnormal metabolism in the pathological processes of the comorbidity of cardiovascular and renal diseases, which was suggested to be influenced by different dietary intake patterns. The composite dietary antioxidant index (CDAI) was often used to assess the level of dietary antioxidant intakes. However, the exact relationship between CDAI and the risk of CKM is still elusive. The purpose of our study was to provide insight into the association between the CDAI and the CKM syndrome, taking into account multiple covariates that may influence this relationship, based on data from the National Health and Nutrition Examination Survey (NHANES). Methods: Information was extracted from NHANES data involving 24,578 participants recruited between 1999 and 2018. The relationship between CDAI levels and CKM syndrome was assessed using logistic regression models, restricted cubic spline (RCS) analysis, mediation analysis, interaction analysis, and Kaplan-Meier (KM) curves analysis. Subsequently, two-sample Mendelian randomization (MR) was employed to explore the associations of dietary antioxidant levels with CKM syndrome. Results: There were 24,578 participants in the study, 5,964 of whom had advanced CKM syndrome (24.27%). CDAI and advanced CKM syndrome were significantly negatively associated, even after adjusting for a series of potential variables (Tertile 2: OR = 0.81, 95% CI: 0.74–0.89, P < 0.001; Tertile 3: OR = 0.74, 95% CI: 0.67–0.82, P < 0.001). According to RCS regression analysis, advanced CKM syndrome had a nonlinear relationship with CDAI and its other components (p for nonlinear < 0.05), except for selenium (p for nonlinear = 0.178). No significant interaction between CDAI and CKM syndrome was observed in most subgroups, except for age, where the interaction was significant (P < 0.05), indicating that the association may vary with age. Specifically, age modified this association, with the inverse association being weaker in the oldest age group (CDAI × age continuous: OR = 1.13, P < 0.001; CDAI × oldest age group: OR = 1.18, P = 0.017). Mediation analysis showed that the atherogenic index of plasma (AIP) statistically accounted for 8.32% of the observed association between CDAI and advanced CKM syndrome, indicating a potential mediating role. Mendelian randomization analysis showed that the suggestive associations of vitamin A with atrial fibrillation and vitamin E with coronary artery disease are exploratory nominal signals. Conclusion: Our analysis showed that an association did exist between antioxidant diets (based on CDAI) and the risk of CKM syndrome. However, prospective cohort studies or randomized controlled trials are still needed to further validate the antioxidant diet's potential role in CKM prevention.