Multi-Omics characterization of biological pathways linking healthy dietary patterns to cardiometabolic disease risk across diverse populations

Abstract Background and Objectives Recent large-scale studies have consistently linked healthy dietary patterns to improved cardiometabolic health; however, the underlying biological pathways remain largely unclear, especially in non-European populations. In this study, we leverage data from four population-based cohorts (UK Biobank, NEO study, GNHS, and 10K) to investigate both common and cohort-specific biological pathways linking healthy dietary patterns to cardiometabolic disease through multi-omics profiling. Material and methods In each cohort, we first assessed the associations between each of the five major dietary pattern scores (i.e., AMED, hPDI, DII, AHEI, and EDIH) and cardiometabolic disease risk using Cox or logistic regression models. To explore the potential mediating role, metabolomics and proteomics measurements were incorporated into the models. All models were adjusted for relevant confounders, and false discovery rate correction was applied to account for multiple testing. Results With a total of 71,679 individuals without pre-existing cardiometabolic disease across four participating cohorts (UKB: 54,024, NEO: 4,838, GNHS: 3,201, and 10K: 9,616), we confirmed that adherence to healthy dietary patterns was associated with a 5-10% reduced risk of cardiometabolic disease. Three common biological pathways were identified: (1) mediation via large HDL particles and apolipoprotein F; (2) mediation via DNAJ/Hsp40 and triglyceride-rich lipoproteins; and (3) mediation via CRHBP-regulated HPA axis activity affecting triglyceride-rich lipoproteins. Conclusions Our integrative multi-omics analysis across diverse populations identifies novel biomarkers that connect healthy dietary patterns with cardiometabolic risk. These findings deepen our understanding of the biological mechanisms underlying diet-related disease and hold promise for enhancing the development of precision nutrition interventions.