Candidate Proteins Linking Plant-Based Diet Quality to Cancer, Type 2 Diabetes, and Cardiovascular Disease: Integrating Evidence from Proteomic Analysis and Mendelian Randomization in the EPIC Study

Plant-based diets may benefit planetary and human health. However, the molecular pathways linking plant-based diet quality to chronic diseases remain unclear. In 4,372 participants from the European Prospective Investigation into Cancer and Nutrition, we assessed 7,285 SomaScan-measured aptamers to identify circulating proteins associated with healthful (hPDI) and unhealthful (uPDI) plant-based dietary patterns using complementary statistical and machine-learning approaches. We then applied cis-pQTL Mendelian randomization (MR) and colocalization to prioritize diet-associated proteins with genetic evidence for associations with overall and site-specific cancers, type 2 diabetes (T2D), and cardiovascular disease (CVD). Among diet-associated proteins with MR evidence, 8 hPDI- and 12 uPDI-related protein-disease associations showed strong colocalization, including EGFR-breast cancer, MMP10-endometrial cancer, NCAN-T2D, and PCSK6-CVD. These findings identify candidate proteins that may link plant-based diet quality to chronic diseases and provide biologicalinsights into the potential health benefits of healthful plant-based diets, which are increasingly relevant to public and planetary health.