Mild ketosis, metabolic syndrome and genetic–lifestyle interactions in the UK Biobank

Abstract The relationship between mild ketosis and metabolic syndrome (MetS) remains unclear. We aimed to investigate the association between serum ketone levels and MetS and to examine how genetic and lifestyle factors influence this relationship. We conducted a cross-sectional observational study using data from the UK Biobank, comprising 269 178 participants. Participants were categorised into low and high serum ketone groups based on β -hydroxybutyrate levels (cut-off: 0·12 mM). Dietary patterns were assessed using validated questionnaires, and a polygenic risk score (PRS) was generated to examine genetic influences on ketone metabolism. Individuals with higher ketone levels showed significantly lower MetS prevalence, with reduced BMI, waist circumference, TAG and glucose levels, alongside higher HDL-cholesterol. These individuals also exhibited distinct dietary patterns, characterised by lower carbohydrate (CHO) and higher fat intake, as well as increased physical activity. The PRS was inversely associated with MetS risk, particularly for abdominal obesity, TAG and HDL-cholesterol components. Notably, PRS modified the relationship between plant-based diet and ketone levels, with stronger positive associations observed in individuals with higher PRS. However, a high CHO diet showed weaker associations with PRS. In conclusion, genetic predisposition influenced ketone metabolism and its protective association with MetS risk. The interaction between genetic predisposition and lifestyle factors has crucial clinical implications for developing personalised dietary and lifestyle interventions. This research provides evidence for individualised approaches to optimise metabolic health through targeted ketone metabolism modulation, which could inform precision medicine strategies for MetS prevention and management.