Proteomics insights: exploring the inflammatory and metabolic signatures of ethnicity and change in physical activity in non-diabetic hyperglycaemia

Background: People of South Asian (SA) origin have an elevated risk of cardiometabolic dysfunction and respond differentially to physical activity. Mechanisms underpinning these observations are incompletely understood. We investigated protein signatures of ethnicity, changing physical activity and their interaction. Methods: A discovery analysis was conducted using data from 794 SA to 49,153 white European (WE) participants in UK Biobank, assessing associations between 726 plasma proteins and physical activity and ethnicity. Findings were validated in a targeted cohort of 58 individuals with non-diabetic hyperglycaemia, taken from a larger randomised controlled trial (PROPELS, n = 1366), stratified by ethnicity and changes in accelerometer assessed physical activity (steps/day) over 48 months. Individuals matched for ethnicity, age and sex that increased and decreased their physical activity over time were sampled, creating four groups (SA increasers [n = 15], SA decreasers [n = 15], WE increasers [n = 14], WE decreasers [n = 14]). Proteins were analysed using Olink inflammation and cardiovascular panels. Findings: In the discovery phase, 464 proteins were associated with physical activity and 375 with ethnicity. In the validation cohort, only interleukin-6 (IL-6) was significantly associated with physical activity, showing downregulation in those who increased activity. Sixteen proteins were validated for ethnicity, including upregulated chemokines (e.g., CCL28, CCL15, CCL13, CCL11, CCL26), hepatokines (FABP1), adipokines (FABP2), and pancreatic proteins (AMY2A, AMY2B), with CXCL14, GHRL and PRTN3 downregulated in SAs. Interpretation: Distinct proteomic profiles were associated with ethnicity and physical activity. IL-6 emerged as a key marker of physical activity response, while ethnicity-related proteins highlighted immune, inflammatory, and metabolic pathways. Funding: NIHR Leicester Biomedical Research Centre.