The Impact of Ethnicity on Lipoproteins in Coronary Artery Disease

Coronary artery disease (CAD) is a leading cause of mortality in the UK, with individuals of South Asian origin at intensified risk, owing to a higher prevalence of diabetes, culminating in an atherogenic phenotype. The epidemiological evidence supporting a protective role for high density lipoprotein-cholesterol in CAD, has failed to be realised in the ILLUMINATE/AIM-high trials. The paradigm has shifted towards an appreciation of the quality of the lipoprotein particles, rather than arbitrary levels. Lipoproteins contain unique protein cargoes, mediating roles in coagulation, redox and inflammation. The objective of this study was to explore differences in the low abundant protein cargo of lipoproteins between South Asian and Caucasian patients with CAD, to further understand the differential risk. A novel lipoaffinity resin was explored and optimised for efficient and reliable lipoprotein pull-down from plasma. Samples were analysed using a label-free bottom-up proteomic approach on an ion-mobility enabled mass spectrometer. Statins remain the cornerstone for prevention of CAD. In a sub-study, statin therapy was associated with the modulation of proteins concerned with the cytoskeletal architecture, cell proliferation and inflammation, in patients with hypercholesterolemia. The controversial link between statin use and new onset diabetes may be explained a depletion of adipsin, a potent insulin secretagogue. In a further sub-study, lipoproteins of CAD patients were enriched with pro-inflammatory mediators compared with age and sex matched controls. A model comprising of 7 proteins accurately predicted CAD status. In the discovery study, lipoproteins of South Asians were enriched with pro-thrombotic and pro-inflammatory mediators, compared with sex-matched Caucasians with stable CAD. Plasma carboxypeptidase B2 was significantly higher in South Asians compared to Caucasians with CAD in verification studies, contributing to impaired fibrinolysis and potentially to their excess risk. The lipoproteomic cargo undergoes subtle changes in CAD, with various dysregulated proteins independently influenced by ethnicity.