Linking cellular lipid trafficking profiles of individuals to the outcomes of statin treatment in the general population

Abstract Aims The outcomes of lipid-lowering therapy (LLT) vary between individuals. Previously we showed that for FH patients cellular lipid trafficking profiles are associated with on-treatment LDL-c levels. Here, we investigated how cellular profiles link with LDL-c levels, lipoprotein profiles, polygenic risk scores, and cardiovascular outcomes in the general population. Methods We used peripheral blood mononuclear cells (PBMCs) collected for the Finnish population-based FINRISK 2012 Study and managed by THL Biobank. We obtained samples for 400 subjects, including 200 recipients of LLT with avaliable genetic, drug reimbursement, NMR metabolomic and longitudinal CVD outcome data. Using a multiplexed high-content imaging platform we aquired over 26 readouts for lipid uptake and storage in leukocytes for each sample. Results Cellular LDL uptake and storage were highly variable in our population-based study sample, and, in patients receiving either medium- or high-intensity statin monotherapy, were negatively correlated with serum LDL-cholesterol. We combined LDL uptake in lipid-rich (-R) and lipid-poor (-P) conditions with lipid storage readouts into cellular lipid trafficking scores LT-R, LT-P and LT. Combination score LT had improved correlation with serum LDL (rs=-0.45, n=39, p=0.004). Combination of LT with LDL-PRS further increased this correlation (rs=-0.54, n=39, p0.001). Furthermore, low LT scores associated with pro-atherogenic lipoprotein profile with increase in small VLDL, IDL and LDL species and altered lipid content of these particles. Subjects in the lowest quintile of the LT-R were at lower odds to be at their target LDL level (OR=0.07, CI 0.007 - 0.63, p=0.01) compared to the rest of the group. Subjects in the lowest quintile of the LT-R score were at higher odds to exprience MI or stroke (OR=30, CI 2.64 – 339.75, p=0.004) in the 8-year follow-up period as compared to the rest of the group. Conclusions Different cellular readouts and their combinations provide novel insight into interindividual variation of LLT outcomes, providing new opportunities for treatment optimization and risk assessment for CVD prevention.