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BACKGROUND: Interindividual differences in outcomes of lipid-lowering therapy are well known. Here, we aimed to characterize how alterations in cellular lipid uptake, storage, and utilization pathways may contribute to different treatment outcomes.METHODS: We performed an observational case-control biobank study quantifying leukocyte LDL (low-density lipoprotein) uptake and lipid storage with an automated multiplexed analysis pipeline for 133 statin recipients and 135 control subjects from the FINRISK 2012 study, a Finnish population survey on risk factors on chronic noncommunicable diseases. Individual cellular readouts as well as their combinations, which we called lipid trafficking scores, were then correlated to blood lipid values and health outcomes of the study participants.RESULTS: Of individuals receiving high-intensity statin therapy, those with lower lipid trafficking scores displayed higher circulating concentrations of several proatherogenic lipoproteins and had higher odds for myocardial infarction and stroke when compared with the rest of the subjects with equivalent treatment. Most subjects with a poor lipid trafficking score did not reach low-density lipoprotein cholesterol target levels on statin monotherapy. Combining lipid trafficking score with a polygenic risk score for low-density lipoprotein cholesterol strengthened the association with a proatherogenic lipoprotein profile.CONCLUSIONS: Our results indicate that quantification of cellular lipid trafficking can aid in treatment selection and risk assessment in dyslipidemia.