Abstract Th0049: Identification of plasma phosphatidylcholines correlated with markers of CVD risk in both a healthy human cohort and a genetically diverse mouse population

Introduction and Hypothesis: Dyslipidemia is a major risk factor for cardiovascular disease (CVD). This study investigated the relationship between plasma phosphatidylcholines (PCs), key components of lipoprotein particle membranes, and markers of CVD risk in humans and genetically diverse mice. Methods: We analyzed plasma PC levels, total cholesterol, and LDL cholesterol in lean and obese human participants (n=333) and in Diversity Outbred mice with transgenes of apolipoprotein E-Leiden (ApoE*3Leiden) and cholesterol ester transfer protein (CETP), (n=472). In humans, arterial stiffness (augmentation index, AI) and endothelial function (reactive hyperemia index, RHI) were assessed using EndoPAT. In mice, aortic sinus lesion area was quantified from oil red O stained sections. Spearman's correlations and quantitative trait loci (QTL) analysis were performed. Results: In the human cohort, 66 PCs were positively correlated with plasma total cholesterol (TC) (ρ =0.12 - 0.63, Benjamini-Hochberg False Discovery Rate (FDR) adj p <0.05), and a subset of 12 of these PCs were positively correlated with AI (ρ =0.12 - 0.25, FDR adj p <0.05) and RHI (ρ =0.12 - 0.19, FDR adj p <0.04). These 12 PCs were also positively correlated with TC in the mouse population (ρ = 0.37 - 0.83, FDR adj p <5.76 x 10 -16 ), 11 of which were also positively correlated with total aortic lesion area (ρ =0.25 - 0.59, FDR adj p <2.04 x 10 -7 ). For the 11 PCs associated with CVD traits in both humans and mice, quantitative trait loci (QTL) analysis identified two PCs with significant QTLs on Chr 4 at 53-54 Mb and three PCs with significant QTLs on Chr 14 at 104.95 Mb. Conclusions: In conclusion, our results identified a subset of PCs positively associated with markers of CVD risk in both a healthy human cohort and a genetically diverse mouse population. This translational study identified circulating PCs associated with CVD risk in both humans and genetically diverse mice, suggesting their potential as biomarkers and therapeutic targets for CVD.