Abstract 15086: Associations Between Apolipoprotein A-I Proteoforms and Markers of Cardiometabolic Health

IntroductionApolipoprotein A-I (apoA-I) is a central structural and functional protein of high-density lipoprotein (HDL) particles. ApoA-I undergoes post-translational modification at specific amino acid residues, which creates distinct proteoforms. The spectrum of apoA-I proteoforms in human serum and their associations with HDL-associated phenotypes are unknown.MethodsWe obtained 150 serum samples from well-phenotyped Coronary Artery Risk Development in Young Adults (CARDIA) cohort study participants and measured their HDL efflux. Next, we submitted the serum samples to liquid chromatography-tandem mass spectrometry (LC-MS) for apoA-I proteoform characterization through top-down proteomics (no protein digestion). We then used a label-free top-down-proteomic quantification workflow for relative proteoform quantification across serum samples. We normalized and standardized the proteoform intensities and quantified the associations between proteoform intensity and CARDIA participant characteristics, as shown in the heat map below. No prior bias was imposed to heatmap clustering.ResultsWe identified 14 distinct proteoforms of apoA-I. The relative abundances of apoA-I proteoforms werecanonical (78-84%), oxidized forms (12-15%), glycated (0.9-1.2%), protoapoA-I (0.9-1.2%), truncated (0.8-1.5%), and K88-acylated forms (0.9-1.4%). ApoA-I proteoforms had differential associations with markers of cardiometabolic health. Notably, several K88-acylated apoA-I proteoforms had stronger associations than canonical apoA-I with HDL-C, HDL efflux, BMI, waist circumference, and triglyceride level.ConclusionsApoA-I proteoforms may be the cause or consequence of cardiometabolic health. Our findings suggest that proteoforms of the same gene product associate differently with metabolism. Thus, characterization of apolipoprotein proteoforms may provide novel insights into cardiovascular health and disease.