Abstract 385: The Complex Nature of High-Density Lipoprotein Particle Diversity and Population Heterogeneity Necessitates High-Definition Constituent Identification and an Organizational Atlas

Introduction: The degree of lipoprotein complexity was unforeseen just a few years ago. Through advances in mass spectrometry it is now recognized that HDL is comprised of >100 proteins and ~200 lipid species in an undetermined number of combinations. These constituents exist in a distribution disequilibrium with each other and to the particle population as a whole. Concealed in this complex particle composition is extensive particle diversity and population heterogeneity and the source of the broad physiology observed with this lipoprotein subclass. Hypothesis: Science is a systematic enterprise that using mathematics and measurement, creates, builds and organizes knowledge in the form of testable observations, explanations and predictions. The ongoing identification of HDL constituents necessitates an effort to catalogue, categorize, map and relate entities in a structured framework. This will lead to fundamental understanding that advances knowledge and guides HDL biological research, clinical diagnostics and eventual therapeutic strategies. Methods: Literature analysis was used to produce an HDL proteome reference set. Proteome specific analysis of isoforms, proteolytic products, amino acid modifications and cSNPs were used to prepare a proteoform index. Theoretical tryptic peptide maps were generated and compared to the PeptideAtlas database and available published peptide lists from mass spec studies. Results: More than 300 non-immunoglobulin proteins were identified from the high-density lipoprotein fraction in published human sample studies. A consensus-based selection process produced an “unofficial” list of 122 genes. UniProtKB was used to expand an index of possible proteoforms and derive a theoretical peptide mass map. The theoretical and empirical mass map demonstrate both consistency and significant differences. Conclusions: The health benefits of HDL are not in dispute. However, its predictive value is being challenged. The reductionist approach to measuring HDL has proven insufficient and undermines the use of a Precision Medicine model for CAD. Constructing a conceptual framework to unify constituent data is an initial step to resolving the relational context that exists and its functional consequences.