7. Project Summary/Abstract Glycans are sugars attached to proteins in the enzymatic process of post-translational glycosylation. This post-translational modification of proteins enhances their functional heterogeneity and is important for many biological processes. Glycans play specific regulatory roles in modulating inflammation, the innate immune system, and other key physiological and pathological processes that are known to promote atherosclerosis. Most proteins are glycosylated, including inflammatory proteins and immunoglobulin G, the most abundant immunoglobulin in circulation. These and other circulating glycosylated proteins form the plasma glycome. Yet functional understanding of the role of glycosylation in ASCVD development and therapeutics has only recently emerged. Glycomics and glycosciences have lagged behind proteomics and other “omics”, in particular for cardiovascular applications where there is a deficiency in understanding the integral role that glycans play in atherosclerosis. However, recent advances in high-throughput glycomics technologies now allow the accurate identification and quantification of distinct glycans on circulating proteins in human plasma. In this competing R01 renewal, we propose to leverage the study design set up in the first funding period, using two nested case-control studies with deeply phenotyped vascular, lipid, and inflammatory biomarkers, to comprehensively evaluate the total plasma and immunoglobulin G glycomes in relation to ASCVD risk. The goal of this study is to advance our understanding of the human glycome by identifying glycosylation patterns related positively or inversely to incident ASCVD and risk factors, in particular inflammatory and vascular risk factors. Furthermore, new cardiovascular therapies targeting protein glycosylation or inflammation will be added on top of statin therapy, yet studies evaluating the impact of statins on protein glycosylation are scarce. To elucidate these important questions, we will conduct two prospective case- control studies (1,050 matched case-control pairs) leveraging the availability in both studies of baseline and year 1 blood samples for repeat measurements of glycans and vascular risk factors. The proposed study will evaluate a comprehensive panel of pro- and anti-inflammatory glycans isolated from both total plasma proteins and immunoglobulin G, examined in relation to vascular biomarkers, risk factors, and clinical events, as well as assess how statins modulate the balance of glycans. The proposed study will be accomplished in a cost- effective and efficient design because of the availability of the extensive phenotypic data from the award’s first cycle. This comprehensive approach utilizing recent advances in glycomics technologies to elucidate specific pro-and anti-inflammatory glycans has the potential to advance the field and develop innovative glycan-based targeted biomarkers or potential therapeutic approaches in line with precision ca...