Branching out: investigating the role of protein glycosylation in the biology and prediction of cardiovascular disease

Glycosylation is the most common post-translational modification to proteins and influences their function and stability. Animal and cellular models indicate that disordered glycosylation of blood proteins impairs the structure and function of cardiac tissue. Population studies have only tested associations between cardiovascular disease and the glycosylation of a small number of proteins. Here, I will employ an ultra-high-throughput mass spectrometry technique to measure, for the first time, serum levels of over 1,000 glycopeptides. Analyses will be performed using 3,000 highly-annotated samples from Generation Scotland. First, I will determine whether these novel glycosylation data enhance the prediction of incident cardiovascular disease over clinical covariates and polygenic risk scores. Second, I will perform genome-wide and epigenome-wide association studies on protein glycosylation to identify genetic and lifestyle factors that alter the glycoproteome. Third, I will apply data from the first two aims to causal modelling approaches. This strategy will enable me to probe causative molecular pathways between the genome, epigenome, glycoproteome and cardiovascular disease risk. I will assess novel relationships between many glycopeptides and cardiovascular diseaseThrough an unparalleled multi-omics resource, this study could refine our ability to predict cardiovascular disease risk and highlight candidate drug targets for follow-up epidemiological and experimental studies.