Glycoinformatic Profiling of Label-Free Intact Heparan Sulfate Oligosaccharides

Heparan sulfates (HSs) are a group of heterogenous linear, sulfated polysaccharides that play a role in health and many diseases, including cancer, cardiovascular, and kidney diseases. The structural variety of HS has greatly challenged the development and utility of HS analytics, particularly for native (nondepolymerized) structures, leaving a significant gap in HS technologies for clinical application. Mass spectrometry-based profiling with bioinformatics offers an approach that can retain variety in large datasets. Using healthy human plasmas, we developed a mass spectrometry glycoprofiling approach for native HS oligosaccharides, which retains the structural complexity of each individual HS chain and generates an HS "index" (or Heparan-ome) for each patient. As a proof of concept, analysis of 53 plasma samples ranging from four groups of kidney disease patients revealed a new subset cluster (21%, 4/19) of membranous glomerulopathy patients with distinct HS profiles, highlighting the potential of HS glycoprofiling as a powerful new approach to clinical practice, which warrants future development into quantitative oligosaccharide glycosaminoglycanomics and clinical diagnostics of kidney and other diseases.