A site-specific map of the human plasma glycome and its age and gender-associated alterations

Abstract

Alterations in the human glycome have been associated with cancer and autoimmunity. Thus, constructing a site-specific map of the human glycome for biomarker research and discovery has been a highly sought-after objective. However, due to analytical barriers, comprehensive site-specific glycoprofiling is difficult to perform. To develop a platform to detect easily quantifiable, site-specific, disease-associated glycan alterations for clinical applications, we have adapted the multiple reaction monitoring mass spectrometry method for use in glycan biomarker research. The adaptations allow for highly precise site-specific glycan monitoring with minimum sample prep. Using this technique, we successfully mapped out the relative abundances of the most common 159 glycopeptides in the plasma of 97 healthy volunteers. This plasma glycome map revealed 796 significant (FDR < 0.05) site-specific inter-protein and intra-protein glycan associations, of which the vast majority were previously unknown. Since age and gender are relevant covariants in biomarker research, these variables were also characterized. 13 glycopeptides were found to be associated with gender and 41 to be associated with age. Using just five age-associated glycopeptides, a highly accurate age prediction model was constructed and validated (r2 = 0.62 ± 0.12). The human plasma site-specific glycan map described herein has utility in applications ranging from glycan biomarker research and discovery to the development of novel glycan-altering interventions.

Diet affects glycosylation of serum proteins in women at risk for cardiometabolic disease

“…It is also a potent anti-inflammatory agent [ 55 ]. Aging is generally associated with more pro-inflammatory glycans that are less sialylated [ 56 ], and the DGA intervention increasing sialylation of A2MG can be indicative of reduced inflammation.…”

“…A2MG is an inhibitor of proteinase activity, it inhibits fibrinolysis by inhibiting kallikrein and plasmin, and inhibits coagulation by inhibiting thrombin [54]. It is also a potent anti-inflammatory agent [55]. Aging is generally associated with more pro-inflammatory glycans that are less sialylated [56], and the DGA intervention increasing sialylation of A2MG can be indicative of reduced inflammation.…”

Glycoprotein Pathways Altered in Frontotemporal Dementia With Autoimmune Disease

“…The majority of glycoproteins are localized to the cell surface and are involved in cell adhesion, signal transduction, and structural maintenance of cells and tissues (42). Glycosylation can be influenced by multiple factors including the type of cell, its activation state, environmental factors, age of the cell and inflammatory mediators such as cytokines (43). Each of these factors can be altered in the setting of disease, therefore glycoprotein expression or in general the 'glycome' could represent the overall health status of an individual (38,44).…”

“…Glycosylation can be influenced by multiple factors including the type of cell, its activation state, environmental factors, age of the cell and inflammatory mediators such as cytokines ( 43 ). Each of these factors can be altered in the setting of disease, therefore glycoprotein expression or in general the ‘glycome’ could represent the overall health status of an individual ( 38 , 44 ). Indeed, alterations in the human glycome have been associated with cancer and various autoimmune diseases ( 37 , 38 ).…”

Glycomic profiling and the mammalian brain

“…Glycans are metabolically synthesized to yield a host of structures that vary heterogeneously by linkage, length, degree of branching (number of antennae), and composition. The glycome differs with gender (2); however, for individuals they remain generally constant over time (3) but are altered with increasing age (1,2,4,5) and changes in health status (6). They are therefore strong indicators of phenotypes and are arguably closer to the disease states.…”