N-glycans as functional effectors of genetic and epigenetic disease risk.

N-glycosylation is a frequent modification of proteins, essential for all domains of life. N-glycan biosynthesis is a dynamic, complex, non-templated process, wherein specific glycoforms are modulated by various microenvironmental cues, cellular signals and local availability of dedicated enzymes and sugar precursors. This intricate regulatory network comprises hundreds of proteins, whose activity is dependent on both sequence of implicated genes and the regulation of their expression. In this regard, variation in N-glycosylation patterns stems from either gene polymorphisms or from stable epigenetic regulation of gene expression in different individuals. Moreover, epigenome alters in response to various environmental factors, representing a direct link between environmental exposure and changes in gene expression, that are subsequently reflected through altered N-glycosylation. N-glycosylation itself has a fundamental role in numerous biological processes, ranging from protein folding, cellular homeostasis, adhesion and immune regulation, to the effector functions in multiple diseases. Moreover, specific modification of the glycan structure can modulate glycoprotein's biological function or direct the faith of the entire cell, as seen on the examples of antibodies and T cells, respectively. Since immunoglobulin G is one of the most profoundly studied glycoproteins in general, the focus of this review will be on its N-glycosylation changes and their functional implications. By deepening the knowledge on the mechanistic roles that certain glycoforms exert in differential pathological processes, valuable insight into molecular perturbations occurring during disease development could be obtained. The prospect of resolving the exact biological pathways involved offers a potential for the development of new therapeutic interventions and molecular tools that would aid in prognosis, early referral and timely treatment of multiple disease conditions.