Genetic Regulation of Immunoglobulin G Glycosylation

Defining the genetic components that control glycosylation of the human immunoglobulin G (IgG) is an ongoing effort, which has so far been addressed by means of heritability, linkage and genome-wide association studies (GWAS). Unlike the synthesis of proteins, N-glycosylation biosynthesis is not a template-driven process, but rather a complex process regulated by both genetic and environmental factors. Current heritability studies have shown that while up to 75% of the variation in levels of some IgG glycan traits can be explained by genetics, some glycan traits are completely defined by environmental influences. Advances in both high-throughput genotyping and glycan quantification methods have enabled genome-wide association studies that are increasingly used to estimate associations of millions of single-nucleotide polymorphisms and glycosylation traits. Using this method, 18 genomic regions have so far been robustly associated with IgG N-glycosylation, discovering associations with genes encoding glycosyltransferases, but also transcription factors, co-factors, membrane transporters and other genes with no apparent role in IgG glycosylation. Further computational analyses have shown that IgG glycosylation is likely to be regulated through the expression of glycosyltransferases, but have also for the first time suggested which transcription factors are involved in the process. Moreover, it was also shown that IgG glycosylation and inflammatory diseases share common underlying causal genetic variants, suggesting that studying genetic regulation of IgG glycosylation helps not only to better understand this complex process but can also contribute to understanding why glycans are changed in disease. However, further studies are needed to unravel whether changes in IgG glycosylation are causing these diseases or the changes in the glycome are caused by the disease.