Alterations in glycosylation are common in physiological and pathological processes. Glycan structures are, in the first instance, controlled by genes, however the complex pathways and epigenetic factors that regulate their expression provide a further mechanism for fine tuning and diversifying the glycans and the functions of the proteins to which they are attached.
A robotic platform to release and label glycoproteins in a 96 well plate format has been developed as a front end to glycan separations technologies including HILC and RP HPLC, MS and capillary electrophoresis, chip technologies and on-line combinations of these techniques. Data bases for these technologies are open source and also incorporated into Waters UNIFI software (http://glycobase.nibrt.ie/tools.html).
By combining genome-wide association studies (GWAS) and high-throughput glycomics analysis of 3000 individuals we identified SNPs in genes encoding Hepatocyte Nuclear Factor 1α (HNF1α) and fucosyltransferases FUT6 and FUT8 that modulate the fucosylation of human plasma glycoproteins, including IgG. HNF1α and its downstream target HNF4α are both necessary and sufficient to regulate the expression of key fucosyltransferase and fucose biosynthesis genes in hepatic cells. Interestingly, levels of outer arm fucosylated glycans proved to be an effective marker for Mid-Onset Diabetes of the Young (MODY).
Glycosylation plays an important role in modulating effector functions of antibodies. In a GWAS of IgG isolated from 4,500 people, we identified 5 genes not previously known to be implicated in IgG glycosylation.
Genomics meets glycomics-the first GWAS study of human N-Glycome identifies HNF1α as a master regulator of plasma protein fucosylation. Lauc G, Essafi A, Huffman JE, Rudd PM, Rudan I. et al., PLoS Genet. 2010;6 (12)
Loci associated with N-glycosylation of human immunoglobulin G show pleiotropy with autoimmune diseases and haematological cancers. Lauc G, Huffman JE, Rudd PM, Rudan I. et al., PLoS Genet. 2013 Jan;9(1):e1003225.
