Genetic association study and plasma protein N- glycan profiling in children newly diagnosed with type 1 diabetes and their healthy siblings

Type 1 diabetes (T1D) is an autoimmune disease with an unknown cause.
It is characterised by the destruction of pancreatic insulin producing beta
cells. Glycosylation is a ubiquitous protein modification, but studies of
glycosylation changes in T1D are scarce. We studied plasma samples of
1105 children and adolescents (0-18 years), collected within three months
of T1D diagnosis through the Danish Registry of Childhood and
Adolescent Diabetes. DNA samples were genotyped for 183,546 single
nucleotide polymorphisms on the Immunochip. N-glycans of both total
plasma proteins and IgG were enzymatically released from plasma proteins using PNGase F, fluorescently labelled, and profiled using hydrophilic interaction ultra-performance liquid chromatography with fluorescence detection. Genetic association analyses identified five genomewide significant loci associated with total plasma proteins and/or IgG
N-glycans. All identified loci, except for the complement C3 gene locus
(C3), had been previously associated with N-glycosylation (MGAT3,
MGAT5, ST6GAL1, and SYNGR1). In a further study, N-glycans from
187 children with T1D and their 244 unaffected siblings were compared.
IgG N-glycans with both core fucose and bisecting N-acetylglucosamine
(GlcNAc) were significantly increased in children with T1D relative to
their healthy siblings. The most significant difference within total plasma
proteins between children with T1D in comparison to their healthy siblings was observed for levels of triantennary disialylated N-glycans and
those N-glycans with terminal mannose and GlcNAc residues. Further
research is needed to elucidate the role of observed changes