Genetic predisposition for change of N-glycosylation of plasma proteins in patients with type 1 diabetes

Genetic studies associated certain N- glycosyltransferase loci with type 1 diabetes development. However, individual variation in plasma N-glycosylation has mostly been studied in the context of diabetes complications, and its role in type 1 diabetes onset is mainly unknown. In this study the aim was to explore N-glycome and genome interplay at the onset of type 1 diabetes. Plasma protein and IgG N-glycans were chromatographically analysed in a study population comprising 1917 children and adolescents (0.6-19.1 years) with recent-onset type 1 diabetes from the DanDiabKids registry. In the follow-up study results for 188 of these participants were compared with those for their 244 unaffected siblings. A total of 1105 new-onset type 1 diabetes patients were genotyped at 183, 546 genetic markers, testing these for genetic association with 24 IgG and 39 plasma protein N- glycans. Significant genetic associations were validated in 455 samples. Our study showed that onset of type 1 diabetes was characterised by an increase in plasma and IgG high-mannose and bisecting GlcNAc structures, a decrease in monogalactosylation, and an increase in IgG disialylation. Models including age, gender and N- glycans yielded significant discriminative power between children with type 1 diabetes and their unaffected siblings, with AUCs of 0.915 and 0.869 for inclusion of plasma and IgG N-glycans, respectively. This study identified novel associations that were not previously reported for the general European population: 1) novel genetic associations of IgG glycans were identified for SNPs on chromosome 22 close to candidate gene MGAT3 ; these include core fucosylated digalactosylated disialylated IgG N-glycan with bisecting GlcNAc and its asialylated version ; 2) novel genetic locus was associated with plasma protein N-glycosylation, the complement C3 gene (C3). C3 variants reside on chromosome 19 within the protein coding region, and the associated high-mannose Man9 glycan is attached on a domain involved in pathogen binding of the complement component C3, whereas identified C3 variants are often co-inherited with another type 1 diabetes risk-associated variant. This study identified distinct N-glycosylation of plasma proteins and IgG at type 1 diabetes onset, novel genetic variants driving these changes and potential underlying molecular mechanisms, which are still unknown for many identified type 1 diabetes risk- associated variants.