engleski

N-glycosylation of plasma proteins is changed in children with early onset type 1 diabetes and regulated by glycosyltransferase and complement C3 genes

Background and aims: Changes in N-glycosylation of plasma proteins have been reported in adult population with type 1 diabetes, as well as was an increase in level of mannose binding lectin that triggers one of the complement activation pathways. However, glycosylation changes have never been studied at the onset of this disease, in children and adolescents. Our study is the first to correlate glycomic and genomic data in recent onset cases in order to identify glycans involved in the aetiology of the disease and their genetic regulation. Materials and methods: Plasma samples from 1, 105 children and adolescents (0-18 years) were collected within three months of diagnosis through the Danish Registry of Childhood and Adolescent Diabetes. Participants were genotyped at 183, 546 single nucleotide polymorphisms (SNPs) on the Immunochip. Both total plasma protein and IgG N-glycans were analyzed using hydrophilic interaction ultra- performance liquid chromatography, and genome wide association study on glycans was performed. Significant associations were further validated by comparing N-glycans released from total plasma proteins and IgG between 187 children with type 1 diabetes and their 244 unaffected siblings. Results: Five genome-wide significant loci associated with total plasma proteins and/or IgG N-glycans were identified. Four loci: MGAT3, MGAT5, ST6GAL1, and SYNGR1 were already associated with N-glycosylation previously. Fifth, complement C3 gene locus (C3), represents the novel finding. SNP within the exon of this gene, causing cyclic to acyclic amino acid change within the C3 protein, is associated with a decrease in oligomannose N- glycan (Man9) levels. Man9 glycan is known to be also attached to the C3 protein in the vicinity of the domain responsible for pathogen binding. When we further compared glycan profiles in children with type 1 diabetes and their healthy siblings, we found that type 1 patients had significantly higher levels of N- glycans associated with MGAT3 and MGAT5 glycosyltransferase loci, as well as levels of plasma N-glycans with terminal mannose (Man5 and Man6) and N-acetylglucosamine (GlcNAc) residues. Conclusion: Our results imply the importance of C3 gene, as well as MGAT3 and MGAT5 genes, in type 1 diabetes development. We suggest that the amino acid change within the C3 protein could increase the accessibility for enzymatic processing of the C3 protein Man9 N-glycan, which, in turn, could significantly decrease Man9 levels and potentially interfere with the complement system activation. We also showed that children with a recent diagnosis of type 1 diabetes, compared to their unaffected siblings, have increased levels of N-glycans that are targets for mannose-binding lectin, suggesting that the complement system could be implicated in type 1 diabetes pathogenesis through the mannose-binding lectin pathway.

N-glycosylation ; type 1 diabetes ; genome-wide association study ; glycosyltransferase ; complement C3 gene

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