Integrated glycomics and genetics analyses reveal a potential role for N-glycosylation of plasma proteins and IgGs, as well as the complement system, in the development of type 1 diabetes

• DOI: 10.1007/s00125-023-05881-z
• Publication Date: 2023-03-26T22:13:32Z
• Authors: Najda Rudman; Simranjeet Kaur; Vesna Simunović; Domagoj Kifer; Dinko Šoić; Toma Keser; Tamara Štambuk; Lucija Klarić; Flemming Pociot; Grant Morahan; Olga Gornik
• Keywords: Glycome; Glycomics

Abstract Aims/hypothesis We previously demonstrated that N-glycosylation of plasma proteins and IgGs is different in children with recent-onset type 1 diabetes compared their healthy siblings. To search for genetic variants contributing to these changes, we undertook a association study the protein IgG N-glycome diabetes. Methods A total 1105 patients from Danish Registry Childhood Adolescent Diabetes were genotyped at 183,546 markers, testing variable levels 24 39 N-glycan traits. In follow-up study, significant associations validated 455 samples. Results This confirmed known and/or loci (candidate genes MGAT3 , MGAT5 ST6GAL1 encoding beta-1,4-mannosyl-glycoprotein 4-beta- N -acetylglucosaminyltransferase, alpha-1,6-mannosylglycoprotein 6-beta- -acetylglucosaminyltransferase ST6 beta-galactoside alpha-2,6-sialyltransferase gene, respectively) identified novel not reported general European population. First, IgG-bound glycans found SNPs on chromosome 22 residing two genomic intervals close candidate gene ; include core fucosylated digalactosylated disialylated bisecting -acetylglucosamine (GlcNAc) ( p discovery =7.65 × 10 −12 replication =8.33 −6 top associated SNP rs5757680) glycan GlcNAc =2.88 −10 =3.03 −3 rs137702). The most those . Second, high linkage disequilibrium (missense rs1047286 synonymous rs2230203) located 19 within coding region complement C3 ) showed oligomannose =2.43 −11 =8.66 −4 rs1047286). Conclusions/interpretation driving distinct onset. Our results highlight importance further exploring potential role its influence activation susceptibility. Graphical abstract