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

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  • Najda Rudman
  • Simranjeet Kaur
  • Vesna Simunović
  • Domagoj Kifer
  • Dinko Šoić
  • Toma Keser
  • Tamara Štambuk
  • Lucija Klarić
  • Pociot, Flemming
  • Grant Morahan
  • Olga Gornik

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

Udgave nummer6
Sider (fra-til)1071-1083
Antal sider13
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
The authors are grateful for and would like to acknowledge the invaluable contributions of all the participants, research nurses, local investigators, administrative teams and other clinical staff. Some of the data were presented as an abstract and/or oral and poster presentation at the Virtual Congress of Croatian Pharmacy and Medical Biochemistry Students’ Association (CPSA) and Portuguese Pharmacy Students’ Association (APEF) ‘Understanding genetics – the key to a healthier GENEration’ in 2022, at the meeting of PhD candidates organised by the Croatian Science Foundation (PhD Caffe #14 meeting) in 2022, at the Congress of the Croatian Society of Biochemistry and Molecular Biology (HDMBM) HDBMB22: From Science to Knowledge in 2022, at the 55th EASD Annual Meeting in 2019, in Glycoconjugate Journal preceding the GLYCO-25 International Symposium on Glycoconjugates in 2019, at the Infoday of Postgraduate Doctoral Study ‘Pharmaceutical-Biochemical Sciences’ of University of Zagreb, Faculty of Pharmacy and Biochemistry in 2019, and at the 29th Joint Glycobiology meeting in 2018, the 2nd GlycoCom in 2018, the 1st Human Glycome Project Meeting in 2018 and the 28th Joint Glycobiology Meeting in 2017. The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. OG and GM conceived, designed and supervised the study. NR, SK, VS, DK, DŠ, TK, TŠ, LK and FP contributed to the data collection, acquisition or analysis, and interpretation of data. NR, GM and OG wrote the manuscript. All authors reviewed the manuscript and approved the final version of the manuscript. OG and GM are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Funding Information:
Open Access funding enabled and organized by CAUL and its Member Institutions. The study was supported by the Croatian National Science Foundation, grant agreement number UIP-2014-09-7769 (to OG). The DanDiabKids biobank is supported by a grant from the Danish Diabetes Association. GM’s laboratory is supported by the Western Australia Diabetes Research Foundation.

Publisher Copyright:
© 2023, The Author(s).

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