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Genetic Regulation of Immunoglobulin G Glycosylation

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Antibody Glycosylation

Part of the book series: Experientia Supplementum ((EXS,volume 112))

Abstract

Defining the genetic components that control glycosylation of the human immunoglobulin G (IgG) is an ongoing effort, which has so far been addressed by means of heritability, linkage and genome-wide association studies (GWAS). Unlike the synthesis of proteins, N-glycosylation biosynthesis is not a template-driven process, but rather a complex process regulated by both genetic and environmental factors. Current heritability studies have shown that while up to 75% of the variation in levels of some IgG glycan traits can be explained by genetics, some glycan traits are completely defined by environmental influences. Advances in both high-throughput genotyping and glycan quantification methods have enabled genome-wide association studies that are increasingly used to estimate associations of millions of single-nucleotide polymorphisms and glycosylation traits. Using this method, 18 genomic regions have so far been robustly associated with IgG N-glycosylation, discovering associations with genes encoding glycosyltransferases, but also transcription factors, co-factors, membrane transporters and other genes with no apparent role in IgG glycosylation. Further computational analyses have shown that IgG glycosylation is likely to be regulated through the expression of glycosyltransferases, but have also for the first time suggested which transcription factors are involved in the process. Moreover, it was also shown that IgG glycosylation and inflammatory diseases share common underlying causal genetic variants, suggesting that studying genetic regulation of IgG glycosylation helps not only to better understand this complex process but can also contribute to understanding why glycans are changed in disease. However, further studies are needed to unravel whether changes in IgG glycosylation are causing these diseases or the changes in the glycome are caused by the disease.

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Abbreviations

CC:

Collaborative Cross

CD4:

Helper T-cells

CD8:

Cytotoxic T-cells

CD14:

Macrophages

CD15:

Neutrophils

CD19:

B-cells

DZ:

Dizygotic

ER:

Endoplasmic reticulum

GWAS:

Genome-wide association study

HDL:

High-density lipoprotein

IgG:

Immunoglobulin G

LD:

Linkage disequilibrium

MZ:

Monozygotic

SNP:

Single nucleotide polymorphism

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Authors and Affiliations

  1. Glycoscience Research Laboratory, Genos Ltd., Zagreb, Croatia

    Azra Frkatovic & Olga O. Zaytseva

  2. MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK

    Lucija Klaric

Authors
  1. Azra Frkatovic
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  2. Olga O. Zaytseva
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  3. Lucija Klaric
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Corresponding author

Correspondence to Lucija Klaric .

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Editors and Affiliations

  1. Glycoscience Research Laboratory, Genos Ltd., Zagreb, Croatia

    Marija Pezer

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Funding

The work of LK was supported by an RCUK Innovation Fellowship from the National Productivity Investment Fund (MR/R026408/1). The work of OOZ was supported by the Croatian National Centre of Research Excellence in Personalized Healthcare grant (#KK.01.1.1.01.0010). The work of AF was supported by European Union’s Horizon 2020 research and innovation programme IMforFUTURE under H2020-MSCA-ITN grant agreement number 721815.

Conflict of Interest

AF and OOZ are the employees of Genos Ltd., which specialises in high-throughput glycoanalysis. LK declares that she has no conflict of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the studies.

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Frkatovic, A., Zaytseva, O.O., Klaric, L. (2021). Genetic Regulation of Immunoglobulin G Glycosylation. In: Pezer, M. (eds) Antibody Glycosylation. Experientia Supplementum, vol 112. Springer, Cham. https://doi.org/10.1007/978-3-030-76912-3_8

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