Glycosylation of immunoglobulin G is regulated by a large network of genes pleiotropic with inflammatory diseases.

Algorithms; Alleles; Computational Biology/methods; Gene Expression Regulation; Genetic Loci; Genome-Wide Association Study; Glycosylation; Humans; Immunoglobulin G/immunology/metabolism; Inflammation/genetics/metabolism; Linkage Disequilibrium; Models, Genetic; Phenotype; Polymorphism, Single Nucleotide; Polysaccharides/metabolism

Abstract :

[en] Effector functions of immunoglobulin G (IgG) are regulated by the composition of a glycan moiety, thus affecting activity of the immune system. Aberrant glycosylation of IgG has been observed in many diseases, but little is understood about the underlying mechanisms. We performed a genome-wide association study of IgG N-glycosylation (N = 8090) and, using a data-driven network approach, suggested how associated loci form a functional network. We confirmed in vitro that knockdown of IKZF1 decreases the expression of fucosyltransferase FUT8, resulting in increased levels of fucosylated glycans, and suggest that RUNX1 and RUNX3, together with SMARCB1, regulate expression of glycosyltransferase MGAT3. We also show that variants affecting the expression of genes involved in the regulation of glycoenzymes colocalize with variants affecting risk for inflammatory diseases. This study provides new evidence that variation in key transcription factors coupled with regulatory variation in glycogenes modifies IgG glycosylation and has influence on inflammatory diseases.

Disciplines :

Gastroenterology & hepatology

Author, co-author :

Klarić, Lucija

Tsepilov, Yakov A.

Stanton, Chloe M.

Mangino, Massimo

Sikka, Timo Tõnis

Esko, Tõnu

Pakhomov, Eugene

Salo, Perttu

Deelen, Joris

McGurnaghan, Stuart J.

More authors (43 more)

Language :

English

Title :

Glycosylation of immunoglobulin G is regulated by a large network of genes pleiotropic with inflammatory diseases.

Publication date :

2020

Journal title :

Science Advances

eISSN :

2375-2548

Publisher :

American Association for the Advancement of Science (AAAS), Washington, United States - District of Columbia

Volume :

Issue :

Pages :

eaax0301

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://advances.sciencemag.org/content/6/8/eaax0301

Commentary :

Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

Available on ORBi :

since 06 February 2021

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