Mapping of the gene network that regulates glycan clock of ageing
Journal article, 2023
Glycans are an essential structural component of immunoglobulin G (IgG) that modulate its structure and function. However, regulatory mechanisms behind this complex posttranslational modification are not well known. Previous genome-wide association studies (GWAS) identified 29 genomic regions involved in regulation of IgG glycosylation, but only a few were functionally validated. One of the key functional features of IgG glycosylation is the addition of galactose (galactosylation), a trait which was shown to be associated with ageing. We performed GWAS of IgG galactosylation (N=13,705) and identified 16 significantly associated loci, indicating that IgG galactosylation is regulated by a complex network of genes that extends beyond the galactosyltransferase enzyme that adds galactose to IgG glycans. Gene prioritization identified 37 candidate genes. Using a recently developed CRISPR/dCas9 system we manipulated gene expression of candidate genes in the in vitro IgG expression system. Upregulation of three genes, EEF1A1, MANBA and TNFRSF13B, changed the IgG glycome composition, which confirmed that these three genes are involved in IgG galactosylation in this in vitro expression system.
glycan clock
glycosylation
CRISPR/dCas9
genome-wide association study
immunoglobulin G
Author
Azra Frkatović-Hodžić
Genos Ltd
Anika Mijakovac
University of Zagreb
Karlo Miškec
University of Zagreb
Arina Nostaeva
Novosibirsk State University
Sodbo Z. Sharapov
Moscow State University
Arianna Landini
Edinburgh Medical School
Toomas Haller
University of Tartu
Erik van den Akker
Delft University of Technology
Leiden University
Sapna Sharma
Helmholtz Association of German Research Centres
Deutsches Zentrum für Diabetesforschung
Rafael R.C. Cuadrat
Helmholtz Association of German Research Centres
Deutsches Zentrum für Diabetesforschung
Massimo Mangino
NHS Foundation Trust
King's College London
Yong Li
Universitats Klinikum Freiburg und Medizinische Fakultat
Toma Keser
Sveučilište u Zagrebu, Farmaceutsko Biokemijski Fakultet
Najda Rudman
Sveučilište u Zagrebu, Farmaceutsko Biokemijski Fakultet
Tamara Stambuk
Genos Ltd
Maja Pučić-Baković
Genos Ltd
Irena Trbojević-Akmačić
Genos Ltd
Ivan Gudelj
University of Rijeka
Genos Ltd
Jerko Štambuk
Genos Ltd
Tea Pribić
Genos Ltd
Barbara Radovani
University of Rijeka
Genos Ltd
Petra Tominac
Genos Ltd
Krista Fischer
University of Tartu
Marian Beekman
Leiden University
Manfred Wuhrer
Leiden University
Christian Gieger
Helmholtz Association of German Research Centres
Deutsches Zentrum für Diabetesforschung
Matthias B. Schulze
Deutsches Zentrum für Diabetesforschung
University of Potsdam
German Institute of Human Nutrition
Clemens Wittenbecher
Chalmers, Life Sciences, Food and Nutrition Science
Harvard School of Public Health
German Institute of Human Nutrition
Ozren Polasek
School of Medicine, University of Split
Algebra University College
Caroline Hayward
Edinburgh Medical School, Medical Research Council Human Genetics Unit
James F. Wilson
Edinburgh Medical School
Edinburgh Medical School, Medical Research Council Human Genetics Unit
Tim D. Spector
King's College London
Anna Köttgen
Johns Hopkins University
Universitats Klinikum Freiburg und Medizinische Fakultat
Frano Vučković
Genos Ltd
Yurii S. Aulchenko
Moscow State University
Russian Academy of Sciences
Aleksandar Vojta
University of Zagreb
Jasminka Krištić
Genos Ltd
Lucija Klarić
Edinburgh Medical School, Medical Research Council Human Genetics Unit
Vlatka Zoldoš
University of Zagreb
Gordan Lauc
Sveučilište u Zagrebu, Farmaceutsko Biokemijski Fakultet
Genos Ltd
Aging
19454589 (eISSN)
Vol. 15 24 14509-14552Subject Categories (SSIF 2011)
Medical Genetics
DOI
10.18632/aging.205106
PubMed
38149987