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.

CRISPR/dCas9

glycan clock

glycosylation

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

Tartu Ülikooli Genoomika Instituut

Erik van den Akker

Leiden University

Delft University of Technology

Sapna Sharma

Helmholtz

Deutsches Zentrum für Diabetesforschung

Rafael R.C. Cuadrat

Helmholtz

Deutsches Zentrum für Diabetesforschung

Massimo Mangino

King's College London

Guy's and St Thomas' NHS Foundation Trust

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

Genos Ltd

Department of Biotechnology, University of Rijeka

Jerko Štambuk

Genos Ltd

Tea Pribić

Genos Ltd

Barbara Radovani

Genos Ltd

Department of Biotechnology, University of Rijeka

Petra Tominac

Genos Ltd

Krista Fischer

Tartu Ülikooli Genoomika Instituut

Tartu Ülikooli matemaatika ja statistika instituut

Marian Beekman

Leiden University

Manfred Wuhrer

Leiden University

Christian Gieger

Helmholtz

Deutsches Zentrum für Diabetesforschung

Matthias B. Schulze

Deutsches Zentrum für Diabetesforschung

German Institute of Human Nutrition

University of Potsdam

Clemens Wittenbecher

German Institute of Human Nutrition

Harvard School of Public Health

Chalmers, Life Sciences, Food and Nutrition Science

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

Universitats Klinikum Freiburg und Medizinische Fakultat

Johns Hopkins University

Frano Vučković

Genos Ltd

Yurii S. Aulchenko

Russian Academy of Sciences

Moscow State University

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 14509-14552

Subject Categories

Medical Genetics

DOI

10.18632/aging.205106

PubMed

38149987

More information

Latest update

1/19/2024