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Research Paper|Volume 15, Issue 24|pp 14509—14552

Mapping of the gene network that regulates glycan clock of ageing

Azra Frkatović-Hodžić1, Anika Mijakovac2, Karlo Miškec2, Arina Nostaeva3, Sodbo Z. Sharapov4, Arianna Landini5, Toomas Haller6, Erik van den Akker7,8, Sapna Sharma9,11, Rafael R. C. Cuadrat10,11, Massimo Mangino12,13, Yong Li14, Toma Keser15, Najda Rudman15, Tamara Štambuk1, Maja Pučić-Baković1, Irena Trbojević-Akmačić1, Ivan Gudelj1,16, Jerko Štambuk1, Tea Pribić1, Barbara Radovani1,16, Petra Tominac1, Krista Fischer6,17, Marian Beekman7, Manfred Wuhrer18, Christian Gieger10,11, Matthias B. Schulze11,19,20, Clemens Wittenbecher19,21,22, Ozren Polasek23,24, Caroline Hayward25, James F. Wilson5,25, Tim D. Spector12, Anna Köttgen14,26, Frano Vučković1, Yurii S. Aulchenko4,27, Aleksandar Vojta2, Jasminka Krištić1, Lucija Klarić25, Vlatka Zoldoš2, Gordan Lauc1,15
  • 1Genos Glycoscience Research Laboratory, Zagreb, Croatia
  • 2Department of Biology, Division of Molecular Biology, Faculty of Science, University of Zagreb, Zagreb, Croatia
  • 3Laboratory of Theoretical and Applied Functional Genomics, Novosibirsk State University, Novosibirsk, Russia
  • 4MSU Institute for Artificial Intelligence, Lomonosov Moscow State University, Moscow, Russia
  • 5Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, UK
  • 6Institute of Genomics, University of Tartu, Tartu, Estonia
  • 7Department of Biomedical Data Sciences, Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
  • 8Department of Pattern Recognition and Bioinformatics, Delft University of Technology, Delft, The Netherlands
  • 9Research Unit Molecular Endocrinology and Metabolism, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
  • 10Research Unit of Molecular Epidemiology, Helmholtz Zentrum München –Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Munich, Germany
  • 11German Center for Diabetes Research (DZD), Neuherberg, Germany
  • 12Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK
  • 13NIHR Biomedical Research Centre at Guy’s and St Thomas’ Foundation Trust, London, UK
  • 14Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
  • 15Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia
  • 16Department of Biotechnology, University of Rijeka, Rijeka, Croatia
  • 17Institute of Mathematics and Statistics, University of Tartu, Tartu, Estonia
  • 18Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
  • 19Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
  • 20Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany
  • 21Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
  • 22SciLifeLab, Division of Food and Nutrition Science, Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden
  • 23University of Split School of Medicine, Split, Croatia
  • 24Algebra University College, Zagreb, Croatia
  • 25MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
  • 26Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
  • 27Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia
* Equal contribution
Received: May 12, 2023Accepted: September 6, 2023Published: December 26, 2023
https://doi.org/10.18632/aging.205106

Copyright: © 2023 Frkatović-Hodžić et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

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.