[en] 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.
Disciplines :
Genetics & genetic processes
Author, co-author :
Frkatović-Hodžić, Azra; Genos Glycoscience Research Laboratory, Zagreb, Croatia
Mijakovac, Anika; Department of Biology, Division of Molecular Biology, Faculty of Science, University of Zagreb, Zagreb, Croatia
Miškec, Karlo; Department of Biology, Division of Molecular Biology, Faculty of Science, University of Zagreb, Zagreb, Croatia
Nostaeva, Arina ; Université de Liège - ULiège > Département de gestion vétérinaire des Ressources Animales (DRA) > Génomique animale ; Laboratory of Theoretical and Applied Functional Genomics, Novosibirsk State University, Novosibirsk, Russia
Sharapov, Sodbo Z; MSU Institute for Artificial Intelligence, Lomonosov Moscow State University, Moscow, Russia
Landini, Arianna; Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, UK
Haller, Toomas; Institute of Genomics, University of Tartu, Tartu, Estonia
Akker, Erik van den; Department of Biomedical Data Sciences, Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands ; Department of Pattern Recognition and Bioinformatics, Delft University of Technology, Delft, The Netherlands
Sharma, Sapna; Research Unit Molecular Endocrinology and Metabolism, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), Neuherberg, Germany ; German Center for Diabetes Research (DZD), Neuherberg, Germany
Cuadrat, Rafael R C; Research Unit of Molecular Epidemiology, Helmholtz Zentrum Mü,nchen –,Deutsches Forschungszentrum fü,r Gesundheit und Umwelt (GmbH), Munich, Germany ; German Center for Diabetes Research (DZD), Neuherberg, Germany
Mangino, Massimo; Department of Twin Research and Genetic Epidemiology, King’,s College London, London, UK ; NIHR Biomedical Research Centre at Guy’,s and St Thomas’, Foundation Trust, London, UK
Li, Yong; Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
Keser, Toma; Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia
Rudman, Najda; Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia
Štambuk, Tamara; Genos Glycoscience Research Laboratory, Zagreb, Croatia
Pučić-Baković, Maja; Genos Glycoscience Research Laboratory, Zagreb, Croatia
Trbojević-Akmačić, Irena; Genos Glycoscience Research Laboratory, Zagreb, Croatia
Gudelj, Ivan; Genos Glycoscience Research Laboratory, Zagreb, Croatia ; Department of Biotechnology, University of Rijeka, Rijeka, Croatia
Štambuk, Jerko; Genos Glycoscience Research Laboratory, Zagreb, Croatia
Pribić, Tea; Genos Glycoscience Research Laboratory, Zagreb, Croatia
Radovani, Barbara; Genos Glycoscience Research Laboratory, Zagreb, Croatia ; Department of Biotechnology, University of Rijeka, Rijeka, Croatia
Tominac, Petra; Genos Glycoscience Research Laboratory, Zagreb, Croatia
Fischer, Krista; Institute of Genomics, University of Tartu, Tartu, Estonia ; Institute of Mathematics and Statistics, University of Tartu, Tartu, Estonia
Beekman, Marian; Department of Biomedical Data Sciences, Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
Wuhrer, Manfred; Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
Gieger, Christian; Research Unit of Molecular Epidemiology, Helmholtz Zentrum Mü,nchen –,Deutsches Forschungszentrum fü,r Gesundheit und Umwelt (GmbH), Munich, Germany ; German Center for Diabetes Research (DZD), Neuherberg, Germany
Schulze, Matthias B; German Center for Diabetes Research (DZD), Neuherberg, Germany ; Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany ; Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany
Wittenbecher, Clemens; Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany ; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA ; SciLifeLab, Division of Food and Nutrition Science, Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden
Polasek, Ozren; University of Split School of Medicine, Split, Croatia ; Algebra University College, Zagreb, Croatia
Hayward, Caroline; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
Wilson, James F; Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, UK ; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
Spector, Tim D; Department of Twin Research and Genetic Epidemiology, King’,s College London, London, UK
Köttgen, Anna; Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany ; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
Vučković, Frano; Genos Glycoscience Research Laboratory, Zagreb, Croatia
Aulchenko, Yurii S; MSU Institute for Artificial Intelligence, Lomonosov Moscow State University, Moscow, Russia ; Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia
Vojta, Aleksandar; Department of Biology, Division of Molecular Biology, Faculty of Science, University of Zagreb, Zagreb, Croatia
Krištić, Jasminka; Genos Glycoscience Research Laboratory, Zagreb, Croatia
Klarić, Lucija; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
Zoldoš, Vlatka; Department of Biology, Division of Molecular Biology, Faculty of Science, University of Zagreb, Zagreb, Croatia
Lauc, Gordan; Genos Glycoscience Research Laboratory, Zagreb, Croatia ; Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia
This work was supported by European Structural and Investment Funds grant for the Croatian National Centre of Competence in Molecular Diagnostics grant KK.01.2.2.03.0006, Croatian National Centre of Research Excellence in Personalized Healthcare grant KK.01.1.1.01.0010, IRI \u201CCardioMetabolic\u201D grant KK.01.2.1.02.0321. The work was co-funded by the European Union (ERC, GlycanSwitch, 101071386). AFH was supported by H2020-MSCA-ITN IMforFUTURE grant 721815. The work of AN was supported by the Ministry of Education and Science of the Russian Federation via the state assignment of the Novosibirsk State University (project \u201CGraduates 2020\u201D). The work of SZS and YSA was partially supported by the Research Program at the MSU Institute for Artificial Intelligence. The work of LK was supported by an RCUK Innovation Fellowship from the National Productivity Investment Fund (MR/R026408/1). The work of YL was supported by the German Research Foundation (grant KO_3598/4-2to AK). The work of AK was supported by the German Research Foundation (grant KO_3598/5-1). RRCC, CW and MBS were supported by German Ministry of Education and Research (BMBF) and the State of Brandenburg DZD grants 82DZD00302 and 82DZD03D03. CW was also supported by SciLifeLab and Wallenberg Data Driven Life Science Program grant KAW 2020.0239. TwinsUK study was funded by Wellcome Trust grant 212904/Z/18/Z, Medical Research Council AIMHY grant MR/M016560/1, European Union H2020 grant 733100. TwinsUK and MM were also supported National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy\u2019s and St Thomas\u2019 NHS Foundation Trust in partnership with King\u2019s College London. Views and opinions expressed are, however, those of the author(s) only and do not necessarily reflect those of the European Union or the European Research Council. Neither the European Union nor the granting authority can be held responsible for them.This work was supported by European Structural and Investment Funds grant for the Croatian National Centre of Competence in Molecular Diagnostics grant KK.01.2.2.03.0006, Croatian National Centre of Research Excellence in Personalized Healthcare grant KK.01.1.1.01.0010, IRI \u201CCardioMetabolic\u201D grant KK.01.2.1.02.0321. The work was co-funded by the European Union (ERC, GlycanSwitch, 101071386). AFH was supported by H2020-MSCA-ITN IMforFUTURE grant 721815. The work of AN was supported by the Ministry of Education and Science of the Russian Federation via the state assignment of the Novosibirsk State University (project \u201CGraduates 2020\u201D). The work of SZS and YSA was partially supported by the Research Program at the MSU Institute for Artificial Intelligence. The work of LK was supported by an RCUK Innovation Fellowship from the National Productivity Investment Fund (MR/R026408/1). The work of YL was supported by the German Research Foundation (grant KO_3598/4-2 to AK). The work of AK was supported by the German Research Foundation (grant KO_3598/5-1). RRCC, CW and MBS were supported by German Ministry of Education and Research (BMBF) and the State of Brandenburg DZD grants 82DZD00302 and 82DZD03D03. CW was also supported by SciLifeLab and Wallenberg Data Driven Life Science Program grant KAW 2020.0239. TwinsUK study was funded by Wellcome Trust grant 212904/Z/18/Z, Medical Research Council AIMHY grant MR/M016560/1, European Union H2020 grant 733100. TwinsUK and MM were also supported National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy\u2019s and St Thomas\u2019 NHS Foundation Trust in partnership with King\u2019s College London. Views and opinions expressed are, however, those of the author(s) only and do not necessarily reflect those of the European Union or the European Research Council. Neither the European Union nor the granting authority can be held responsible for them.
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