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Front. Immunol. | doi: 10.3389/fimmu.2018.00277

Genome-wide Association Study on IgG Glycosylation Patterns

 Annika Wahl1, 2*, Erik van den Akker3, 4,  Lucija Klaric5, 6, 7, Jerko Štambuk5, Elisa Benedetti8, Rosina Plomp9,  Genadij Razdorov5,  Irena Trbojević-Akmačić5,  Joris Deelen3, 10,  Diana Van Heemst11, P. Eline Slagboom6, Frano Vučković5, Harald Grallert1, 2, 12, Jan Krumsiek8, 12, Konstantin Strauch13, 14, Annette Peters2,  Thomas Meitinger15, Caroline Hayward6, Manfred Wuhrer9,  Marian Beekman3, Gordan Lauc5, 16 and  Christian Gieger1, 2
  • 1Research Unit Molecular Epidemiology, Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt, Germany
  • 2Institute of Epidemiology 2, Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt, Germany
  • 3Department of Molecular Epidemiology, Leiden University Medical Center, Netherlands
  • 4Pattern Recognition & Bioinformatics, Delft University of Technology, Netherlands
  • 5Genos Glycoscience Research Laboratory, Croatia
  • 6Institute of Genetics and Molecular Medicine, University of Edinburgh, United Kingdom
  • 7Centre for Global Health Research Population Health Sciences, Usher Institute of Population Health Sciences and Informatics, School of Molecular, Genetic and Population Health Sciences, University of Edinburgh, United Kingdom
  • 8Institute of Computational Biology, Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt, Germany
  • 9Center for Proteomics & Metabolomics, Leiden University Medical Center, Netherlands
  • 10Max Planck Institute for Biology of Ageing (MPG), Germany
  • 11Department of Internal Medicine, Section Gerontology and Geriatrics, Leiden University Medical Center, Netherlands
  • 12Deutsches Diabetes-Zentrum - Leibniz-Zentrum für Diabetes-Forschung, Germany
  • 13Institute of Genetic Epidemiology, Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt, Germany
  • 14Faculty of Medicine, Ludwig-Maximilians-Universität München, Germany
  • 15Institute of Human Genetics, Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt, Germany
  • 16Faculty of Pharmacy and Biochemistry, University of Zagreb, Croatia

Immunoglobulin G (IgG), a glycoprotein secreted by plasma B-cells, plays a major role in the human adaptive immune response and are associated to a wide range of diseases. Glycosylation of the Fc binding region of IgGs, responsible for the antibody’s effector function, is essential for prompting a proper immune response. This study focuses on the general genetic impact on IgG glycosylation as well as corresponding subclass-specificities. To identify genetic loci involved in IgG glycosylation, we performed a genome-wide association study (GWAS) on liquid chromatography electrospray mass spectrometry (LC-ESI-MS) – measured IgG glycopeptides of 1,823 individuals in the Cooperative Health Research in the Augsburg Region (KORA F4) study cohort. In addition, we performed GWAS on subclass-specific ratios of IgG glycans in order to gain power in identifying genetic factors underlying single enzymatic steps in the glycosylation pathways. We replicated our findings in 1,836 individuals from the Leiden Longevity Study (LLS). We were able to show subclass-specific genetic influences on single IgG glycan structures. The replicated results indicate that, in addition to genes encoding for glycosyltransferases (i.e. ST6GAL1, B4GALT1, FUT8 and MGAT3), other genetic loci have strong influences on the IgG glycosylation patterns. A novel locus on chromosome 1, harboring RUNX3, which encodes for a transcription-factor of the runt domain-containing family, is associated with decreased galactosylation. Interestingly, members of the RUNX family are cross-regulated and RUNX3 is involved in both IgA class switching and B-cell maturation as well as T-cell differentiation and apoptosis.
Besides the involvement of glycosyltransferases in IgG glycosylation, we suggest that, due to the impact of variants within RUNX3, potentially mechanisms involved in B-cell activation and T-cell differentiation during the immune response as well as cell migration and invasion involve IgG glycosylation.

Keywords: GWAS, IgG, Glycosylation, RUNX3, LC-ESI-MS/MS

Received: 15 Nov 2017; Accepted: 31 Jan 2018.

Edited by:

Deborah K. Dunn-Walters, University of Surrey, United Kingdom

Reviewed by:

Bruce D. Mazer, Research Institute of the McGill University Health Center, Canada
Katie J. Doores, King's College London, United Kingdom  

Copyright: © 2018 Wahl, van den Akker, Klaric, Štambuk, Benedetti, Plomp, Razdorov, Trbojević-Akmačić, Deelen, Van Heemst, Slagboom, Vučković, Grallert, Krumsiek, Strauch, Peters, Meitinger, Hayward, Wuhrer, Beekman, Lauc and Gieger. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Mrs. Annika Wahl, Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt, Research Unit Molecular Epidemiology, Munich, Germany,