Abstract

Immunoglobulin G (IgG) is the main isotype of antibody in human blood. IgG consists of four subclasses (IgG1 to IgG4), encoded by separate constant region genes within the Ig heavy chain locus (IGH). Here, we report a genome-wide association study on blood IgG subclass levels. Across 4334 adults and 4571 individuals under 18 years, we discover ten new and identify four known variants at five loci influencing IgG subclass levels. These variants also affect the risk of asthma, autoimmune diseases, and blood traits. Seven variants map to the IGH locus, three to the Fcγ receptor (FCGR) locus, and two to the human leukocyte antigen (HLA) region, affecting the levels of all IgG subclasses. The most significant associations are observed between the G1m (f), G2m(n) and G3m(b*) allotypes, and IgG1, IgG2 and IgG3, respectively. Additionally, we describe selective associations with IgG4 at 16p11.2 (ITGAX) and 17q21.1 (IKZF3, ZPBP2, GSDMB, ORMDL3). Interestingly, the latter coincides with a highly pleiotropic signal where the allele associated with lower IgG4 levels protects against childhood asthma but predisposes to inflammatory bowel disease. Our results provide insight into the regulation of antibody-mediated immunity that can potentially be useful in the development of antibody based therapeutics.

Immunoglobulin G (IgG) is the main isotype of antibody in human blood. Here the authors describe 14 genetic variants that affect IgG levels in blood. The data provide new insight into the regulation of humoral immunity that could be useful in the development of antibody-based therapeutics.

Details

Title
Sequence variants influencing the regulation of serum IgG subclass levels
Author
Olafsdottir, Thorunn A. 1   VIAFID ORCID Logo  ; Thorleifsson, Gudmar 2   VIAFID ORCID Logo  ; Lopez de Lapuente Portilla, Aitzkoa 3 ; Jonsson, Stefan 4 ; Stefansdottir, Lilja 2 ; Niroula, Abhishek 5   VIAFID ORCID Logo  ; Jonasdottir, Aslaug 2 ; Eggertsson, Hannes P. 2   VIAFID ORCID Logo  ; Halldorsson, Gisli H. 6   VIAFID ORCID Logo  ; Thorlacius, Gudny E. 2 ; Arnthorsson, Asgeir O. 2 ; Bjornsdottir, Unnur S. 7 ; Asselbergs, Folkert W. 8   VIAFID ORCID Logo  ; Bentlage, Arthur E. H. 9   VIAFID ORCID Logo  ; Eyjolfsson, Gudmundur I. 10 ; Gudmundsdottir, Steinunn 2   VIAFID ORCID Logo  ; Gunnarsdottir, Kristbjorg 2 ; Halldorsson, Bjarni V. 11   VIAFID ORCID Logo  ; Holm, Hilma 2   VIAFID ORCID Logo  ; Ludviksson, Bjorn R. 12 ; Melsted, Pall 6 ; Norddahl, Gudmundur L. 2 ; Olafsson, Isleifur 13 ; Saevarsdottir, Saedis 1   VIAFID ORCID Logo  ; Sigurdardottir, Olof 14 ; Sigurdsson, Asgeir 2 ; Temming, Robin 15 ; Önundarson, Pall T. 14 ; Thorsteinsdottir, Unnur 1 ; Vidarsson, Gestur 9   VIAFID ORCID Logo  ; Sulem, Patrick 2   VIAFID ORCID Logo  ; Gudbjartsson, Daniel F. 6   VIAFID ORCID Logo  ; Jonsdottir, Ingileif 2   VIAFID ORCID Logo  ; Nilsson, Björn 5   VIAFID ORCID Logo  ; Stefansson, Kari 1   VIAFID ORCID Logo 

1  deCODE genetics/Amgen Inc., Reykjavik, Iceland (GRID:grid.421812.c) (ISNI:0000 0004 0618 6889); University of Iceland, Faculty of Medicine, School of Health Sciences, Reykjavik, Iceland (GRID:grid.14013.37) (ISNI:0000 0004 0640 0021) 
2  deCODE genetics/Amgen Inc., Reykjavik, Iceland (GRID:grid.421812.c) (ISNI:0000 0004 0618 6889) 
3  Lund University, Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund, Sweden (GRID:grid.4514.4) (ISNI:0000 0001 0930 2361); Lund University, Lund Stem Cell Center, Lund, Sweden (GRID:grid.4514.4) (ISNI:0000 0001 0930 2361) 
4  deCODE genetics/Amgen Inc., Reykjavik, Iceland (GRID:grid.421812.c) (ISNI:0000 0004 0618 6889); Sæmundargötu 15-19, Alvotech, Reykjavík, Iceland (GRID:grid.421812.c) 
5  Lund University, Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund, Sweden (GRID:grid.4514.4) (ISNI:0000 0001 0930 2361); Lund University, Lund Stem Cell Center, Lund, Sweden (GRID:grid.4514.4) (ISNI:0000 0001 0930 2361); Broad Institute, Cambridge, USA (GRID:grid.66859.34) (ISNI:0000 0004 0546 1623) 
6  deCODE genetics/Amgen Inc., Reykjavik, Iceland (GRID:grid.421812.c) (ISNI:0000 0004 0618 6889); University of Iceland, School of Engineering and Natural Sciences, Reykjavik, Iceland (GRID:grid.14013.37) (ISNI:0000 0004 0640 0021) 
7  The National University Hospital of Iceland, Department of Respiratory Medicine and Sleep, Landspitali, Reykjavik, Iceland (GRID:grid.410540.4) (ISNI:0000 0000 9894 0842) 
8  University College London, Institute of Health Informatics, London, UK (GRID:grid.83440.3b) (ISNI:0000 0001 2190 1201); University College London, The National Institute for Health Research University College London Hospitals Biomedical Research Centre, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201); University of Amsterdam, Department of Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centre, Amsterdam, The Netherlands (GRID:grid.7177.6) (ISNI:0000000084992262) 
9  Sanquin Research, Immunoglobulin Research laboratory, Amsterdam, The Netherlands (GRID:grid.417732.4) (ISNI:0000 0001 2234 6887); Utrecht University, Department of Biomolecular Mass Spectrometry and Proteomics, Utrecht Institute for Pharmaceutical Sciences and Bijvoet Center for Biomolecular Research, Utrecht, The Netherlands (GRID:grid.5477.1) (ISNI:0000 0000 9637 0671) 
10  The Laboratory in Mjodd, Reykjavik, Iceland (GRID:grid.5477.1) 
11  deCODE genetics/Amgen Inc., Reykjavik, Iceland (GRID:grid.421812.c) (ISNI:0000 0004 0618 6889); Reykjavik University, School of Technology, Reykjavik, Iceland (GRID:grid.9580.4) (ISNI:0000 0004 0643 5232) 
12  University of Iceland, Faculty of Medicine, School of Health Sciences, Reykjavik, Iceland (GRID:grid.14013.37) (ISNI:0000 0004 0640 0021); the National University Hospital of Iceland, Department of Immunology, Landsspitali, Reykjavik, Iceland (GRID:grid.410540.4) (ISNI:0000 0000 9894 0842) 
13  the National University Hospital of Iceland, Department of Clinical Biochemistry, Landsspitali, Reykjavik, Iceland (GRID:grid.410540.4) (ISNI:0000 0000 9894 0842) 
14  University of Iceland, Faculty of Medicine, School of Health Sciences, Reykjavik, Iceland (GRID:grid.14013.37) (ISNI:0000 0004 0640 0021); Akureyri Hospital, Department of Clinical Biochemistry, Akureyri, Iceland (GRID:grid.440311.3) 
15  Utrecht University, Department of Biomolecular Mass Spectrometry and Proteomics, Utrecht Institute for Pharmaceutical Sciences and Bijvoet Center for Biomolecular Research, Utrecht, The Netherlands (GRID:grid.5477.1) (ISNI:0000 0000 9637 0671); The Laboratory in Mjodd, Reykjavik, Iceland (GRID:grid.5477.1) 
Pages
8054
Publication year
2024
Publication date
2024
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-024-52470-8
ProQuest document ID
3104620565
Copyright
© The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.