Sequence variants influencing the regulation of serum IgG subclass levels

Olafsdottir, Thorunn A.; Thorleifsson, Gudmar; de Lapuente Portilla, Aitzkoa Lopez; Jonsson, Stefan; Stefansdottir, Lilja; Niroula, Abhishek; Jonasdottir, Aslaug; Eggertsson, Hannes P.; Halldorsson, Gisli H.; Thorlacius, Gudny E.; Arnthorsson, Asgeir O.; Bjornsdottir, Unnur S.; Asselbergs, Folkert W.; Bentlage, Arthur E. H.; Eyjolfsson, Gudmundur I.; Gudmundsdottir, Steinunn; Gunnarsdottir, Kristbjorg; Halldorsson, Bjarni V.; Holm, Hilma; Ludviksson, Bjorn R.; Melsted, Pall; Norddahl, Gudmundur L.; Olafsson, Isleifur; Saevarsdottir, Saedis; Sigurdardottir, Olof; Sigurdsson, Asgeir; Temming, Robin; Önundarson, Pall T.; Thorsteinsdottir, Unnur; Vidarsson, Gestur; Sulem, Patrick; Gudbjartsson, Daniel F.; Jonsdottir, Ingileif; Nilsson, Björn; Stefansson, Kari

Sequence variants influencing the regulation of serum IgG subclass levels

Thorunn A. Olafsdottir (), Gudmar Thorleifsson, Aitzkoa Lopez de Lapuente Portilla, Stefan Jonsson, Lilja Stefansdottir, Abhishek Niroula, Aslaug Jonasdottir, Hannes P. Eggertsson, Gisli H. Halldorsson, Gudny E. Thorlacius, Asgeir O. Arnthorsson, Unnur S. Bjornsdottir, Folkert W. Asselbergs, Arthur E. H. Bentlage, Gudmundur I. Eyjolfsson, Steinunn Gudmundsdottir, Kristbjorg Gunnarsdottir, Bjarni V. Halldorsson, Hilma Holm, Bjorn R. Ludviksson, Pall Melsted, Gudmundur L. Norddahl, Isleifur Olafsson, Saedis Saevarsdottir, Olof Sigurdardottir, Asgeir Sigurdsson, Robin Temming, Pall T. Önundarson, Unnur Thorsteinsdottir, Gestur Vidarsson, Patrick Sulem, Daniel F. Gudbjartsson, Ingileif Jonsdottir, Björn Nilsson () and Kari Stefansson ()
Additional contact information
Thorunn A. Olafsdottir: deCODE genetics/Amgen Inc.
Gudmar Thorleifsson: deCODE genetics/Amgen Inc.
Aitzkoa Lopez de Lapuente Portilla: Lund University
Stefan Jonsson: deCODE genetics/Amgen Inc.
Lilja Stefansdottir: deCODE genetics/Amgen Inc.
Abhishek Niroula: Lund University
Aslaug Jonasdottir: deCODE genetics/Amgen Inc.
Hannes P. Eggertsson: deCODE genetics/Amgen Inc.
Gisli H. Halldorsson: deCODE genetics/Amgen Inc.
Gudny E. Thorlacius: deCODE genetics/Amgen Inc.
Asgeir O. Arnthorsson: deCODE genetics/Amgen Inc.
Unnur S. Bjornsdottir: The National University Hospital of Iceland
Folkert W. Asselbergs: University College London
Arthur E. H. Bentlage: Sanquin Research
Gudmundur I. Eyjolfsson: The Laboratory in Mjodd
Steinunn Gudmundsdottir: deCODE genetics/Amgen Inc.
Kristbjorg Gunnarsdottir: deCODE genetics/Amgen Inc.
Bjarni V. Halldorsson: deCODE genetics/Amgen Inc.
Hilma Holm: deCODE genetics/Amgen Inc.
Bjorn R. Ludviksson: University of Iceland
Pall Melsted: deCODE genetics/Amgen Inc.
Gudmundur L. Norddahl: deCODE genetics/Amgen Inc.
Isleifur Olafsson: the National University Hospital of Iceland
Saedis Saevarsdottir: deCODE genetics/Amgen Inc.
Olof Sigurdardottir: University of Iceland
Asgeir Sigurdsson: deCODE genetics/Amgen Inc.
Robin Temming: Utrecht University
Pall T. Önundarson: University of Iceland
Unnur Thorsteinsdottir: deCODE genetics/Amgen Inc.
Gestur Vidarsson: Sanquin Research
Patrick Sulem: deCODE genetics/Amgen Inc.
Daniel F. Gudbjartsson: deCODE genetics/Amgen Inc.
Ingileif Jonsdottir: deCODE genetics/Amgen Inc.
Björn Nilsson: Lund University
Kari Stefansson: deCODE genetics/Amgen Inc.

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52470-8

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