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Sequence variants influencing the regulation of serum IgG subclass levels

Olafsdottir, Thorunn A. ; Thorleifsson, Gudmar ; Lopez de Lapuente Portilla, Aitzkoa LU ; Jonsson, Stefan ; Stefansdottir, Lilja ; Niroula, Abhishek LU ; Jonasdottir, Aslaug ; Eggertsson, Hannes P. ; Halldorsson, Gisli H. and Thorlacius, Gudny E. , et al. (2024) In Nature Communications 15(1).
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
15
issue
1
article number
8054
publisher
Nature Publishing Group
external identifiers
  • scopus:85204000395
  • pmid:39277589
ISSN
2041-1723
DOI
10.1038/s41467-024-52470-8
language
English
LU publication?
yes
id
9806d38b-bf78-4339-901e-c00d3367220f
date added to LUP
2024-11-12 15:28:37
date last changed
2025-08-20 15:06:01
@article{9806d38b-bf78-4339-901e-c00d3367220f,
  abstract     = {{<p>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.</p>}},
  author       = {{Olafsdottir, Thorunn A. and Thorleifsson, Gudmar and Lopez de Lapuente Portilla, Aitzkoa and Jonsson, Stefan and Stefansdottir, Lilja and Niroula, Abhishek and Jonasdottir, Aslaug and Eggertsson, Hannes P. and Halldorsson, Gisli H. and Thorlacius, Gudny E. and Arnthorsson, Asgeir O. and Bjornsdottir, Unnur S. and Asselbergs, Folkert W. and Bentlage, Arthur E.H. and Eyjolfsson, Gudmundur I. and Gudmundsdottir, Steinunn and Gunnarsdottir, Kristbjorg and Halldorsson, Bjarni V. and Holm, Hilma and Ludviksson, Bjorn R. and Melsted, Pall and Norddahl, Gudmundur L. and Olafsson, Isleifur and Saevarsdottir, Saedis and Sigurdardottir, Olof and Sigurdsson, Asgeir and Temming, Robin and Önundarson, Pall T. and Thorsteinsdottir, Unnur and Vidarsson, Gestur and Sulem, Patrick and Gudbjartsson, Daniel F. and Jonsdottir, Ingileif and Nilsson, Björn and Stefansson, Kari}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Sequence variants influencing the regulation of serum IgG subclass levels}},
  url          = {{http://dx.doi.org/10.1038/s41467-024-52470-8}},
  doi          = {{10.1038/s41467-024-52470-8}},
  volume       = {{15}},
  year         = {{2024}},
}