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; Kari Stefansson

doi:10.1038/s41467-024-52470-8

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 LudvikssonPall 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, Kari Stefansson^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Article number	8054
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-52470-8
Publication status	Published - 14 Sept 2024

Keywords

Adolescent
Adult
Alleles
Asthma/genetics
Autoimmune Diseases/genetics
Child
Chromosomes, Human, Pair 17/genetics
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
HLA Antigens/genetics
Humans
Immunoglobulin G/blood
Immunoglobulin Heavy Chains/genetics
Male
Membrane Proteins
Middle Aged
Polymorphism, Single Nucleotide
Receptors, IgG/genetics
Young Adult

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Olafsdottir, T. A., Thorleifsson, G., Lopez de Lapuente Portilla, A., Jonsson, S., Stefansdottir, L., Niroula, A., Jonasdottir, A., Eggertsson, H. P., Halldorsson, G. H., Thorlacius, G. E., Arnthorsson, A. O., Bjornsdottir, U. S., Asselbergs, F. W., Bentlage, A. E. H., Eyjolfsson, G. I., Gudmundsdottir, S., Gunnarsdottir, K., Halldorsson, B. V., Holm, H., ... Stefansson, K. (2024). Sequence variants influencing the regulation of serum IgG subclass levels. Nature Communications, 15(1), Article 8054. https://doi.org/10.1038/s41467-024-52470-8

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title = "Sequence variants influencing the regulation of serum IgG subclass levels",

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.",

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Olafsdottir, TA, Thorleifsson, G, Lopez de Lapuente Portilla, A, Jonsson, S, Stefansdottir, L, Niroula, A, Jonasdottir, A, Eggertsson, HP, Halldorsson, GH, Thorlacius, GE, Arnthorsson, AO, Bjornsdottir, US, Asselbergs, FW, Bentlage, AEH, Eyjolfsson, GI, Gudmundsdottir, S, Gunnarsdottir, K, Halldorsson, BV, Holm, H, Ludviksson, BR, Melsted, P, Norddahl, GL, Olafsson, I, Saevarsdottir, S, Sigurdardottir, O, Sigurdsson, A, Temming, R, Önundarson, PT, Thorsteinsdottir, U, Vidarsson, G, Sulem, P, Gudbjartsson, DF, Jonsdottir, I, Nilsson, B & Stefansson, K 2024, 'Sequence variants influencing the regulation of serum IgG subclass levels', Nature Communications, vol. 15, no. 1, 8054. https://doi.org/10.1038/s41467-024-52470-8

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T1 - Sequence variants influencing the regulation of serum IgG subclass levels

AU - Olafsdottir, Thorunn A

AU - Thorleifsson, Gudmar

AU - Lopez de Lapuente Portilla, Aitzkoa

AU - Jonsson, Stefan

AU - Stefansdottir, Lilja

AU - Niroula, Abhishek

AU - Jonasdottir, Aslaug

AU - Eggertsson, Hannes P

AU - Halldorsson, Gisli H

AU - Thorlacius, Gudny E

AU - Arnthorsson, Asgeir O

AU - Bjornsdottir, Unnur S

AU - Asselbergs, Folkert W

AU - Bentlage, Arthur E H

AU - Eyjolfsson, Gudmundur I

AU - Gudmundsdottir, Steinunn

AU - Gunnarsdottir, Kristbjorg

AU - Halldorsson, Bjarni V

AU - Holm, Hilma

AU - Ludviksson, Bjorn R

AU - Melsted, Pall

AU - Norddahl, Gudmundur L

AU - Olafsson, Isleifur

AU - Saevarsdottir, Saedis

AU - Sigurdardottir, Olof

AU - Sigurdsson, Asgeir

AU - Temming, Robin

AU - Önundarson, Pall T

AU - Thorsteinsdottir, Unnur

AU - Vidarsson, Gestur

AU - Sulem, Patrick

AU - Gudbjartsson, Daniel F

AU - Jonsdottir, Ingileif

AU - Nilsson, Björn

AU - Stefansson, Kari

N1 - Publisher Copyright: © The Author(s) 2024.

PY - 2024/9/14

Y1 - 2024/9/14

N2 - 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.

AB - 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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KW - Adult

KW - Alleles

KW - Asthma/genetics

KW - Autoimmune Diseases/genetics

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KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - HLA Antigens/genetics

KW - Humans

KW - Immunoglobulin G/blood

KW - Immunoglobulin Heavy Chains/genetics

KW - Male

KW - Membrane Proteins

KW - Middle Aged

KW - Polymorphism, Single Nucleotide

KW - Receptors, IgG/genetics

KW - Young Adult

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DO - 10.1038/s41467-024-52470-8

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SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

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ER -

Sequence variants influencing the regulation of serum IgG subclass levels

Abstract

Keywords

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