Genome-Wide Association Study on Immunoglobulin G Glycosylation Patterns

Annika Wahl; Erik van den Akker; Lucija Klaric; Jerko Štambuk; Elisa Benedetti; Rosina H Plomp; Genadij Razdorov; Irena Trbojević Akmačić; Joris Deelen; Diana van Heemst; P Eline Slagboom; Frano Vučković; Harald Grallert; Jan Krumsiek; Konstantin Strauch; Annette Peters; Thomas Meitinger; Caroline Hayward; Manfred Wuhrer; Marian Beekman; Gordan Lauc; Christian Gieger

doi:10.3389/fimmu.2018.00277

Genome-Wide Association Study on Immunoglobulin G Glycosylation Patterns

Annika Wahl, Erik van den Akker, Lucija Klaric, Jerko Štambuk, Elisa Benedetti, Rosina H Plomp, Genadij Razdorov, Irena Trbojević Akmačić, Joris Deelen, Diana van Heemst, P Eline Slagboom, Frano Vučković, Harald Grallert, Jan Krumsiek, Konstantin Strauch, Annette Peters, Thomas Meitinger, Caroline Hayward, Manfred Wuhrer, Marian BeekmanGordan Lauc, Christian Gieger

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

Abstract / Description of output

Immunoglobulin G (IgG), a glycoprotein secreted by plasma B-cells, plays a major role in the human adaptive immune response and are associated with 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 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, andMGAT3), other genetic loci have strong influences on the IgG glycosylation patterns. A novel locus on chromosome 1, harboringRUNX3, which encodes for a transcription factor of the runt domain-containing family, is associated with decreased galactosylation. Interestingly, members of theRUNXfamily are cross-regulated, andRUNX3is 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 withinRUNX3, 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.

Original language	English
Pages (from-to)	277
Journal	Frontiers in Immunology
Volume	9
DOIs	https://doi.org/10.3389/fimmu.2018.00277
Publication status	Published - 26 Feb 2018

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Journal Article

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10.3389/fimmu.2018.00277

Genome-Wide Associaiton Study...
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.
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Wahl, A., van den Akker, E., Klaric, L., Štambuk, J., Benedetti, E., Plomp, R. H., Razdorov, G., Trbojević Akmačić, I., Deelen, J., van Heemst, D., Slagboom, P. E., Vučković, F., Grallert, H., Krumsiek, J., Strauch, K., Peters, A., Meitinger, T., Hayward, C., Wuhrer, M., ... Gieger, C. (2018). Genome-Wide Association Study on Immunoglobulin G Glycosylation Patterns. Frontiers in Immunology, 9, 277. https://doi.org/10.3389/fimmu.2018.00277

@article{9768e55964454ac993eee94ecaae1dbd,

title = "Genome-Wide Association Study on Immunoglobulin G Glycosylation Patterns",

abstract = "Immunoglobulin G (IgG), a glycoprotein secreted by plasma B-cells, plays a major role in the human adaptive immune response and are associated with 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 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, andMGAT3), other genetic loci have strong influences on the IgG glycosylation patterns. A novel locus on chromosome 1, harboringRUNX3, which encodes for a transcription factor of the runt domain-containing family, is associated with decreased galactosylation. Interestingly, members of theRUNXfamily are cross-regulated, andRUNX3is 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 withinRUNX3, 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 = "Journal Article",

author = "Annika Wahl and {van den Akker}, Erik and Lucija Klaric and Jerko {\v S}tambuk and Elisa Benedetti and Plomp, {Rosina H} and Genadij Razdorov and {Trbojevi{\'c} Akma{\v c}i{\'c}}, Irena and Joris Deelen and {van Heemst}, Diana and Slagboom, {P Eline} and Frano Vu{\v c}kovi{\'c} and Harald Grallert and Jan Krumsiek and Konstantin Strauch and Annette Peters and Thomas Meitinger and Caroline Hayward and Manfred Wuhrer and Marian Beekman and Gordan Lauc and Christian Gieger",

year = "2018",

month = feb,

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doi = "10.3389/fimmu.2018.00277",

language = "English",

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journal = "Frontiers in Immunology",

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Wahl, A, van den Akker, E, Klaric, L, Štambuk, J, Benedetti, E, Plomp, RH, Razdorov, G, Trbojević Akmačić, I, Deelen, J, van Heemst, D, Slagboom, PE, Vučković, F, Grallert, H, Krumsiek, J, Strauch, K, Peters, A, Meitinger, T, Hayward, C, Wuhrer, M, Beekman, M, Lauc, G & Gieger, C 2018, 'Genome-Wide Association Study on Immunoglobulin G Glycosylation Patterns', Frontiers in Immunology, vol. 9, pp. 277. https://doi.org/10.3389/fimmu.2018.00277

TY - JOUR

T1 - Genome-Wide Association Study on Immunoglobulin G Glycosylation Patterns

AU - Wahl, Annika

AU - van den Akker, Erik

AU - Klaric, Lucija

AU - Štambuk, Jerko

AU - Benedetti, Elisa

AU - Plomp, Rosina H

AU - Razdorov, Genadij

AU - Trbojević Akmačić, Irena

AU - Deelen, Joris

AU - van Heemst, Diana

AU - Slagboom, P Eline

AU - Vučković, Frano

AU - Grallert, Harald

AU - Krumsiek, Jan

AU - Strauch, Konstantin

AU - Peters, Annette

AU - Meitinger, Thomas

AU - Hayward, Caroline

AU - Wuhrer, Manfred

AU - Beekman, Marian

AU - Lauc, Gordan

AU - Gieger, Christian

PY - 2018/2/26

Y1 - 2018/2/26

N2 - Immunoglobulin G (IgG), a glycoprotein secreted by plasma B-cells, plays a major role in the human adaptive immune response and are associated with 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 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, andMGAT3), other genetic loci have strong influences on the IgG glycosylation patterns. A novel locus on chromosome 1, harboringRUNX3, which encodes for a transcription factor of the runt domain-containing family, is associated with decreased galactosylation. Interestingly, members of theRUNXfamily are cross-regulated, andRUNX3is 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 withinRUNX3, 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.

AB - Immunoglobulin G (IgG), a glycoprotein secreted by plasma B-cells, plays a major role in the human adaptive immune response and are associated with 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 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, andMGAT3), other genetic loci have strong influences on the IgG glycosylation patterns. A novel locus on chromosome 1, harboringRUNX3, which encodes for a transcription factor of the runt domain-containing family, is associated with decreased galactosylation. Interestingly, members of theRUNXfamily are cross-regulated, andRUNX3is 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 withinRUNX3, 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.

KW - Journal Article

U2 - 10.3389/fimmu.2018.00277

DO - 10.3389/fimmu.2018.00277

M3 - Article

C2 - 29535710

SN - 1664-3224

VL - 9

SP - 277

JO - Frontiers in Immunology

JF - Frontiers in Immunology

ER -

Genome-Wide Association Study on Immunoglobulin G Glycosylation Patterns

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