Glycosylation of immunoglobulin G is regulated by a large network of genes pleiotropic with inflammatory diseases

Lucija Klaric; Yakov A. Tsepilov; Chloe M. Stanton; Massimo Mangino; Timo Tõnis Sikka; Tõnu Esko; Eugene Pakhomov; Perttu Salo; Joris Deelen; Stuart J. McGurnaghan; Toma Keser; Frano Vučković; Ivo Ugrina; Jasminka Krištić; Ivan Gudelj; Jerko Štambuk; Rosina Plomp; Maja Pučić-Baković; Tamara Pavić; Marija Vilaj; Irena Trbojević Akmačić; Camilla Drake; Paula Dobrinić; Maria Timofeeva; Jelena Mlinarec; Barbara Jelušić; Anne  Richmond; Maria Timofeeva; Alexander K. Grishchenko; Julia Dmitrieva; Mairead L. Bermingham; Sodbo Zh Sharapov; Susan Farrington; Evropi Theodoratou; Hae-Won Uh; Marian Beekman; Eline P. Slagboom; Edouard Louis; Michel Georges; Manfred Wuhrer; Helen M. Colhoun; Malcolm G. Dunlop; Markus Perola; Krista Fischer; Ozren Polasek; Harry Campbell; Igor Rudan; James F. Wilson; Vlatka Zoldos; Veronique Vitart; Tim Spector; Yurii S. Aulchenko; Gordan Lauc; Caroline Hayward

doi:10.1126/sciadv.aax0301

Glycosylation of immunoglobulin G is regulated by a large network of genes pleiotropic with inflammatory diseases

Lucija Klaric, Yakov A. Tsepilov, Chloe M. Stanton, Massimo Mangino, Timo Tõnis Sikka, Tõnu Esko, Eugene Pakhomov, Perttu Salo, Joris Deelen, Stuart J. McGurnaghan, Toma Keser, Frano Vučković, Ivo Ugrina, Jasminka Krištić, Ivan Gudelj, Jerko Štambuk, Rosina Plomp, Maja Pučić-Baković, Tamara Pavić, Marija VilajIrena Trbojević Akmačić, Camilla Drake, Paula Dobrinić, Maria Timofeeva, Jelena Mlinarec, Barbara Jelušić, Anne Richmond , Maria Timofeeva, Alexander K. Grishchenko, Julia Dmitrieva, Mairead L. Bermingham, Sodbo Zh Sharapov, Susan Farrington, Evropi Theodoratou, Hae-Won Uh, Marian Beekman, Eline P. Slagboom, Edouard Louis, Michel Georges, Manfred Wuhrer, Helen M. Colhoun, Malcolm G. Dunlop, Markus Perola, Krista Fischer, Ozren Polasek, Harry Campbell, Igor Rudan, James F. Wilson, Vlatka Zoldos, Veronique Vitart, Tim Spector, Yurii S. Aulchenko, Gordan Lauc, Caroline Hayward

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

Abstract

Effector functions of immunoglobulin G (IgG) are regulated by the composition of a glycan moiety, thus affecting activity of the immune system. Aberrant glycosylation of IgG has been observed in many diseases, but little is understood about the underlying mechanisms. We performed a genome-wide association study of IgG N-glycosylation (N = 8090) and, using a data-driven network approach, suggested how associated loci form a functional network. We confirmed in vitro that knockdown of IKZF1 decreases the expression of fucosyltransferase FUT8, resulting in increased levels of fucosylated glycans, and suggest that RUNX1 and RUNX3, together with SMARCB1, regulate expression of glycosyltransferase MGAT3. We also show that variants affecting the expression of genes involved in the regulation of glycoenzymes colocalize with variants affecting risk for inflammatory diseases. This study provides new evidence that variation in key transcription factors coupled with regulatory variation in glycogenes modifies IgG glycosylation and has influence on inflammatory diseases.

Original language	English
Article number	eaax0301
Journal	Science Advances
Volume	6
Issue number	8
DOIs	https://doi.org/10.1126/sciadv.aax0301
Publication status	Published - 19 Feb 2020

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10.1126/sciadv.aax0301

Glycosylation ofimmunoglobulin GFinal published version, 6.71 MB

Determining the causal links and clinical significance of rare genetic variants
Haley, C. (Principal Investigator)
MRC
12/02/18 → 11/02/21
Project: Research
Orkney Complex Disease Study ORCADES Cardiovascular Study
Wilson, J. (Principal Investigator), Campbell, H. (Co-investigator) & Wild, S. (Co-investigator)
UK central government bodies/local authorities, health and hospital authorities
1/04/09 → 31/12/12
Project: Research
Orkney Cardiovascular Disease Study
Wilson, J. (Principal Investigator), Campbell, H. (Co-investigator) & Webb, D. (Co-investigator)
UK central government bodies/local authorities, health and hospital authorities
1/10/04 → 30/09/07
Project: Research

GWAS summary statistics for UPLC IgG N-glycosylation traits
Klaric, L. (Creator), Tsepilov, Y. A. (Creator), Lauc, G. (Creator), Aulchenko, Y. (Creator) & Hayward, C. (Creator), Edinburgh DataShare, 30 Jun 2019
DOI: 10.7488/ds/2481
Dataset

Cite this

Klaric, L., Tsepilov, Y. A., Stanton, C. M., Mangino, M., Sikka, T. T., Esko, T., Pakhomov, E., Salo, P., Deelen, J., McGurnaghan, S. J., Keser, T., Vučković, F., Ugrina, I., Krištić, J., Gudelj, I., Štambuk, J., Plomp, R., Pučić-Baković, M., Pavić, T., ... Hayward, C. (2020). Glycosylation of immunoglobulin G is regulated by a large network of genes pleiotropic with inflammatory diseases. Science Advances, 6(8), Article eaax0301. https://doi.org/10.1126/sciadv.aax0301

@article{60a1d49d406f49a29d23e4425b87f305,

title = "Glycosylation of immunoglobulin G is regulated by a large network of genes pleiotropic with inflammatory diseases",

abstract = "Effector functions of immunoglobulin G (IgG) are regulated by the composition of a glycan moiety, thus affecting activity of the immune system. Aberrant glycosylation of IgG has been observed in many diseases, but little is understood about the underlying mechanisms. We performed a genome-wide association study of IgG N-glycosylation (N = 8090) and, using a data-driven network approach, suggested how associated loci form a functional network. We confirmed in vitro that knockdown of IKZF1 decreases the expression of fucosyltransferase FUT8, resulting in increased levels of fucosylated glycans, and suggest that RUNX1 and RUNX3, together with SMARCB1, regulate expression of glycosyltransferase MGAT3. We also show that variants affecting the expression of genes involved in the regulation of glycoenzymes colocalize with variants affecting risk for inflammatory diseases. This study provides new evidence that variation in key transcription factors coupled with regulatory variation in glycogenes modifies IgG glycosylation and has influence on inflammatory diseases.",

author = "Lucija Klaric and Tsepilov, {Yakov A.} and Stanton, {Chloe M.} and Massimo Mangino and Sikka, {Timo T{\~o}nis} and T{\~o}nu Esko and Eugene Pakhomov and Perttu Salo and Joris Deelen and McGurnaghan, {Stuart J.} and Toma Keser and Frano Vu{\v c}kovi{\'c} and Ivo Ugrina and Jasminka Kri{\v s}ti{\'c} and Ivan Gudelj and Jerko {\v S}tambuk and Rosina Plomp and Maja Pu{\v c}i{\'c}-Bakovi{\'c} and Tamara Pavi{\'c} and Marija Vilaj and {Trbojevi{\'c} Akma{\v c}i{\'c}}, Irena and Camilla Drake and Paula Dobrini{\'c} and Maria Timofeeva and Jelena Mlinarec and Barbara Jelu{\v s}i{\'c} and Anne Richmond and Maria Timofeeva and Grishchenko, {Alexander K.} and Julia Dmitrieva and Bermingham, {Mairead L.} and Sharapov, {Sodbo Zh} and Susan Farrington and Evropi Theodoratou and Hae-Won Uh and Marian Beekman and Slagboom, {Eline P.} and Edouard Louis and Michel Georges and Manfred Wuhrer and Colhoun, {Helen M.} and Dunlop, {Malcolm G.} and Markus Perola and Krista Fischer and Ozren Polasek and Harry Campbell and Igor Rudan and Wilson, {James F.} and Vlatka Zoldos and Veronique Vitart and Tim Spector and Aulchenko, {Yurii S.} and Gordan Lauc and Caroline Hayward",

year = "2020",

month = feb,

day = "19",

doi = "10.1126/sciadv.aax0301",

language = "English",

volume = "6",

journal = "Science Advances",

issn = "2375-2548",

publisher = "American Association for the Advancement of Science",

number = "8",

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Klaric, L, Tsepilov, YA, Stanton, CM, Mangino, M, Sikka, TT, Esko, T, Pakhomov, E, Salo, P, Deelen, J, McGurnaghan, SJ, Keser, T, Vučković, F, Ugrina, I, Krištić, J, Gudelj, I, Štambuk, J, Plomp, R, Pučić-Baković, M, Pavić, T, Vilaj, M, Trbojević Akmačić, I, Drake, C, Dobrinić, P, Timofeeva, M, Mlinarec, J, Jelušić, B, Richmond , A, Timofeeva, M, Grishchenko, AK, Dmitrieva, J, Bermingham, ML, Sharapov, SZ, Farrington, S , Theodoratou, E, Uh, H-W, Beekman, M, Slagboom, EP, Louis, E, Georges, M, Wuhrer, M, Colhoun, HM , Dunlop, MG, Perola, M, Fischer, K, Polasek, O, Campbell, H , Rudan, I , Wilson, JF, Zoldos, V, Vitart, V, Spector, T, Aulchenko, YS, Lauc, G & Hayward, C 2020, 'Glycosylation of immunoglobulin G is regulated by a large network of genes pleiotropic with inflammatory diseases', Science Advances, vol. 6, no. 8, eaax0301. https://doi.org/10.1126/sciadv.aax0301

TY - JOUR

T1 - Glycosylation of immunoglobulin G is regulated by a large network of genes pleiotropic with inflammatory diseases

AU - Klaric, Lucija

AU - Tsepilov, Yakov A.

AU - Stanton, Chloe M.

AU - Mangino, Massimo

AU - Sikka, Timo Tõnis

AU - Esko, Tõnu

AU - Pakhomov, Eugene

AU - Salo, Perttu

AU - Deelen, Joris

AU - McGurnaghan, Stuart J.

AU - Keser, Toma

AU - Vučković, Frano

AU - Ugrina, Ivo

AU - Krištić, Jasminka

AU - Gudelj, Ivan

AU - Štambuk, Jerko

AU - Plomp, Rosina

AU - Pučić-Baković, Maja

AU - Pavić, Tamara

AU - Vilaj, Marija

AU - Trbojević Akmačić, Irena

AU - Drake, Camilla

AU - Dobrinić, Paula

AU - Timofeeva, Maria

AU - Mlinarec, Jelena

AU - Jelušić, Barbara

AU - Richmond , Anne

AU - Timofeeva, Maria

AU - Grishchenko, Alexander K.

AU - Dmitrieva, Julia

AU - Bermingham, Mairead L.

AU - Sharapov, Sodbo Zh

AU - Farrington, Susan

AU - Theodoratou, Evropi

AU - Uh, Hae-Won

AU - Beekman, Marian

AU - Slagboom, Eline P.

AU - Louis, Edouard

AU - Georges, Michel

AU - Wuhrer, Manfred

AU - Colhoun, Helen M.

AU - Dunlop, Malcolm G.

AU - Perola, Markus

AU - Fischer, Krista

AU - Polasek, Ozren

AU - Campbell, Harry

AU - Rudan, Igor

AU - Wilson, James F.

AU - Zoldos, Vlatka

AU - Vitart, Veronique

AU - Spector, Tim

AU - Aulchenko, Yurii S.

AU - Lauc, Gordan

AU - Hayward, Caroline

PY - 2020/2/19

Y1 - 2020/2/19

N2 - Effector functions of immunoglobulin G (IgG) are regulated by the composition of a glycan moiety, thus affecting activity of the immune system. Aberrant glycosylation of IgG has been observed in many diseases, but little is understood about the underlying mechanisms. We performed a genome-wide association study of IgG N-glycosylation (N = 8090) and, using a data-driven network approach, suggested how associated loci form a functional network. We confirmed in vitro that knockdown of IKZF1 decreases the expression of fucosyltransferase FUT8, resulting in increased levels of fucosylated glycans, and suggest that RUNX1 and RUNX3, together with SMARCB1, regulate expression of glycosyltransferase MGAT3. We also show that variants affecting the expression of genes involved in the regulation of glycoenzymes colocalize with variants affecting risk for inflammatory diseases. This study provides new evidence that variation in key transcription factors coupled with regulatory variation in glycogenes modifies IgG glycosylation and has influence on inflammatory diseases.

AB - Effector functions of immunoglobulin G (IgG) are regulated by the composition of a glycan moiety, thus affecting activity of the immune system. Aberrant glycosylation of IgG has been observed in many diseases, but little is understood about the underlying mechanisms. We performed a genome-wide association study of IgG N-glycosylation (N = 8090) and, using a data-driven network approach, suggested how associated loci form a functional network. We confirmed in vitro that knockdown of IKZF1 decreases the expression of fucosyltransferase FUT8, resulting in increased levels of fucosylated glycans, and suggest that RUNX1 and RUNX3, together with SMARCB1, regulate expression of glycosyltransferase MGAT3. We also show that variants affecting the expression of genes involved in the regulation of glycoenzymes colocalize with variants affecting risk for inflammatory diseases. This study provides new evidence that variation in key transcription factors coupled with regulatory variation in glycogenes modifies IgG glycosylation and has influence on inflammatory diseases.

U2 - 10.1126/sciadv.aax0301

DO - 10.1126/sciadv.aax0301

M3 - Article

SN - 2375-2548

VL - 6

JO - Science Advances

JF - Science Advances

IS - 8

M1 - eaax0301

ER -

Glycosylation of immunoglobulin G is regulated by a large network of genes pleiotropic with inflammatory diseases

Abstract

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Projects

Determining the causal links and clinical significance of rare genetic variants

Orkney Complex Disease Study ORCADES Cardiovascular Study

Orkney Cardiovascular Disease Study

Datasets

GWAS summary statistics for UPLC IgG N-glycosylation traits

Cite this