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

Lucija Klarić; 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; Jelena Mlinarec; Barbara Jelušić; Anne Richmond; Maria Timofeeva; Alexander K Grishchenko; Julia Dmitrieva; Mairead L Bermingham; Sodbo Zh Sharapov; Susan M 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 Zoldoš; 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 Klarić, 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, Jelena Mlinarec, Barbara Jelušić, Anne Richmond, Maria Timofeeva, Alexander K Grishchenko, Julia Dmitrieva, Mairead L Bermingham, Sodbo Zh Sharapov, Susan M 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 Zoldoš, Veronique Vitart, Tim Spector, Yurii S Aulchenko, Gordan Lauc, Caroline Hayward

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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
Number of pages	18
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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Klarić, 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{59e690183489476d8915cd7d25f2b285,

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 Klari{\'c} 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 Irena Trbojevi{\'c}-Akma{\v c}i{\'c} and Camilla Drake and Paula Dobrini{\'c} 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 Farrington, {Susan M} 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 Zoldo{\v s} and Veronique Vitart and Tim Spector and Aulchenko, {Yurii S} and Gordan Lauc and Caroline Hayward",

note = "Copyright {\textcopyright} 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).",

year = "2020",

month = feb,

day = "19",

doi = "10.1126/sciadv.aax0301",

language = "English",

volume = "6",

number = "8",

}

Klarić, 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, Mlinarec, J, Jelušić, B, Richmond, A, Timofeeva, M, Grishchenko, AK, Dmitrieva, J, Bermingham, ML, Sharapov, SZ, Farrington, SM, 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, Zoldoš, 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 - Klarić, 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 - 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 M

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 - Zoldoš, Vlatka

AU - Vitart, Veronique

AU - Spector, Tim

AU - Aulchenko, Yurii S

AU - Lauc, Gordan

AU - Hayward, Caroline

N1 - Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

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.

UR - http://www.scopus.com/inward/record.url?scp=85080069751&partnerID=8YFLogxK

U2 - 10.1126/sciadv.aax0301

DO - 10.1126/sciadv.aax0301

M3 - Article

C2 - 32128391

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

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