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

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 assoc...

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Published inScience advances Vol. 6; no. 8; p. eaax0301
Main Authors Klarić, Lucija, Tsepilov, Yakov A, Stanton, Chloe M, Mangino, Massimo, Sikka, Timo Tõnis, Esko, Tõnu, Pakhomov, Eugene, Salo, Perttu, Deelen, Joris, McGurnaghan, Stuart J, Keser, Toma, Vučković, Frano, Ugrina, Ivo, Krištić, Jasminka, Gudelj, Ivan, Štambuk, Jerko, Plomp, Rosina, Pučić-Baković, Maja, Pavić, Tamara, Vilaj, Marija, Trbojević-Akmačić, Irena, Drake, Camilla, Dobrinić, Paula, Mlinarec, Jelena, Jelušić, Barbara, Richmond, Anne, Timofeeva, Maria, Grishchenko, Alexander K, Dmitrieva, Julia, Bermingham, Mairead L, Sharapov, Sodbo Zh, Farrington, Susan M, Theodoratou, Evropi, Uh, Hae-Won, Beekman, Marian, Slagboom, Eline P, Louis, Edouard, Georges, Michel, Wuhrer, Manfred, Colhoun, Helen M, Dunlop, Malcolm G, Perola, Markus, Fischer, Krista, Polasek, Ozren, Campbell, Harry, Rudan, Igor, Wilson, James F, Zoldoš, Vlatka, Vitart, Veronique, Spector, Tim, Aulchenko, Yurii S, Lauc, Gordan, Hayward, Caroline
Format Journal Article Web Resource
LanguageEnglish
Published United States American Association for the Advancement of Science (AAAS) 01.02.2020
American Association for the Advancement of Science
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Summary: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 ( = 8090) and, using a data-driven network approach, suggested how associated loci form a functional network. We confirmed in vitro that knockdown of 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.
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scopus-id:2-s2.0-85080069751
These authors contributed equally to this work.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.aax0301