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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.

SUBMITTER: Klaric L 

PROVIDER: S-EPMC7030929 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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

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

Science advances 20200219 8


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 (<i>N</i> = 8090) and, using a data-driven network approach, suggested how associated loci form a functional network. We confirmed in vitro that knockdown of <i>IKZ  ...[more]

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