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

Результат исследования: Научные публикации в периодических изданияхстатья

2 Цитирования (Scopus)

Аннотация

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.

Язык оригиналаанглийский
Номер статьиeaax0301
Число страниц18
ЖурналScience advances
Том6
Номер выпуска8
DOI
СостояниеОпубликовано - фев 2020

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