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

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.; Vuckovic, F.; Ugrina, I.; Kristic, J.; Gudelj, I.; Stambuk, J.; Plomp, R.; Pucic-Bakovic, M.; Pavic, T.; Vilaj, M.; Trbojevic-Akmacic, I.; Drake, C.; Dobrinic, P.; Mlinarec, J.; Jelusic, B.; Richmond, A.; Timofeeva, M.; Grishchenko, A.K.; Dmitrieva, J.; Bermingham, M.L.; Sharapov, S.Z.; Farrington, S.M.; Theodoratou, E.; Uh, H.W.; Beekman, M.; Slagboom, E.P.; Louis, E.; Georges, M.; Wuhrer, M.; Colhoun, H.M.; Dunlop, M.G.; Perola, M.; Fischer, K.; Polasek, O.; Campbell, H.; Rudan, I.; Wilson, J.F.; Zoldos, V.; Vitart, V.; Spector, T.; Aulchenko, Y.S.; Lauc, G.; Hayward, C.

doi:doi:10.1126/sciadv.aax0301

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...Show moreEffector 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.Show less

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