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LOCI ASSOCIATED WITH N-GLYCOSYLATION OF HUMAN IGG SHOW PLEIOTROPY WITH AUTOIMMUNE DISEASES AND HAEMATOLOGICAL CANCERS (CROSBI ID 621037)

Prilog sa skupa u zborniku | sažetak izlaganja sa skupa | međunarodna recenzija

Pučić, Maja ; Lauc, Gordan ; Huffman, Jennifer E ; Zgaga, Lina ; Adamczyk, Barbara ; Mužinić, Ana ; Novokmet, Mislav ; Polašek, Ozren ; Gornik, Olga ; Krištić, Jasminka et al. LOCI ASSOCIATED WITH N-GLYCOSYLATION OF HUMAN IGG SHOW PLEIOTROPY WITH AUTOIMMUNE DISEASES AND HAEMATOLOGICAL CANCERS. 2013

Podaci o odgovornosti

Pučić, Maja ; Lauc, Gordan ; Huffman, Jennifer E ; Zgaga, Lina ; Adamczyk, Barbara ; Mužinić, Ana ; Novokmet, Mislav ; Polašek, Ozren ; Gornik, Olga ; Krištić, Jasminka ; Keser, Toma ; Vitart, Veronique ; Scheijen, B ; Uh, HW ; Molokhia, M ; Patrick, AL ; McKeigue, P ; Kolčić, Ivana ; Lukić, IK ; Swann, O ; van Leeuwen, FN ; Ruhaak, LR ; Houwing-Duistermaat, JJ ; Slagboom, PE ; Beekman, M ; de Craen, AJM ; Deelder, AM ; Zeng, Q ; Wang, W ; Hastie, ND ; Gyllensten, U ; Wilson, JF ; Wuhrer, Manfred ; Wright, AF ; Rudd, Pauline M ; Hayward, Caroline ; Aulchenko, Yurii ; Campbell, Harry ; Rudan, Igor

engleski

LOCI ASSOCIATED WITH N-GLYCOSYLATION OF HUMAN IGG SHOW PLEIOTROPY WITH AUTOIMMUNE DISEASES AND HAEMATOLOGICAL CANCERS

Glycosylation of immunoglobulin G (IgG) influences IgG effector function by modulating binding to Fc receptors. To identify genetic loci associated with IgG glycosylation, we quantitated N-linked IgG glycans using two approaches. After isolating IgG from human plasma, we performed 77 quantitative measurements of N-glycosylation using ultra-performance liquid chromatography (UPLC) in 2, 247 individuals from four European discovery populations. In parallel, we measured IgG N-glycans using MALDI-TOF mass spectrometry (MS) in a replication cohort of 1, 848 Europeans. Meta-analysis of genome-wide association study (GWAS) results identified 9 genome-wide significant loci in the discovery analysis and two of the same loci(B4GALT1 and MGAT3)in the replication cohort. Four loci contained genes encoding glycosyltransferases (ST6GAL1, B4GALT1, FUT8, and MGAT3), while the remaining 5 contained genes that have not been previously implicated in protein glycosylation (IKZF1, IL6ST-ANKRD55, ABCF2-SMARCD3, SUV420H1, and SMARCB1-DERL3). However, most of them have been strongly associated with autoimmune and inflammatory conditions (e.g., systemic lupus erythematosus, rheumatoid arthritis, ulcerative colitis, Crohn’s disease, diabetes type 1, multiple sclerosis, Graves’ disease, celiac disease, nodular sclerosis) and/or haematological cancers (acute lymphoblastic leukaemia, Hodgkin lymphoma, and multiple myeloma). Follow-up functional experiments in haplodeficientIkzf1 knock-out mice showed the same general pattern of changes in IgG glycosylation as identified in the meta-analysis. AsIKZF1 was associated with multiple IgGNglycan traits, we explored biomarker potential of affectedN-glycans in 101 cases with SLE and 183 matched controls and demonstrated substantial discriminative power in a ROC-curveanalysis (area under the curve = 0.842). Our study shows that it is possible to identify new loci that control glycosylation of a single plasma protein using GWAS. The results may also provide an explanation for the reported pleiotropy andantagonistic effects of loci involved in autoimmune diseases and haematological cancer.

IgG; GWAS; glycomics; autoimmune diseases

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Podaci o prilogu

2013.

objavljeno

Podaci o matičnoj publikaciji

Podaci o skupu

7th Glycan Forum Berlin

predavanje

20.03.2013-22.03.2013

Berlin, Njemačka

Povezanost rada

Temeljne medicinske znanosti