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Loci associated with N-glycosylation of human immunoglobulin G show pleiotropy with autoimmune diseases and haematological cancers

Glycosylation of immunoglobulin G (IgG) influences IgG effector fu nction 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-perform ance liquid chromatography (UPLC) in 2, 247 individuals from four European discove ry populations. In parallel, we measured IgG N -glycans using MALDI- TOF mass spectrometry (MS) in a replication cohort of 1, 848 Europeans. Me ta-analysis of genome-wide asso ciation study (GWAS) results identified 9 genome-wide significant loci (P , 2.27 6 10 2 9 ) in the discovery analysis and two of the same loci ( B4GALT1 and MGAT3 )in the replication cohort. Four loci contain ed genes encoding glycosyltransferases ( ST6GAL1 , B4GALT1 , FUT8 , and MGAT3 ), while the remaining 5 contained genes that have not been previously implica ted in protein glycosylation ( IKZF1 , IL6ST- ANKRD55 , ABCF2- SMARCD3 , SUV420H1 , and SMARCB1-DERL3 ). However, most of them have been stro ngly associated with autoimmune and inflammatory conditions (e.g., systemic lupus erythematosus, rheumatoid arthritis, ulcerative colitis, Crohn’s disease, diabetes type 1, multiple sclerosis, Graves’ diseas e, celiac disease, nodular scleros is) and/or haematological cancers (acute lymphoblastic leukaemia, Hodgkin lymphoma, and multiple my eloma). Follow-up functional experiments in haplodeficient Ikzf1 knock-out mice showed the same general pattern of changes in IgG glycosyl ation as identified in the meta-analysis. As IKZF1 was associated with multiple IgG N - glycan traits, we explored biomarker potential of affected N -glycans in 101 cases with SLE and 183 matched controls and demonstrated substantial discriminative power in a ROC-curve analysis (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 and antagonistic effects of loci involved in aut oimmune diseases and haematological cancer

genetic loci ; glycosylation ; human immunoglobulin G ; pleiotropy ; autoimmune diseases ; haematological cancers

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