Loci Associated with N-Glycosylation of Human Immunoglobulin G Show Pleiotropy with Autoimmune Diseases and Haematological Cancers

摘要: Glycosylation of immunoglobulin G (IgG) influences IgG effector function by modulating binding to Fc receptors. To identify genetic loci associated with glycosylation, we quantitated N-linked glycans using two approaches. After isolating from human plasma, performed 77 quantitative measurements N-glycosylation ultra-performance liquid chromatography (UPLC) in 2,247 individuals four European discovery populations. In parallel, measured N-glycans MALDI-TOF mass spectrometry (MS) a replication cohort 1,848 Europeans. Meta-analysis genome-wide association study (GWAS) results identified 9 significant (P,2.27610 29 ) the analysis and same (B4GALT1 MGAT3 )i n cohort. Four contained genes encoding glycosyltransferases (ST6GAL1, B4GALT1, FUT8 ,a ndMGAT3), while remaining 5 that have not been previously implicated protein glycosylation (IKZF1, IL6ST-ANKRD55, ABCF2SMARCD3, SUV420H1 ndSMARCB1-DERL3). However, most them strongly autoimmune inflammatory conditions (e.g., systemic lupus erythematosus, rheumatoid arthritis, ulcerative colitis, Crohn’s disease, diabetes type 1, multiple sclerosis, Graves’ celiac nodular sclerosis) and/or haematological cancers (acute lymphoblastic leukaemia, Hodgkin lymphoma, myeloma). Follow-up functional experiments haplodeficient Ikzf1 knock-out mice showed general pattern changes as meta-analysis. As IKZF1 was Nglycan traits, explored biomarker potential affected 101 cases SLE 183 matched controls demonstrated substantial discriminative power ROC-curve (area under curve = 0.842). Our shows it is possible new control single plasma GWAS. The may also provide an explanation for reported pleiotropy antagonistic effects involved diseases cancer.