title: Loci associated with N-glycosylation of human immunoglobulin G show pleiotropy with autoimmune diseases and haematological cancers.
abstract: 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 (P<2.27 × 10(-9)) 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 haplodeficient Ikzf1 knock-out mice showed the same general pattern of changes in IgG glycosylation 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 autoimmune diseases and haematological cancer.
authors: Glycobiology Laboratory, Genos, Zagreb, Croatia.
authors: Gordan
authors: G
authors: Lauc
authors: Jennifer E
authors: JE
authors: Huffman
authors: Maja
authors: M
authors: Pučić
authors: Lina
authors: L
authors: Zgaga
authors: Barbara
authors: B
authors: Adamczyk
authors: Ana
authors: A
authors: Mužinić
authors: Mislav
authors: M
authors: Novokmet
authors: Ozren
authors: O
authors: Polašek
authors: Olga
authors: O
authors: Gornik
authors: Jasminka
authors: J
authors: Krištić
authors: Toma
authors: T
authors: Keser
authors: Veronique
authors: V
authors: Vitart
authors: Blanca
authors: B
authors: Scheijen
authors: Hae-Won
authors: HW
authors: Uh
authors: Mariam
authors: M
authors: Molokhia
authors: Alan Leslie
authors: AL
authors: Patrick
authors: Paul
authors: P
authors: McKeigue
authors: Ivana
authors: I
authors: Kolčić
authors: Ivan Krešimir
authors: IK
authors: Lukić
authors: Olivia
authors: O
authors: Swann
authors: Frank N
authors: FN
authors: van Leeuwen
authors: L Renee
authors: LR
authors: Ruhaak
authors: Jeanine J
authors: JJ
authors: Houwing-Duistermaat
authors: P Eline
authors: PE
authors: Slagboom
authors: Marian
authors: M
authors: Beekman
authors: Anton J M
authors: AJ
authors: de Craen
authors: André M
authors: AM
authors: Deelder
authors: Qiang
authors: Q
authors: Zeng
authors: Wei
authors: W
authors: Wang
authors: Nicholas D
authors: ND
authors: Hastie
authors: Ulf
authors: U
authors: Gyllensten
authors: James F
authors: JF
authors: Wilson
authors: Manfred
authors: M
authors: Wuhrer
authors: Alan F
authors: AF
authors: Wright
authors: Pauline M
authors: PM
authors: Rudd
authors: Caroline
authors: C
authors: Hayward
authors: Yurii
authors: Y
authors: Aulchenko
authors: Harry
authors: H
authors: Campbell
authors: Igor
authors: I
authors: Rudan
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000378:metabolism; D058685:Genetic Pleiotropy; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006031:Glycosylation; D016695:Glycosyltransferases / Q000097:blood / Q000235:genetics*; D019337:Hematologic Neoplasms / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000235:genetics
chemical_list: D007074:Immunoglobulin G; D016695:Glycosyltransferases
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