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

作者：Gordan Lauc, Jennifer E. Huffman, Maja Pučić‐Baković, Lina Zgaga, B Adamczyk, Ana Mužinić, Mislav Novokmet, Ozren Polašek, Olga Gornik, Jasminka Krištić, Toma Keser, Véronique Vitart, Blanca Scheijen, Hae‐Won Uh, Mariam Molokhia, Alan Leslie Patrick, Paul McKeigue, Ivana Kolčić, Ivan Krešimir Lukić, Olivia V. Swann, Frank N. van Leeuwen, L. Renee Ruhaak, Jeanine J. Houwing‐Duistermaat, P. Eline Slagboom, Marian Beekman, Anton J.M. de Craen, André M. Deelder, Qiang Zeng, Wei Qiang Wang, Nicholas Dixon Hastie, Ulf B Gyllensten, James Fox Wilson, Manfred Wuhrer, Alan F. Wright, Pauline Mary Rudd, Caroline Hayward, Yurii S. Aulchenko, Harry Campbell, Igor Rudan · 发表于：PLoS Genetics · 年份：2013 · DOI：10.1371/journal.pgen.1003225 · 被引用次数：379 · 研究领域：Monoclonal and Polyclonal Antibodies Research、Glycosylation and Glycoproteins Research、Galectins and Cancer Biology

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-...