Loci Associated with N-Glycosylation of Human Immunoglobulin G Show Pleiotropy with Autoimmune Diseases and Haematological Cancers
Year: 2013
Type: review
Study design: Observational Study
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.
Source: PLoS Genetics
Authors: Gordan Lauc, Jennifer E. Huffman, Maja Pučić, Lina Zgaga, Barbara Adamczyk, Ana Mužinić, Mislav Novokmet, Ozren Polašek, Olga Gornik, Jasminka Krištić, Toma Keser, Veronique Vitart, Blanca Scheijen, Hae-Won Uh, Mariam Molokhia, Alan Leslie Patrick, Paul McKeigue, Ivana Kolčić, Ivan Krešimir Lukić, Olivia 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 Wang, Nicholas D. Hastie, Ulf Gyllensten, James F. Wilson, Manfred Wuhrer, Alan F. Wright, Pauline M. Rudd, Caroline Hayward, Yurii Aulchenko, Harry Campbell, Igor Rudan
Institutions: University of Zagreb, Genos (Croatia), Institute of Genetics and Cancer, University of Edinburgh, National Institute for Bioprocessing Research and Training, University of Split, Radboud University Medical Center, Leiden University Medical Center, Netherlands Consortium for Healthy Ageing, King's College London, Port of Spain General Hospital, University of California, Davis, Chinese PLA General Hospital, Edith Cowan University, Capital Medical University, Chinese Academy of Sciences, Uppsala University, Science for Life Laboratory, Institute of Cytology and Genetics
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,043
Funders: Wellcome Trust, Scottish Government, National Institute for Health and Care Research, Royal Society, King's College London, European Commission, National Natural Science Foundation of China, Russian Foundation for Basic Research, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Hrvatska Zaklada za Znanost, Stichting Kinderen Kankervrij, Centre for Medical Systems Biology, Medical Research Council
Awards: G1495020029, G1689944598, G2476663878, G3001543491, Tools for the Detection of Novel Glyco-biomarkers, G4486034022, G4571683210, G4786922132, G5649515030, G5702163051, Integrated research on DEvelopmental determinants of Aging and Longevity, Centre for Immunity, Infection and Evolution., G7003971911, Development of carbohydrate array technology to systematically explore the functional role of glycans in healthy and diseased states, Methods for high-throughput (HTP) analysis of protein glycosylation, G8897002470, G970400076
OpenAlex ID: W2154100133