Glycosylation is a common post-translational modification of proteins. Glycosylation is associated with a number of human diseases. Defining genetic factors altering glycosylation may provide a basis for novel approaches to diagnostic and pharmaceutical applications. Here we report a genome-wide association study of the human blood plasma N-glycome composition in up to 3811 people measured by Ultra Performance Liquid Chromatography (UPLC) technology. Starting with the 36 original traits measured by UPLC, we computed an additional 77 derived traits leading to a total of 113 glycan traits. We studied associations between these traits and genetic polymorphisms located on human autosomes. We discovered and replicated 12 loci. This allowed us to demonstrate an overlap in genetic control between total plasma protein and IgG glycosylation. The majority of revealed loci contained genes that encode enzymes directly involved in glycosylation (FUT3/FUT6, FUT8, B3GAT1, ST6GAL1, B4GALT1, ST3GAL4, MGAT3 and MGAT5) and a known regulator of plasma protein fucosylation (HNF1A). However, we also found loci that could possibly ref lect other more complex aspects of glycosylation process. Functional genomic annotation suggested the role of several genes including DERL3, CHCHD10, TMEM121, IGH and IKZF1. The hypotheses we generated may serve as a starting point for further functional studies in this research area.
Immunoglobulin (Ig) glycosylation is recognized for its influence on Ig turnover and effector functions. However, the large-scale profiling of Ig glycosylation in a biomedical setting is challenged by the existence of different Ig isotypes and subclasses, their varying serum concentrations, and the presence of multiple glycosylation sites per Ig. Here, a high-throughput nanoliquid chromatography (LC)-mass spectrometry (MS)-based method for simultaneous analysis of IgG and IgA glycopeptides was developed and applied on a serum sample set from 185 healthy donors. Sample preparation from minute amounts of serum was performed in 96well plate format. Prior to trypsin digestion, IgG and IgA were enriched simultaneously, followed by a one-step denaturation, reduction, and alkylation. The obtained nanoLC-MS data were subjected to semiautomated, targeted feature integration and quality control. The combined and simplified protocol displayed high overall method repeatability, as assessed using pooled plasma and serum standards. Taking all samples together, 143 individual Nand O-glycopeptides were reliably quantified. These glycopeptides were attributable to 11 different peptide backbones, derived from IgG1, IgG2/3, IgG4, IgA1, IgA2, and the joining chain from dimeric IgA. Using this method, novel associations were found between IgA N-and O-glycosylation and age. Furthermore, previously reported associations of IgG Fc glycosylation with age in healthy individuals were confirmed. In conclusion, the new method paves the way for high-throughput multiprotein plasma glycoproteomics.
45Glycosylation is a common post-translational modification of proteins. It is known, that glycans 46 are directly involved in the pathophysiology of every major disease. Defining genetic factors 47 altering glycosylation may provide a basis for novel approaches to diagnostic and pharmaceutical 48 applications. Here, we report a genome-wide association study of the human blood plasma N-49 glycome composition in up to 3811 people. We discovered and replicated twelve loci. This 50 allowed us to demonstrate a clear overlap in genetic control between total plasma and IgG 51 glycosylation. Majority of loci contained genes that encode enzymes directly involved in 52 glycosylation (FUT3/FUT6, FUT8, B3GAT1, ST6GAL1, B4GALT1, ST3GAL4, MGAT3, and 53 MGAT5). We, however, also found loci that are likely to reflect other, more complex, aspects of 54 plasma glycosylation process. Functional genomic annotation suggested the role of DERL3, which 55 potentially highlights the role of glycoprotein degradation pathway, and such transcription factor 56 as IKZF1. 57 58 59Glycosylation -addition of carbohydrates to a substrate -is a common cotranslational and 60 posttranslational modification of proteins. that affects the physical properties of proteins 61 (solubility, conformation, folding, stability, trafficking, etc.) [1-4] as well as their biological 62 functions -from protein-protein interactions, interaction of proteins with receptors, to cell-cell, 63 cell-matrix, and host-pathogen interactions [2,3,5,6]. It has been estimated that more than half of 64 all proteins are glycosylated [7][8][9]. Given the fact that glycans participate in many biological 65 processes, it is therefore not surprising that molecular defects in protein glycosylation pathways 66 are increasingly recognized as direct causes of diseases, such as rheumatoid arthritis, 67 cardiometabolic disorders, cancer, variety of autoimmune diseases, type 2 diabetes, inflammatory 68 bowel disease and others [10][11][12][13][14][15][16][17]. More specifically, a variety of N-glycan structures are now 69 considered as disease markers and represent diagnostic as well as therapeutic targets [5,12,[18][19][20][21][22][23][24][25]. 70Defining the genetic control of protein glycosylation expands our knowledge about the regulation 71 of this fundamental biological process, and it may also shed new light onto how alterations in 72 glycosylation can lead to the development of complex human diseases [11]. 73
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