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Hum Mol Genet. 2019 Jun 15;28(12):2062-2077. doi: 10.1093/hmg/ddz054.

Defining the genetic control of human blood plasma N-glycome using genome-wide association study.

Author information

1
Institute of Cytology and Genetics SB RAS, Prospekt Lavrentyeva 10, Novosibirsk, Russia.
2
Novosibirsk State University, 1, Pirogova str., Novosibirsk, Russia.
3
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh, UK.
4
Genos Glycoscience Research Laboratory, Borongajska cesta 83h, Zagreb, Croatia.
5
Department of Twin Research and Genetic Epidemiology, School of Life Course Sciences, King's College London, St Thomas' Campus, London, UK.
6
NIHR Biomedical Research Centre at Guy's and St Thomas' Foundation Trust, London, UK.
7
Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Doha, Qatar.
8
Faculty of Pharmacy and Biochemistry, University of Zagreb, Ante Kovacica 1, Zagreb, Croatia.
9
Department of Medicine and Surgery, University of Parma, Via Gramsci 14, Parma, Italy.
10
Unit of Animal Genomics, WELBIO, GIGA-R and Faculty of Veterinary Medicine, University of Liège, Liège, Belgium.
11
Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh, Edinburgh, UK.
12
Colon Cancer Genetics Group, MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine, Western General Hospital, The University of Edinburgh, Edinburgh, UK.
13
Institute of Technology Sligo, Department of Life Sciences, Sligo, Ireland.
14
National Institute for Bioprocessing Research & Training, Dublin, Ireland.
15
Institute of Epidemiology II, Research Unit of Molecular Epidemiology, Helmholtz Centre Munich, German Research Center for Environmental Health, Ingolstädter Landstr. 1, Neuherberg, Germany.
16
Pain Therapy Department, Policlinico Monza Hospital, Monza, Italy.
17
CHU-Liège and Unit of Gastroenterology, GIGA-R and Faculty of Medicine, University of Liège, 1 Avenue de l'Hôpital, Liège, Belgium.
18
PolyOmica, Het Vlaggeschip 61, PA 's-Hertogenbosch, The Netherlands.

Abstract

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 reflect 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.

PMID:
31163085
PMCID:
PMC6664388
[Available on 2020-06-15]
DOI:
10.1093/hmg/ddz054
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