Journal
HUMAN MOLECULAR GENETICS
Volume 20, Issue 24, Pages 5000-5011Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddr414
Keywords
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Funding
- Medical Research Council (UK)
- Ministry of Science, Education and Sport of the Republic of Croatia [108-1080315-0302]
- European Union [LSHG-CT-2006-018947, 215536]
- Chief Scientist Office of the Scottish Government
- Royal Society
- Croatian Ministry of Science, Education and Sport [309-0061194-2023]
- Croatian Science Foundation [04-47]
- European Commission
- MRC [MC_U127561128, MC_PC_U127561128] Funding Source: UKRI
- Chief Scientist Office [CZB/4/728, CZB/4/710] Funding Source: researchfish
- Medical Research Council [MC_U127561128, MC_PC_U127561128] Funding Source: researchfish
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The majority of human proteins are post-translationally modified by covalent addition of one or more complex oligosaccharides (glycans). Alterations in glycosylation processing are associated with numerous diseases and glycans are attracting increasing attention both as disease biomarkers and as targets for novel therapeutic approaches. Using a recently developed high-throughput high-performance liquid chromatography (HPLC) analysis method, we have reported, in a pilot genome-wide association study of 13 glycan features in 2705 individuals from three European populations, that polymorphisms at three loci (FUT8, FUT6/FUT3 and HNF1A) affect plasma levels of N-glycans. Here, we extended the analysis to 33 directly measured and 13 derived glycosylation traits in 3533 individuals and identified three novel gene association (MGAT5, B3GAT1 and SLC9A9) as well as replicated the previous findings using an additional European cohort. MGAT5 (meta-analysis association P-value = 1.80 x 10(-10) for rs1257220) encodes a glycosyltransferase which is known to synthesize the associated glycans. In contrast, neither B3GAT1 (rs7928758, P = 1.66 x 10(-08)) nor SLC9A9 (rs4839604, P = 3.50 x 10(-13)) had previously been associated functionally with glycosylation of plasma proteins. Given the glucuronyl transferase activity of B3GAT1, we were able to show that glucuronic acid is present on antennae of plasma glycoproteins underlying the corresponding HPLC peak. SLC9A9 encodes a proton pump which affects pH in the endosomal compartment and it was recently reported that changes in Golgi pH can impair protein sialylation, giving a possible mechanism for the observed association.
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