Genomics Meets Glycomics—The First GWAS Study of Human N-Glycome Identifies HNF1α as a Master Regulator of Plasma Protein Fucosylation

Gordan Lauc, Abdelkader Essafi, Jennifer E Huffman, Caroline Hayward, Ana Knežević, Jayesh J Kattla, Ozren Polašek, Olga Gornik, Veronique Vitart, Jodie L Abrahams, Maja Pučić, Mislav Novokmet, Irma Redžić, Susan Campbell, Sarah H Wild, Fran Borovečki, Wei Wang, Ivana Kolčić, Lina Zgaga, Ulf Gyllensten, James F Wilson, Alan F Wright, Nicholas D Hastie, Harry Campbell, Pauline M Rudd and Igor Rudan

PLOS Genetics, 2010, vol. 6, issue 12, 1-14

Abstract: Over half of all proteins are glycosylated, and alterations in glycosylation have been observed in numerous physiological and pathological processes. Attached glycans significantly affect protein function; but, contrary to polypeptides, they are not directly encoded by genes, and the complex processes that regulate their assembly are poorly understood. A novel approach combining genome-wide association and high-throughput glycomics analysis of 2,705 individuals in three population cohorts showed that common variants in the Hepatocyte Nuclear Factor 1α (HNF1α) and fucosyltransferase genes FUT6 and FUT8 influence N-glycan levels in human plasma. We show that HNF1α and its downstream target HNF4α regulate the expression of key fucosyltransferase and fucose biosynthesis genes. Moreover, we show that HNF1α is both necessary and sufficient to drive the expression of these genes in hepatic cells. These results reveal a new role for HNF1α as a master transcriptional regulator of multiple stages in the fucosylation process. This mechanism has implications for the regulation of immunity, embryonic development, and protein folding, as well as for our understanding of the molecular mechanisms underlying cancer, coronary heart disease, and metabolic and inflammatory disorders.Author Summary: By combining recently developed high-throughput glycan analysis with genome-wide association study, we performed the first comprehensive analysis of common genetic polymorphisms that affect protein glycosylation. Over half of all proteins are glycosylated; but, due to difficulties in glycan analysis and the absence of a genetic template for their synthesis, knowledge about the complex processes that regulate glycan assembly is still limited. We demonstrated that HNF1α regulates the expression of key fucosyltransferase and fucose biosynthesis genes and acts as a master regulator of plasma protein fucosylation. Proper protein fucosylation is essential in numerous processes including inflammation, cancer, and coronary heart disease, thus the identification of a master regulator of plasma protein fucosylation has important implications for understanding both normal biological functions and disease processes.

Date: 2010
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pgen00:1001256

DOI: 10.1371/journal.pgen.1001256

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