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Genomics meets glycomics—The first GWAS study of human N-Glycome identifies HNF1α as a master regulator of plasma protein fucosylation

Research output: Contribution to journalArticle

  • 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
  • Igor Rudan
Original languageEnglish
Article numbere1001256
JournalPLoS Genetics
Volume6
Issue number12
DOIs
DatePublished - 23 Dec 2010

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.

    Research areas

  • Adolescent, Adult, Aged, Aged, 80 and over, Blood Proteins, Cohort Studies, Female, Fucose, Fucosyltransferases, Gene Expression Regulation, Genome-Wide Association Study, Genomics, Glycomics, Hep G2 Cells, Hepatocyte Nuclear Factor 1-alpha, Hepatocytes, Humans, Male, Middle Aged, Polysaccharides, Young Adult

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