title: Genomics meets glycomics-the first GWAS study of human N-Glycome identifies HNF1α as a master regulator of plasma protein fucosylation.
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.
authors.affiliation: Glycobiology Laboratory, Genos Ltd., Zagreb, Croatia.
authors.forename: Gordan
authors.initials: G
authors.lastname: Lauc
authors.forename: Abdelkader
authors.initials: A
authors.lastname: Essafi
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Huffman
authors.forename: Caroline
authors.initials: C
authors.lastname: Hayward
authors.forename: Ana
authors.initials: A
authors.lastname: Knežević
authors.forename: Jayesh J
authors.initials: JJ
authors.lastname: Kattla
authors.forename: Ozren
authors.initials: O
authors.lastname: Polašek
authors.forename: Olga
authors.initials: O
authors.lastname: Gornik
authors.forename: Veronique
authors.initials: V
authors.lastname: Vitart
authors.forename: Jodie L
authors.initials: JL
authors.lastname: Abrahams
authors.forename: Maja
authors.initials: M
authors.lastname: Pučić
authors.forename: Mislav
authors.initials: M
authors.lastname: Novokmet
authors.forename: Irma
authors.initials: I
authors.lastname: Redžić
authors.forename: Susan
authors.initials: S
authors.lastname: Campbell
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Wild
authors.forename: Fran
authors.initials: F
authors.lastname: Borovečki
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Ivana
authors.initials: I
authors.lastname: Kolčić
authors.forename: Lina
authors.initials: L
authors.lastname: Zgaga
authors.forename: Ulf
authors.initials: U
authors.lastname: Gyllensten
authors.forename: James F
authors.initials: JF
authors.lastname: Wilson
authors.forename: Alan F
authors.initials: AF
authors.lastname: Wright
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Hastie
authors.forename: Harry
authors.initials: H
authors.lastname: Campbell
authors.forename: Pauline M
authors.initials: PM
authors.lastname: Rudd
authors.forename: Igor
authors.initials: I
authors.lastname: Rudan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001798:Blood Proteins / Q000378:metabolism*; D015331:Cohort Studies; D005260:Female; D005643:Fucose / Q000096:biosynthesis; D005647:Fucosyltransferases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D023281:Genomics; D054794:Glycomics; D056945:Hep G2 Cells; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D011134:Polysaccharides / Q000378:metabolism; D055815:Young Adult
chemical_list: D001798:Blood Proteins; D051538:Hepatocyte Nuclear Factor 1-alpha; D011134:Polysaccharides; D005643:Fucose; D005647:Fucosyltransferases; C515956:FUT6 protein, human; C020559:Glycoprotein 6-alpha-L-fucosyltransferase