title: Genome-wide association study identifies two loci strongly affecting transferrin glycosylation.
abstract: Polysaccharide sidechains attached to proteins play important roles in cell-cell and receptor-ligand interactions. Variation in the carbohydrate component has been extensively studied for the iron transport protein transferrin, because serum levels of the transferrin isoforms asialotransferrin + disialotransferrin (carbohydrate-deficient transferrin, CDT) are used as biomarkers of excessive alcohol intake. We conducted a genome-wide association study to assess whether genetic factors affect CDT concentration in serum. CDT was measured in three population-based studies: one in Switzerland (CoLaus study, n = 5181) and two in Australia (n = 1509, n = 775). The first cohort was used as the discovery panel and the latter ones served as replication. Genome-wide single-nucleotide polymorphism (SNP) typing data were used to identify loci with significant associations with CDT as a percentage of total transferrin (CDT%). The top three SNPs in the discovery panel (rs2749097 near PGM1 on chromosome 1, and missense polymorphisms rs1049296, rs1799899 in TF on chromosome 3) were successfully replicated , yielding genome-wide significant combined association with CDT% (P = 1.9 × 10(-9), 4 × 10(-39), 5.5 × 10(-43), respectively) and explain 5.8% of the variation in CDT%. These allelic effects are postulated to be caused by variation in availability of glucose-1-phosphate as a precursor of the glycan (PGM1), and variation in transferrin (TF) structure.
authors.affiliation: Department of Medical Genetics, University of Lausanne, Lausanne, 1005, Switzerland. zoltan.kutalik@unil.ch
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Kutalik
authors.forename: Beben
authors.initials: B
authors.lastname: Benyamin
authors.forename: Sven
authors.initials: S
authors.lastname: Bergmann
authors.forename: Vincent
authors.initials: V
authors.lastname: Mooser
authors.forename: Gérard
authors.initials: G
authors.lastname: Waeber
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.forename: Pamela A F
authors.initials: PA
authors.lastname: Madden
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Heath
authors.forename: Jacques S
authors.initials: JS
authors.lastname: Beckmann
authors.forename: Peter
authors.initials: P
authors.lastname: Vollenweider
authors.forename: Pedro
authors.initials: P
authors.lastname: Marques-Vidal
authors.forename: John B
authors.initials: JB
authors.lastname: Whitfield
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000428:Alcohol Drinking / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D055106:Genome-Wide Association Study; D006031:Glycosylation; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D013557:Switzerland; D014168:Transferrin / Q000031:analogs & derivatives / Q000235:genetics* / Q000378:metabolism*; D044465:White People / Q000235:genetics
chemical_list: D014168:Transferrin; C056759:carbohydrate-deficient transferrin