title: Identification of a common variant in the TFR2 gene implicated in the physiological regulation of serum iron levels.
abstract: The genetic determinants of variation in iron status are actively sought, but remain incompletely understood. Meta-analysis of two genome-wide association (GWA) studies and replication in three independent cohorts was performed to identify genetic loci associated in the general population with serum levels of iron and markers of iron status, including transferrin, ferritin, soluble transferrin receptor (sTfR) and sTfR-ferritin index. We identified and replicated a novel association of a common variant in the type-2 transferrin receptor (TFR2) gene with iron levels, with effect sizes highly consistent across samples. In addition, we identified and replicated an association between the HFE locus and ferritin and confirmed previously reported associations with the TF, TMPRSS6 and HFE genes. The five replicated variants were tested for association with expression levels of the corresponding genes in a publicly available data set of human liver samples, and nominally statistically significant expression differences by genotype were observed for all genes, although only rs3811647 in the TF gene survived the Bonferroni correction for multiple testing. In addition, we measured for the first time the effects of the common variant in TMPRSS6, rs4820268, on hepcidin mRNA in peripheral blood (n = 83 individuals) and on hepcidin levels in urine (n = 529) and observed an association in the same direction, though only borderline significant. These functional findings require confirmation in further studies with larger sample sizes, but they suggest that common variants in TMPRSS6 could modify the hepcidin-iron feedback loop in clinically unaffected individuals, thus making them more susceptible to imbalances of iron homeostasis.
authors.affiliation: Institute of Genetic Medicine, European Academy Bozen/Bolzano, 39100 Bolzano, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Pichler
authors.forename: Cosetta
authors.initials: C
authors.lastname: Minelli
authors.forename: Serena
authors.initials: S
authors.lastname: Sanna
authors.forename: Toshiko
authors.initials: T
authors.lastname: Tanaka
authors.forename: Christine
authors.initials: C
authors.lastname: Schwienbacher
authors.forename: Silvia
authors.initials: S
authors.lastname: Naitza
authors.forename: Eleonora
authors.initials: E
authors.lastname: Porcu
authors.forename: Cristian
authors.initials: C
authors.lastname: Pattaro
authors.forename: Fabio
authors.initials: F
authors.lastname: Busonero
authors.forename: Alessandra
authors.initials: A
authors.lastname: Zanon
authors.forename: Andrea
authors.initials: A
authors.lastname: Maschio
authors.forename: Scott A
authors.initials: SA
authors.lastname: Melville
authors.forename: Maria
authors.initials: M
authors.lastname: Grazia Piras
authors.forename: Dan L
authors.initials: DL
authors.lastname: Longo
authors.forename: Jack
authors.initials: J
authors.lastname: Guralnik
authors.forename: Dena
authors.initials: D
authors.lastname: Hernandez
authors.forename: Stefania
authors.initials: S
authors.lastname: Bandinelli
authors.forename: Elmar
authors.initials: E
authors.lastname: Aigner
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Murphy
authors.forename: Victor
authors.initials: V
authors.lastname: Wroblewski
authors.forename: Fabio
authors.initials: F
authors.lastname: Marroni
authors.forename: Igor
authors.initials: I
authors.lastname: Theurl
authors.forename: Carsten
authors.initials: C
authors.lastname: Gnewuch
authors.forename: Eric
authors.initials: E
authors.lastname: Schadt
authors.forename: Manfred
authors.initials: M
authors.lastname: Mitterer
authors.forename: David
authors.initials: D
authors.lastname: Schlessinger
authors.forename: Luigi
authors.initials: L
authors.lastname: Ferrucci
authors.forename: Derrick R
authors.initials: DR
authors.lastname: Witcher
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Hicks
authors.forename: Günter
authors.initials: G
authors.lastname: Weiss
authors.forename: Manuela
authors.initials: M
authors.lastname: Uda
authors.forename: Peter P
authors.initials: PP
authors.lastname: Pramstaller
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003430:Cross-Sectional Studies; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007501:Iron / Q000097:blood*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011990:Receptors, Transferrin / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D011990:Receptors, Transferrin; C503640:TFR2 protein, human; D007501:Iron