Identification of a common variant in the TFR2 gene implicated in the physiological regulation of serum iron levels

Irene Pichler, Cosetta Minelli, Serena Sanna, Toshiko Tanaka, Christine Schwienbacher, Silvia Naitza, Eleonora Porcu, Cristian Pattaro, Fabio Busonero, Alessandra Zanon, Andrea Maschio, Scott A. Melville, Maria Grazia piras, Dan L. Longo, Jack Guralnik, Dena Hernandez, Stefania Bandinelli, Elmar Aigner, Anthony T. Murphy, Victor WroblewskiFabio Marroni, Igor Theurl, Carsten Gnewuch, Eric Schadt, Manfred Mitterer, David Schlessinger, Luigi Ferrucci, Derrick R. Witcher, Andrew A. Hicks, Günter Weiss, Manuela Uda, Peter P. Pramstaller

Research output: Contribution to journalArticlepeer-review

55 Scopus citations


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.

Original languageEnglish (US)
Article numberddq552
Pages (from-to)1232-1240
Number of pages9
JournalHuman Molecular Genetics
Issue number6
StatePublished - Mar 2011
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology


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