• Medientyp: E-Artikel
  • Titel: Identification and characterization of two functional variants in the human longevity gene FOXO3
  • Beteiligte: Flachsbart, Friederike; Dose, Janina; Gentschew, Liljana; Geismann, Claudia; Caliebe, Amke; Knecht, Carolin; Nygaard, Marianne; Badarinarayan, Nandini; ElSharawy, Abdou; May, Sandra; Luzius, Anne; Torres, Guillermo G.; Jentzsch, Marlene; Forster, Michael; Häsler, Robert; Pallauf, Kathrin; Lieb, Wolfgang; Derbois, Céline; Galan, Pilar; Drichel, Dmitriy; Arlt, Alexander; Till, Andreas; Krause-Kyora, Ben; Rimbach, Gerald; [...]
  • Erschienen: Springer Science and Business Media LLC, 2017
  • Erschienen in: Nature Communications
  • Sprache: Englisch
  • DOI: 10.1038/s41467-017-02183-y
  • ISSN: 2041-1723
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title><jats:p><jats:italic>FOXO3</jats:italic> is consistently annotated as a human longevity gene. However, functional variants and underlying mechanisms for the association remain unknown. Here, we perform resequencing of the <jats:italic>FOXO3</jats:italic> locus and single-nucleotide variant (SNV) genotyping in three European populations. We find two <jats:italic>FOXO3</jats:italic> SNVs, rs12206094 and rs4946935, to be most significantly associated with longevity and further characterize them functionally. We experimentally validate the in silico predicted allele-dependent binding of transcription factors (CTCF, SRF) to the SNVs. Specifically, in luciferase reporter assays, the longevity alleles of both variants show considerable enhancer activities that are reversed by IGF-1 treatment. An eQTL database search reveals that the alleles are also associated with higher <jats:italic>FOXO3</jats:italic> mRNA expression in various human tissues, which is in line with observations in long-lived model organisms. In summary, we present experimental evidence for a functional link between common intronic variants in <jats:italic>FOXO3</jats:italic> and human longevity.</jats:p>
  • Zugangsstatus: Freier Zugang