Identification and characterization of two functional variants in the human longevity gene FOXO3

Friederike Flachsbart, Janina Dose, Liljana Gentschew, Claudia Geismann, Amke Caliebe, Carolin Knecht, Marianne Nygaard, Nandini Badarinarayan, Abdou ElSharawy, Sandra May, Anne Luzius, Guillermo G. Torres, Marlene Jentzsch, Michael Forster, Robert Häsler, Kathrin Pallauf, Wolfgang Lieb, Céline Derbois, Pilar Galan, Dmitriy Drichel, Alexander Arlt, Andreas Till, Ben Krause-Kyora, Gerald Rimbach, Hélène Blanché, Jean-François Deleuze, Lene Christiansen, Kaare Christensen, Michael Nothnagel, Philip Rosenstiel, Stefan Schreiber, Andre Franke, Susanne Sebens and Almut Nebel ()
Additional contact information
Friederike Flachsbart: Kiel University, University Hospital Schleswig-Holstein, Campus Kiel
Janina Dose: Kiel University, University Hospital Schleswig-Holstein, Campus Kiel
Liljana Gentschew: Kiel University, University Hospital Schleswig-Holstein, Campus Kiel
Claudia Geismann: University Hospital Schleswig-Holstein, Campus Kiel
Amke Caliebe: Kiel University, University Hospital Schleswig-Holstein, Campus Kiel
Carolin Knecht: Kiel University, University Hospital Schleswig-Holstein, Campus Kiel
Marianne Nygaard: University of Southern Denmark
Nandini Badarinarayan: Kiel University, University Hospital Schleswig-Holstein, Campus Kiel
Abdou ElSharawy: Kiel University, University Hospital Schleswig-Holstein, Campus Kiel
Sandra May: Kiel University, University Hospital Schleswig-Holstein, Campus Kiel
Anne Luzius: Kiel University, University Hospital Schleswig-Holstein, Campus Kiel
Guillermo G. Torres: Kiel University, University Hospital Schleswig-Holstein, Campus Kiel
Marlene Jentzsch: Kiel University, University Hospital Schleswig-Holstein, Campus Kiel
Michael Forster: Kiel University, University Hospital Schleswig-Holstein, Campus Kiel
Robert Häsler: Kiel University, University Hospital Schleswig-Holstein, Campus Kiel
Kathrin Pallauf: Kiel University
Wolfgang Lieb: Kiel University, University Hospital Schleswig-Holstein, Campus Kiel, Niemannsweg 11
Céline Derbois: Centre National de Recherche en Génomique Humaine CNRGH-CEA
Pilar Galan: Université Sorbonne Paris Cité-UREN, Unité de Recherche en Epidémiologie Nutritionnelle, U557 Inserm, U1125 Inra, Cnam, Université Paris 13, CRNH IdF
Dmitriy Drichel: University of Cologne, Weyertal 115b
Alexander Arlt: University Hospital Schleswig-Holstein, Campus Kiel
Andreas Till: Kiel University, University Hospital Schleswig-Holstein, Campus Kiel
Ben Krause-Kyora: Kiel University, University Hospital Schleswig-Holstein, Campus Kiel
Gerald Rimbach: Kiel University
Hélène Blanché: Fondation Jean Dausset-Centre d’Etude du Polymorphisme Humain (CEPH), 27 Rue Juliette Dodu
Jean-François Deleuze: Centre National de Recherche en Génomique Humaine CNRGH-CEA
Lene Christiansen: University of Southern Denmark
Kaare Christensen: University of Southern Denmark
Michael Nothnagel: University of Cologne, Weyertal 115b
Philip Rosenstiel: Kiel University, University Hospital Schleswig-Holstein, Campus Kiel
Stefan Schreiber: Kiel University, University Hospital Schleswig-Holstein, Campus Kiel
Andre Franke: Kiel University, University Hospital Schleswig-Holstein, Campus Kiel
Susanne Sebens: Kiel University, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Straße 3
Almut Nebel: Kiel University, University Hospital Schleswig-Holstein, Campus Kiel

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract FOXO3 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 FOXO3 locus and single-nucleotide variant (SNV) genotyping in three European populations. We find two FOXO3 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 FOXO3 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 FOXO3 and human longevity.

Date: 2017
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DOI: 10.1038/s41467-017-02183-y

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