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.

Details

Title
Identification and characterization of two functional variants in the human longevity gene FOXO3
Author
Flachsbart, Friederike 1 ; Dose, Janina 1 ; Gentschew, Liljana 1 ; Geismann, Claudia 2 ; Caliebe, Amke 3 ; Knecht, Carolin 3 ; Nygaard, Marianne 4 ; Badarinarayan, Nandini 1 ; Abdou ElSharawy 5 ; May, Sandra 1 ; Luzius, Anne 1 ; Torres, Guillermo G 1 ; Jentzsch, Marlene 1 ; Forster, Michael 1 ; Häsler, Robert 1 ; Pallauf, Kathrin 6 ; Lieb, Wolfgang 7 ; Derbois, Céline 8 ; Galan, Pilar 9 ; Drichel, Dmitriy 10 ; Arlt, Alexander 2   VIAFID ORCID Logo  ; Till, Andreas 11   VIAFID ORCID Logo  ; Krause-Kyora, Ben 12   VIAFID ORCID Logo  ; Rimbach, Gerald 6 ; Blanché, Hélène 13   VIAFID ORCID Logo  ; Deleuze, Jean-François 14 ; Christiansen, Lene 4 ; Christensen, Kaare 15 ; Nothnagel, Michael 10 ; Rosenstiel, Philip 1 ; Schreiber, Stefan 16 ; Franke, Andre 1   VIAFID ORCID Logo  ; Sebens, Susanne 17 ; Nebel, Almut 1 

1  Institute of Clinical Molecular Biology, Kiel University, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany 
2  Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany 
3  Institute of Medical Informatics and Statistics, Kiel University, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany 
4  The Danish Aging Research Center, and the Danish Twin Registry, Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Odense C, Denmark 
5  Institute of Clinical Molecular Biology, Kiel University, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; Faculty of Sciences, Division of Biochemistry, Chemistry Department, Damietta University, New Damietta City, Egypt 
6  Institute of Human Nutrition and Food Science, Kiel University, Kiel, Germany 
7  Institute of Epidemiology, Kiel University, University Hospital Schleswig-Holstein, Campus Kiel, Niemannsweg 11, Kiel, Germany 
8  Centre National de Recherche en Génomique Humaine CNRGH-CEA, Evry, France 
9  Université Sorbonne Paris Cité-UREN, Unité de Recherche en Epidémiologie Nutritionnelle, U557 Inserm, U1125 Inra, Cnam, Université Paris 13, CRNH IdF, Bobigny, France 
10  Department of Statistical Genetics and Bioinformatics, Cologne Center for Genomics, University of Cologne, Weyertal 115b, Cologne, Germany 
11  Institute of Clinical Molecular Biology, Kiel University, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; Institute of Reconstructive Neurobiology and Life & Brain GmbH, University of Bonn, Sigmund-Freud-Straße 25, Bonn, Germany 
12  Institute of Clinical Molecular Biology, Kiel University, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; Max Planck Institute for the Science of Human History, Jena, Germany 
13  Fondation Jean Dausset-Centre d’Etude du Polymorphisme Humain (CEPH), 27 Rue Juliette Dodu, Paris, France 
14  Centre National de Recherche en Génomique Humaine CNRGH-CEA, Evry, France; Fondation Jean Dausset-Centre d’Etude du Polymorphisme Humain (CEPH), 27 Rue Juliette Dodu, Paris, France 
15  The Danish Aging Research Center, and the Danish Twin Registry, Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, Odense C, Denmark; Department of Clinical Genetics, and Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Sdr. Boulevard 29, Odense C, Denmark 
16  Institute of Clinical Molecular Biology, Kiel University, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany 
17  Institute for Experimental Cancer Research, Kiel University, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Straße 3, Kiel, Germany 
Pages
1-12
Publication year
2017
Publication date
Dec 2017
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-017-02183-y
ProQuest document ID
1983423864
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.