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

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, Häesler, Robert, Pallauf, Kathrin, Lieb, Wolfgang, Derbois, Céline, Galan, Pilar, Drichel, Dmitriy, Arlt, Alexander, Till, Andreas, Krause-Kyora, Ben, Rimbach, Gerald, Blanché, Hélène, Deleuze, Jean-François, Christiansen, Lene, Christensen, Kaare, Nothnagel, Michael, Rosenstiel, Philip, Schreiber, Stefan, Franke, Andrea, Sebens, Susanne and Nebel, Almut (2017) Identification and characterization of two functional variants in the human longevity gene FOXO3 Nature Communications, 8 (1). DOI 10.1038/s41467-017-02183-y.

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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.

Document Type: Article
Research affiliation: Kiel University > Kiel Marine Science
Kiel University
OceanRep > The Future Ocean - Cluster of Excellence
Refereed: Yes
DOI etc.: 10.1038/s41467-017-02183-y
ISSN: 2041-1723
Date Deposited: 19 Dec 2017 15:21
Last Modified: 08 Jan 2018 10:41
URI: http://eprints.uni-kiel.de/id/eprint/40939

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