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

Authors:
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 Häesler, 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, Almut Nebel
Year of publication:
2017
Volume:
8
Issue:
1
Issn:
2041-1723
Journal title abbreviated:
NAT COMMUN
Journal title long:
Nature communications
Impact factor:
12.353
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.