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

Lene Christiansen, Pilar Galan, Dmitriy Drichel, Alexander Arlt, Andreas Till, Ben Krause-Kyora, Gerald Rimbach, Hélène Blanché, Jean-François Deleuze, Céline Derbois, Kaare Christensen, Michael Nothnagel, Stefan Schreiber, Susanne Sebens, Almut Nebel, Philip Rosenstiel, Andre Franke, Sandra May, Janina Dose, Liljana Gentschew, Claudia Geismann, Amke Caliebe, Carolin Knecht, Marianne Nygaard, Nandini Badarinarayan, Abdou ElSharawy, Friederike Flachsbart, Anne Luzius, Guillermo G Torres, Marlene Jentzsch, Michael Forster, Robert Häsler, Kathrin Pallauf, Wolfgang Lieb

Journal: Nature communications 2018;8(1):2063

PMID: 29234056

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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.

Address: Institute of Clinical Molecular Biology, Kiel University, University Hospital Schleswig-Holstein, Campus Kiel, Rosalind-Franklin-Straße 12, 24105, Kiel, Germany.; Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Straße 3, 24105, Kiel, Germany.; Institute of Medical Informatics and Statistics, Kiel University, University Hospital Schleswig-Holstein, Campus Kiel, Brunswiker Straße 10, 24105, Kiel, Germany.; The Danish Aging Research Center, and the Danish Twin Registry, Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, J. B. Winslows Vej 9B, 5000, Odense C, Denmark.; Faculty of Sciences, Division of Biochemistry, Chemistry Department, Damietta University, 34511, New Damietta City, Egypt.; Institute of Human Nutrition and Food Science, Kiel University, Hermann-Rodewald-Straße 6, 24118, Kiel, Germany.; Institute of Epidemiology, Kiel University, University Hospital Schleswig-Holstein, Campus Kiel, Niemannsweg 11, 24105, Kiel, Germany.; Centre National de Recherche en Génomique Humaine CNRGH-CEA, 91000, Evry, France.; Université Sorbonne Paris Cité-UREN, Unité de Recherche en Epidémiologie Nutritionnelle, U557 Inserm, U1125 Inra, Cnam, Université Paris 13, CRNH IdF, 93000, Bobigny, France.; Department of Statistical Genetics and Bioinformatics, Cologne Center for Genomics, University of Cologne, Weyertal 115b, 50931, Cologne, Germany.; Institute of Reconstructive Neurobiology and Life & Brain GmbH, University of Bonn, Sigmund-Freud-Straße 25, 53127, Bonn, Germany.; Max Planck Institute for the Science of Human History, Kahlaische Straße 10, 07745, Jena, Germany.; Fondation Jean Dausset-Centre d'Etude du Polymorphisme Humain (CEPH), 27 Rue Juliette Dodu, 75010, Paris, France.; Department of Clinical Genetics, and Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense C, Denmark.; Institute for Experimental Cancer Research, Kiel University, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Straße 3, 24105, Kiel, Germany.; Institute of Clinical Molecular Biology, Kiel University, University Hospital Schleswig-Holstein, Campus Kiel, Rosalind-Franklin-Straße 12, 24105, Kiel, Germany. [email protected].

DOI: 10.1038/s41467-017-02183-y

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MeSH Terms: Age Factors, Aged, Aged, 80 and over, Alleles, CCCTC-Binding Factor, Computer Simulation, Female, Forkhead Box Protein O3, Haplotypes, Humans, Insulin-Like Growth Factor I, Introns, Longevity, Male, Middle Aged, Polymorphism, Single Nucleotide, RNA, Messenger, Serum Response Factor, White People