Flachsbart, Friederike, Dose, Janina, Gentschew, Liljana, Geismann, Claudia, Caliebe, Amke, Knecht, Carolin, Nygaard, Marianne ORCID: 0000-0003-0703-2665, Badarinarayan, Nandini, ElSharawy, Abdou, May, Sandra, Luzius, Anne, Torres, Guillermo G., Jentzsch, Marlene, Forster, Michael ORCID: 0000-0001-9927-5124, Haeesler, Robert, Pallauf, Kathrin ORCID: 0000-0002-7223-2738, Lieb, Wolfgang, Derbois, Celine, Galan, Pilar, Drichel, Dmitriy ORCID: 0000-0001-5978-3458, Arlt, Alexander ORCID: 0000-0002-6160-1059, Till, Andreas, Krause-Kyora, Ben ORCID: 0000-0001-9435-2872, Rimbach, Gerald ORCID: 0000-0001-7888-4684, Blanche, Helene, Deleuze, Jean-Francois, Christiansen, Lene, Christensen, Kaare ORCID: 0000-0002-5429-5292, Nothnagel, Michael ORCID: 0000-0001-8305-7114, Rosenstiel, Philip ORCID: 0000-0002-9692-8828, Schreiber, Stefan, Franke, Andre, Sebens, Susanne and Nebel, Almut (2017). Identification and characterization of two functional variants in the human longevity gene FOXO3. Nat. Commun., 8. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Flachsbart, FriederikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dose, JaninaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gentschew, LiljanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Geismann, ClaudiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Caliebe, AmkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knecht, CarolinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nygaard, MarianneUNSPECIFIEDorcid.org/0000-0003-0703-2665UNSPECIFIED
Badarinarayan, NandiniUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
ElSharawy, AbdouUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
May, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Luzius, AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Torres, Guillermo G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jentzsch, MarleneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Forster, MichaelUNSPECIFIEDorcid.org/0000-0001-9927-5124UNSPECIFIED
Haeesler, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pallauf, KathrinUNSPECIFIEDorcid.org/0000-0002-7223-2738UNSPECIFIED
Lieb, WolfgangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Derbois, CelineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Galan, PilarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Drichel, DmitriyUNSPECIFIEDorcid.org/0000-0001-5978-3458UNSPECIFIED
Arlt, AlexanderUNSPECIFIEDorcid.org/0000-0002-6160-1059UNSPECIFIED
Till, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krause-Kyora, BenUNSPECIFIEDorcid.org/0000-0001-9435-2872UNSPECIFIED
Rimbach, GeraldUNSPECIFIEDorcid.org/0000-0001-7888-4684UNSPECIFIED
Blanche, HeleneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deleuze, Jean-FrancoisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Christiansen, LeneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Christensen, KaareUNSPECIFIEDorcid.org/0000-0002-5429-5292UNSPECIFIED
Nothnagel, MichaelUNSPECIFIEDorcid.org/0000-0001-8305-7114UNSPECIFIED
Rosenstiel, PhilipUNSPECIFIEDorcid.org/0000-0002-9692-8828UNSPECIFIED
Schreiber, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Franke, AndreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sebens, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nebel, AlmutUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-207998
DOI: 10.1038/s41467-017-02183-y
Journal or Publication Title: Nat. Commun.
Volume: 8
Date: 2017
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENOME-WIDE ASSOCIATION; SERUM RESPONSE FACTOR; TRANSCRIPTION FACTOR; DIETARY RESTRICTION; SIGNALING PATHWAY; CONFIRMS APOE; WHOLE GENOME; CANCER CELLS; MAJOR GENE; LIFE-SPANMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/20799

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