title: A functional EXO1 promoter variant is associated with prolonged life expectancy in centenarians.
abstract: Human longevity is heritable with a genetic component of 25-32%. Variation in genes regulating the levels of somatic maintenance and DNA repair functions is thought to modulate the aging process and to contribute to survival at advanced age. We tested 92 non-synonymous SNPs in 49 DNA repair genes for a possible association with longevity in a sample of 395 German centenarians and 411 controls. The obtained association signal in exonuclease 1 (EXO1) was further investigated by fine mapping and mutation detection, leading to the identification of the functionally relevant SNP rs1776180. Our detailed analyses revealed that the C allele of this promoter SNP is significantly enriched in female centenarians. This finding replicated in 455 female French centenarians and 109 controls. The C allele leads to the loss of a binding site for the basic helix-loop-helix transcription factor E47, resulting in higher EXO1 expression. Thus, we have detected a hitherto undescribed role for E47 as a negative regulator of EXO1 transcription and a genetic variant in the EXO1 promoter that counteracts the E47-mediated repression of the gene. Given the survival advantage that is associated with the C allele of rs1776180, EXO1 can be considered a candidate for a novel longevity-enabling gene.
authors.affiliation: Institute of Clinical Molecular Biology, the Christian-Albrechts-University, Kiel, Germany.
authors.forename: Almut
authors.initials: A
authors.lastname: Nebel
authors.forename: Friederike
authors.initials: F
authors.lastname: Flachsbart
authors.forename: Andreas
authors.initials: A
authors.lastname: Till
authors.forename: Amke
authors.initials: A
authors.lastname: Caliebe
authors.forename: Hélène
authors.initials: H
authors.lastname: Blanché
authors.forename: Alexander
authors.initials: A
authors.lastname: Arlt
authors.forename: Robert
authors.initials: R
authors.lastname: Häsler
authors.forename: Gunnar
authors.initials: G
authors.lastname: Jacobs
authors.forename: Rabea
authors.initials: R
authors.lastname: Kleindorp
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.forename: Binghui
authors.initials: B
authors.lastname: Shen
authors.forename: Susanna
authors.initials: S
authors.lastname: Nikolaus
authors.forename: Michael
authors.initials: M
authors.lastname: Krawczak
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenstiel
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001665:Binding Sites; D016022:Case-Control Studies; D045643:DNA Repair Enzymes / Q000235:genetics* / Q000378:metabolism; D005090:Exodeoxyribonucleases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D005858:Germany; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D016015:Logistic Models; D008136:Longevity / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D012737:Sex Factors; D051820:TCF Transcription Factors / Q000378:metabolism; D058125:Transcription Factor 7-Like 1 Protein; D014162:Transfection; D015854:Up-Regulation
chemical_list: D012333:RNA, Messenger; D051820:TCF Transcription Factors; C544912:TCF7L1 protein, human; D058125:Transcription Factor 7-Like 1 Protein; C114331:EXO1 protein, human; D005090:Exodeoxyribonucleases; D045643:DNA Repair Enzymes