Journal
MECHANISMS OF AGEING AND DEVELOPMENT
Volume 130, Issue 10, Pages 691-699Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.mad.2009.08.004
Keywords
Aging; Longevity; EXO1; Centenarians; Case-control association; Candidate genes
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Funding
- DFG Excellence Clusters 'Inflammation at Interfaces' and 'Future Ocean'
- German Federal Ministry of Science and Education (BMBF) [EP-S23T01]
- National Genome Research Network (NGFN) [01GS0426]
- French Ministere de l'Enseignement Superieur et dela Recherche
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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. (C) 2009 Elsevier Ireland Ltd. All rights reserved.
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