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

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Abstract

<jats:title>Abstract</jats:title><jats:p><jats:italic>FOXO3</jats:italic> 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 <jats:italic>FOXO3</jats:italic> locus and single-nucleotide variant (SNV) genotyping in three European populations. We find two <jats:italic>FOXO3</jats:italic> 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 <jats:italic>FOXO3</jats:italic> 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 <jats:italic>FOXO3</jats:italic> and human longevity.</jats:p>

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