title: FOXO3 gene variants and human aging: coding variants may not be key players.
abstract: FOXO3 is generally recognized as a "master" gene in aging since its association with longevity has been replicated in multiple organisms and human populations. A group of single nucleotide polymorphisms in linkage disequilibrium with a coding region has been associated with human longevity, but the actual functional variant is unidentified. Therefore, we sequenced the coding region in our long-lived Japanese American population in order to enhance resources for fine mapping this region. We demonstrate that of 38 published variants, 6 are misalignments with homologous nonallelic sequences from FOXO3B (ZNF286B), a pseudogene on a different chromosome; 2 are attributable to ZNF286B only, and the remaining 30 were unconfirmed, indicating that they are very rare and not likely involved in longevity. Furthermore, we identified a novel, unique, nonsynonymous coding variant in exon 3 (Gly566Ala; rs138174682) that is prevalent in multiple ethnic groups but appeared too rare for major longevity effects in our study populations.
authors.affiliation: Honolulu Heart Program, Kuakini Medical Center, Honolulu Hawaii, USA. donlon@hawaii.edu
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Donlon
authors.forename: J David
authors.initials: JD
authors.lastname: Curb
authors.forename: Qimei
authors.initials: Q
authors.lastname: He
authors.forename: John S
authors.initials: JS
authors.lastname: Grove
authors.forename: Kamal H
authors.initials: KH
authors.lastname: Masaki
authors.forename: Beatriz
authors.initials: B
authors.lastname: Rodriguez
authors.forename: Ayako
authors.initials: A
authors.lastname: Elliott
authors.forename: D Craig
authors.initials: DC
authors.lastname: Willcox
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Willcox
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D000483:Alleles; D001213:Asian / Q000235:genetics; D016022:Case-Control Studies; D002874:Chromosome Mapping; D015331:Cohort Studies; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D008136:Longevity / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016366:Open Reading Frames / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012680:Sensitivity and Specificity; D044465:White People / Q000235:genetics
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors