title: Association study of FOXO3A SNPs and aging phenotypes in Danish oldest-old individuals.
abstract: FOXO3A variation has repeatedly been reported to associate with human longevity, yet only few studies have investigated whether FOXO3A variation also associates with aging-related traits. Here, we investigate the association of 15 FOXO3A tagging single nucleotide polymorphisms (SNPs) in 1088 oldest-old Danes (age 92-93) with 4 phenotypes known to predict their survival: cognitive function, hand grip strength, activity of daily living (ADL), and self-rated health. Based on previous studies in humans and foxo animal models, we also explore self-reported diabetes, cancer, cardiovascular disease, osteoporosis, and bone (femur/spine/hip/wrist) fracture. Gene-based testing revealed significant associations of FOXO3A variation with ADL (P = 0.044) and bone fracture (P = 0.006). The single-SNP statistics behind the gene-based analysis indicated increased ADL (decreased disability) and reduced bone fracture risk for carriers of the minor alleles of 8 and 10 SNPs, respectively. These positive directions of effects are in agreement with the positive effects on longevity previously reported for these SNPs. However, when correcting for the test of 9 phenotypes by Bonferroni correction, bone fracture showed borderline significance (P = 0.054), while ADL did not (P = 0.396). Although the single-SNP associations did not formally replicate in another study population of oldest-old Danes (n = 1279, age 94-100), the estimates were of similar direction of effect as observed in the Discovery sample. A pooled analysis of both study populations displayed similar or decreased sized P-values for most associations, hereby supporting the initial findings. Nevertheless, confirmation in additional study populations is needed.
authors.affiliation: The Danish Aging Research Center, Epidemiology, Biostatistics and Biodemography, Institute of Public Health, University of Southern Denmark, J.B. Winsloews Vej 9B, 5000, Odense C, Denmark; Department of Clinical Genetics, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense C, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Soerensen
authors.forename: Marianne
authors.initials: M
authors.lastname: Nygaard
authors.forename: Serena
authors.initials: S
authors.lastname: Dato
authors.forename: Tinna
authors.initials: T
authors.lastname: Stevnsner
authors.forename: Vilhelm A
authors.initials: VA
authors.lastname: Bohr
authors.forename: Kaare
authors.initials: K
authors.lastname: Christensen
authors.forename: Lene
authors.initials: L
authors.lastname: Christiansen
mesh_terms: D000203:Activities of Daily Living; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D003718:Denmark; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics*; D050723:Fractures, Bone / Q000235:genetics; D056726:Genetic Association Studies; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015203:Reproducibility of Results
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors
keywords: Forkhead box O3; SNPs; aging phenotypes; association study; oldest-old