Effects of FOXO3 Polymorphisms on Survival to Extreme Longevity in Four Centenarian Studies

Abstract

Previous studies note specific FOXO3 single-nucleotide polymorphisms (SNPs) associated with human longevity. However, it is not clear if these SNPs influence mortality risk beyond the oldest 1 percentile of survival. Using data from four longevity studies (total n = 8,266, age range 96-119 years for cases), we tested gene-wide association between 107 SNPs and survival to at least the oldest 1 percentile of survival for the 1900 birth cohort (≥96, white males; ≥100 white females). This analysis replicated 17 previously published variants, several of which are significant expression quantitative trait loci of FOXO3; rs6911407 and rs2253310 have the most significant effect on FOXO3 expressions in brain tissue. We then performed a survival analysis to determine if any of these 107 SNPs impact upon mortality risk beyond the oldest 1 percentile. While none of the 17 published variants was significantly associated with mortality risk beyond this extreme age, an uncommon homozygote genotype of rs9384680 exhibited the strongest association with mortality risk (p = 2.68E-04) in only 11 females, a heretofore unreported association. These analyses replicate the previous association of common variants of FOXO3 with older age but these common variants do not modify risk for mortality at ages beyond the oldest 1 percentile age of survival.

Figure 1.

Study flow of analyses. In the first step, meta-analysis of case–control data was performed. In the second step, survival analysis in the restricted set of cases only was performed.

Figure 2.

Regional association plot of meta-analysis results. The x-axis represents the genomic positions within FOXO3, the y-axis on the left represents –log10 of the p-values from the meta-analysis, and the y-axis on the right represent the recombination rate. The colors show the strength of the linkage disequilibrium between the most strongly associated single-nucleotide polymorphism (SNP) (rs4946935) and the other FOXO3 SNPs studied.

Figure 3.

Forest plot of odds ratios for rs4946935 in the SICS, LLFS, LGP, NECS, and meta-analysis. LGP = Longevity Genes Project; LLFS = Long Life Family Study; NECS = New England Centenarian Study; SICS = Southern Italian Centenarian Study.

Figure 4.

Kaplan–Meier curve of survival stratified by the genotypes of rs4946935 and rs9384690. Blue: carriers of homozygote non-longevity variant. Red: carriers of the heterozygote genotype. Green: carriers of the homozygote longevity variant. Left: analysis in survivors past the age at which less than 1% of the 1900 birth year cohort survived. Right: analysis includes all study participants. Note that the risk table at the bottom of each Kaplan–Meier curve excludes alive subjects at last contact since their age at death is censored. The Kaplan–Meier curves are generated assuming noninformative censoring.

Figure 5.

Boxplot of gene expression levels by genotype of rs6911407 using the genotype-tissue expression database. Reference allele C, alternative allele A.