One hundred and forty-three of the 1089 1905 cohort reached 100 years of age. Because the associations of SNPs with longevity have previously been reported to be significant for centenarians (Flachsbart et al. 2009), we conducted the association studies for the centenarian group separately.

In addition to the case-control setup, we analyzed the follow-up survival data for oldest old. When conducting Cox regression, rs10499051, rs7762395, and rs9486902 were found to be nominally associated with longevity. When correcting for multiple testing by Bonferroni correction, none of the results remained significant.

Numerous genes and variations have been investigated for their contribution to human longevity, and FOXO3A gene is emerging as a convincing longevity candidate gene. This study investigates the possible association of variation in the FOXO3A gene with human longevity by covering the known common genetic variation of FOXO3A using tagging SNPs and analyzing frequency data both by case-control and longitudinal approaches. 

The frequencies of rare alleles and rare genotypes tended to increase in the oldest old when compared to younger controls, except for rs13220810 where the most frequent allele and most frequent genotype were increased in the oldest old. Moreover, as reported by Flachsbart et al., allele and genotype frequencies for nonagenarians in our cohort were generally between frequencies for younger controls and centenarians, supporting an increase in allele and genotype frequencies with age.

The recessive model shows low PGGC values, indicating that association effects may be most pronounced for rare homozygotes giving these individuals a survival advantage. The rs13220810 shows significance only when applying a dominant model, indicating that its positive effect is most pronounced for individuals holding the common allele. Flachsbart et al. (2009) and Li et al. (2009) reported significant findings in populations composed of both genders. However, the differences in allele, genotype, and haplotype frequencies in our cohorts were most pronounced for males.The association of SNPs in FOXO3A (Willcox et al. 2008) was investigated in an all-male population. Anselmi et al. (2009) reported five of six SNPs specific to males, while only one was specific to females, indicating a gender effect. In the case-control study, no associations were observed in females even though the sample size was larger than for males. Nominal differences between the oldest old males and male controls were found for five SNPs (rs12206094, rs13220810, rs2802292, rs3800231, and rs9486902), and one SNP (rs479744) was significantly different between centenarians and controls when analyzing both genders combined. All except rs12206094, rs13220210, and rs9486902 have been found to be associated with longevity at the allele level in at least one previous study. The associations point in the same direction as in previously published studies, supporting the findings.

However, at the allelic level, data did not hold after correction for multiple testing, possibly due to lack of power to detect an association. Flachsbart et al. (2009) and Li et al. (2009) reported significant findings in populations composed of both genders, but differences in allele, genotype, and haplotype frequencies were found to be most pronounced for males in this study. Haplotypes including rs9486902 and rs12206094 were found to be associated with longevity.

When comparing genotype frequencies, all SNPs except rs10499051, rs12212067, and rs12207868 were nominally significantly associated with longevity. After correction for multiple testing, eight of the 12 SNPs remained significant; two for both genders combined (rs479744 and rs7762395) and eight when analyzing males separately (rs12206094, rs13220810, rs13217795, rs2764264, rs479744, rs7762395, rs9486902, and rs9400239).

The study investigated the association of FOXO3A SNPs in controls compared to the entire group of oldest old and centenarians. The association of FOXO3A SNPs with longevity was previously reported to be most pronounced for centenarians (Flachsbart et al. 2009). However, none of the three SNPs found to be nominally associated with longevity in the longitudinal analysis held significance after correction for multiple testing.

The genomic region investigated in this study is position 108,982,719-109,113,664 of chromosome 6, which corresponds to FOXO3A and 5000 base pairs upstream and 1000 base pairs downstream. Variation data in this gene region were obtained through the HapMap consortium database for the CEPH cohort. The HaploView software was used to analyze genotype SNP data.and males and females separately, adjusted for age, gender, and cohort.No changes needed. The sentence is already correct.