Discussion: AKT1 has recently been suggested as a third universal longevity gene, together with APOE and FOXO3. To further elucidate this potential role of AKT1, case-control studies involving Danish and German long-lived individuals and younger controls were performed. In addition to the previously described candidate variation rs3803304,9 our study was expanded to include a number of additional SNPs to ensure better coverage of the known allelic variance in AKT1. To account for the multiple testing of seven SNPs, Bonferroni-corrected power calculations were performed using the freely available software Quanto (Quanto version 1.2.4, http://hydra.usc.edu/gxe/), assuming a 1 in 20 chance of becoming 93-93 years old, a 1 in 400 chance of becoming a centenarian and a Bonferroni-corrected significance level of 0.007.

Results: The main finding of this study was a lack of formal replication of the association of rs3803304 with longevity as previously found in three independent populations.9 In the initial report by Pawlikowska et al., they found that the association with longevity appeared driven by the minor allele homozygous genotype, as subjects homozygous for the minor allele were underrepresented among long-lived cases. In line with this, restricting the analysis to centenarians revealed a trend of supportive evidence in Danish men, with the same direction of effect as identified before. It should be noted, though, that the sample size of the refined group of centenarian men was very limited (n=37), and when applying a Bonferroni correction for multiple statistical testing, the association did not remain significant.

Characteristics of the Danish and German study populations are summarized in Table 1. All genotyped SNPs were in Hardy-Weinberg equilibrium in both control groups, except for rs2494738, which displayed an excess of heterozygotes in the Danish control group (P=0.02). The set of tested AKT1 SNPs included the candidate rs3803304 and six additional SNPs, of which three are tagging (rs2494731, rs2494738, and rs1130214). The remaining (rs2494732, rs2498796, and rs2494748) are distributed evenly throughout the gene and were added to enable more comprehensive coverage of the gene. To facilitate a more exhaustive exploration of the possible relevance AKT1 variations in longevityThere are no clear errors in the text that require correction. However, the text is a table and the formatting is not preserved in the current format.No corrections needed.