In the present study we investigated genetic variations in the TERT and TERC loci, and the possible association with LTL and longevity. The results point to association of TERC variants with both LTL and mortality at advanced ages.
We observed that rs3772190 and rs12696304 of TERC
were associated with a significantly shorter LTL, in line with the results recently observed by Levy et al. (2010)
, Codd et al. (2010)
and Shen et al. (2011)
, although in our study the association of rs12696304 with LTL was restricted to males. Correcting for multiple testing by the Bonferroni-Step down approach left the estimates borderline significant (p-corrected: 0.066 for rs3772190 and 0.07 for rs12696304). If instead applying the less conservative Benjamini and Hochberg correction method the effect of rs12696304 remains significant (p=0.042), illustrating the difference in the use of diverse correction methods. We found no significant association of the TERT
candidate SNPs rs2853669, rs2736098, rs33954691, and rs2853691 or their haplotypes with LTL or longevity, i.e. we did not replicate the findings by Atzmon et al. (2010)
. Our sample size of 865 was much larger than that of Atzmon et al. (74 centenarians and 49 controls), thus giving our study a higher statistical power. A lack of association of TERT
variants to LTL is also supported by two recent genome-wide association studies (Codd et al. (2010)
; Levy et al. (2010)
) and one candidate study (Mirabello et al. (2010)
). The underlying reasons for the discrepancy in the findings might, however, relate to differences between the populations (Ashkenazi Jews versus Danes) and perhaps different LTL measurement methods. We have employed Southern blot analysis, while the Atzmon et al (2010)
used qPCR to measure LTL. We also found that individuals carrying the minor allele A of TERC
rs3772190 experienced reduced survival during old age, in line with the association of this SNP with shortened LTL, although the finding did not remain significant after Bonferroni step-down correction (p-corrected = 0.108 using a dominant model and p = 0.153 for comparison of GG vs. AG). If instead applying the less conservative Benjamini and Hochberg correction method the p-values were 0.108 for the dominant model and 0.081 for GG vs. AG, respectively. In any case this finding seems relevant, since several reports have provided evidence that LTL is associated with increased risk of age-related disease and mortality in humans (Bakaysa et al. (2007)
; Fitzpatrick et al. (2011)
; Kimura et al. (2008)
). One puzzling observation was, however, that cross sectional comparison of genotype frequencies in predefined age groups suggested that the minor allele frequency (MAF) of rs3772190 was significantly increased in the centenarians, in an apparent conflict with the mortality analysis using follow-up data. However, this cross sectional estimate was based on the rather small sample size of centenarians (127 out of 1013 study participants), hence it might simply be a chance finding. Moreover, repeating the mortality analysis for rs3772190 with exclusion of the centenarian subgroup did not change the results, while performing the mortality analysis of the centenarians separately eliminated the association. Hence, it appears that the centenarian subgroup did not contribute to the mortality risk estimate of follow-up data.
Finally, despite the very thorough examination of the genetic variation in the TERT
encoding locus in the present study, we found no evidence for association of TERT
SNPs or haplotypes with longevity. Applying both a cross sectional and a longitudinal study approach, we investigated the association of mortality to common genetic variation in TERT
by examining the 4 candidate SNPs investigated by Atzmon et al. (2010)
in 1069 individuals in the age range of 58–100+ years, as well as 11 tagging SNPs in 736 middle-aged and 1089 oldest-old individuals. Nonetheless, we cannot rule out that a putative effect of TERT
variation on longevity might be population specific, i.e. relevant in a population of Ashkenazi Jews, but not in Danes.
In conclusion, we have replicated associations of genetic variation in the TERC locus with LTL and, moreover, have found association of variation in the TERC locus with longevity. Hence, our study suggests that TERC is associated with both LTL and human longevity.