Genetic variation in TERT and TERC is associated with human leukocyte telomere length (LTL) and longevity. The minor alleles of rs3772190 (A) and rs12696304 (G) in TERC were negatively correlated with LTL. No associations were observed for the TERT SNPs or haplotypes. Our study indicates that TERC is associated with both LTL and longevity in humans. This was confirmed by a significant increase in minor allele frequency of rs3772190 (A) in centenarians compared to the < 80 age group. The study involved a large sample of 58-100+ year-old Danish individuals. The two major telomerase genes are telomerase RNA component (TERC), encoding the subunit of the enzyme, which provides a template for the synthesis of the TTAGGG repeats, and telomerase reverse transcriptase (TERT), encoding its catalytic subunit. Telomere maintenance genes, particularly those that regulate telomerase activity, might also be longevity genes.Mortality analysis did not show any associations (data not shown). A similar evaluation of TERC was not possible because no tagging SNPs were known for Caucasians in the TERC encoding region at the time of conducting this study.

Longevity association study
First, we analyzed the association of the two TERC candidate SNPs with longevity using participants from the UT, LSADT, 1905, and DLCS cohorts (N = 1013). Comparison of allele and genotype frequencies between age groups is presented in Table 1.

Table 1 Characteristics of the study cohorts investigated for the two TERC and four TERT candidate SNPs

The Cohorts UT LSADT 1905 DLCS 

Mean age at intake [years (range)] 68.2 (58.8-80.9) 78.8 (73.3-94.2) 93.2 (92.4-93.7) 100 (99.1-100.3) 
Females (%) 100 66.1 82.3 77.1 
N (2 TERC candidate SNPs) 213 547 125 128 
MAF of rs12696304 0.28 0.28 0.28 0.33 
MAF of rs3772190 0.26 0.26 0.25 0.33 
N (4 TERT candidate SNPs) 213 549 175 132 
MAF of rs2853691 0.32 0.37 0.39 0.35 
MAF of rs33954691 0.11 0.11 0.12 0.11 
MAF of rs2736098 0.32 0.24 0.25 0.25 
MAF of rs2853669 0.36 0.28 0.29 0.29 
N (mTRFL) 214 468 119 63 
Mean age at mTRFL assessment (years) 68.2 79.3 99.7 102.2 
mTRFL SD 6.25 0.042 5.71 0.023 5.20 0.043 5.18 0.06 

UT, Unilever Twin Cohort Study; LSADT, the Longitudinal Study of Aging Danish Twins; 1905: the Danish 1905 Birth Cohort Study; DLCS, the Danish Longitudinal Centenarian Study; MAF, minor allele frequency; mTRFL, mean terminal restriction fragment length (LTL), SD, standard deviation; TERC, telomerase RNA component; TERT, telomerase reverse transcriptase.

Table 2 Regression analysis of LTL by TERC candidate SNP genotypes

Several reports have provided evidence that LTL is associated with an increased risk of age-related disease and mortality in humans (Bakaysa et al., 2007; Kimura et al., 2008; Fitzpatrick et al., 2011). One puzzling observation was, however, that cross-sectional comparison of genotype frequencies in predefined age groups suggested that the 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 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. 

Table 3 Cox regression analysis by TERC rs3772190 genotypes

Genotype HR P-value 95% CI 

rs3772190 AG 1.31 0.009 1.070; 1.611 (age > 80, N = 720) 
AA 1.32 0.112 0.936; 1.862 
AG + AA 1.31 0.006 1.081; 1.598 

HR, hazard rate; 95% CI, 95% confidence interval; TERC, telomerase RNA component. P-values below 0.05 are shown in bold.

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 longevity to common genetic variation in TERT by examining the fourMikael Thinggaard contributed by providing data and data cleaning and assisting in establishing and conducting the statistical analysis. Marianne Nygaard contributed by the acquisition of data. Qihua Tan contributed by assisting in establishing the statistical methods. Jacob Hjelmborg contributed by assisting in establishing the statistical methods. Karen Andersen-Ranberg contributed by the acquisition of data. Serena Dato contributed by generating the study concept and study design and by acquiring data. Tinna Stevnsner and Vilhelm A. Bohr contributed by generating the study concept and study design. Abraham Aviv contributed by the acquisition and interpretation of data. Masayuki Kimura contributed by the acquisition of data. Kaare Christensen contributed by generating the study concept, study design, and interpretation of data. Lene Christiansen contributed by generating the conception of the study, study design, acquisition of data, and interpretation of data. The authors have revised the manuscript and given their final approval.

Statistical analysis: Chi-square test statistics were applied for all cross-sectional association studies of genotype, allele, and haplotype frequencies using the Plink statistical program (http://pngu.mgh.harvard.edu/purcell/plink; Purcell et al., 2007). Among the subjects genotyped for the TERT and TERC candidate SNPs were 381 intact twin pairs, which could lead to an increased risk of false positive findings because of the non-independence of twin samples. However, repeating all cross-sectional analyses while excluding one arbitrarily chosen twin from each pair completely mirrored the presented findings, thus leading to the same conclusions.