Genetic variation in TERT and TERC and human leukocyte telomere length and longevity: a cross-sectional and longitudinal analysis

(AG + AA) = 1.31, P = 0.006]. No associations with were observed for the TERT SNPs or haplotypes. Our thus, indicates that TERC is associated with both LTL and gevity in humans. Key words: association study; cross-sectional data and gitudinal data; human longevity; leukocyte telomere telomerase reverse transcriptase; telomerase RNA nent.

(AG + AA) =

, P =

]. No associations with longevity were observed for the TERT SNPs or haplotypes. Our study, thus, indicates that TERC is associated with both LTL and lon- gevity in humans. Key words: association study; cross-sectional data and lon- gitudinal data; human longevity; leukocyte telomere length; telomerase reverse transcriptase; telomerase RNA compo- nent.

Mette Mikael Marianne Nygaard,1,2 Serena Dato,1,2,3 Qihua Tan,1,2 Jacob Hjelmborg,1 Karen Andersen-Ranberg,1 Tinna Stevnsner,4 Vilhelm A. Bohr,4,5 Masayuki Kimura,6 Abraham Aviv,6 Kaare Christensen1,2 and Lene Christiansen1,2

The Danish Aging Research Center, Epidemiology, Institute of Public Health, University of Southern Denmark, J.B. Winsloews Vej

B,

Odense C, Denmark

Departments of Clinical Genetics and Clinical Biochemistry and Pharmacology, Odense University Hospital, Sdr. Boulevard

,

C, Denmark

Department of Cell Biology, University of Calabria, Ponte Pietro Bucci

C,

Rende (Cs), Italy

The Danish Aging Research Center, Department of Molecular Biology, Aarhus University, C. F. Moellers Alle´

,

Aarhus C, Denmark

Laboratory of Molecular Gerontology, National Institute on Aging, National Institute of Health,

Bayview Blvd., Baltimore, MD, USA

The Center for Human Development and Aging, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ,

Introduction

Genetic factors explain approximately 25% of the variation in the human life span (Herskind et al., 1996). Such factors exert a minimal effect before age 60 years and the most profound effect after the age of 85 years (Hjelmborg et al., 2006). Candidate longevity genes encode pro- teins engaged in several biological processes, including the maintenance of genomic stability. These include telomere maintenance genes (Chris- tensen et al., 2006).

The ends of human chromosomes, the telomeres, consist of repeats that undergo shortening with each replication cycle of cells lack telomerase, the reverse transcriptase which adds telomeres to ends of chromosomes (reviewed by Wong & Collins, 2003; et al., 2006; Campisi & d’Adda de Fagagna, 2007). Telomere ing is associated with organismal aging; in humans, leukocyte length (LTL) is inversely related to age (Lindsey et al., 1991; et al., 1994) and is associated with increased risk of age-related and with mortality (Bakaysa et al., 2007; Njajou et al., 2007; et al., 2008; Shay & Woodring, 2008). Leukocyte telomere length heritable; its heritability has been estimated to be between 35% 80% (Slagboom et al., 1994; Bischoff et al., 2005; Vasa-Nicotera et 2005; Andrew et al., 2006). Hence, telomere maintenance genes, ticularly those that regulate telomerase activity, might also be genes. The two major telomerase genes are telomerase RNA nent (TERC), encoding the subunit of the enzyme, which provides template for the synthesis of the TTAGGG repeats, and reverse transcriptase (TERT), encoding its catalytic subunit et al., 2006).

Summary

Telomerase is of key importance for telomere maintenance, and variants of the genes encoding its major subunits, telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC), are candidates for interindividual variation in telomere length. Recently, the two SNPs rs3772190 and rs12696304 in the TERC locus were reported to be associated with leukocyte telomere length (LTL) in two genome-wide association studies, while one haplotype of TERT (rs2853669, rs2736098, rs33954691, and rs2853691) has been reported to be associated with both LTL and longevity in a candidate gene study. In this study, we investigated the two TERC and four TERT SNPs in middle-aged, old, and oldest-old Danes (58–100 years) and their association with LTL (n = 864) and longevity (n = 1069). Furthermore, data on 11 TERT tagging SNPs in 1089 oldest-old and 736 middle- aged Danes were investigated with respect to longevity. For all SNPs, the association with longevity was investigated using both a cross-sectional and a longitudinal approach. Applying an additive model, we found association of LTL with the minor TERC alleles of rs3772190 (A) and rs12696304 (G), such that a shorter LTL was seen in rs3772190 A carriers (regression coeffi- cient = )0.08, P = 0.011) and in male rs12696304 G carriers (regression coefficient = )0.13, P = 0.014). No TERT variations showed association. Moreover, the A allele of rs3772190 (TERC) was found to be associated with longevity [hazard rate

Two recent genome-wide association studies observed association of LTL with two SNPs (rs12696304 and rs3772190) of the TERC locus in individuals of European descent (Codd et al., 2010; Levy et al., 2010). The association of rs12696304 with LTL was recently confirmed in a Chinese population (Shen et al., 2011). Another study by Atzmon et al. (2010) reported that Ashkenazi centenarians have a longer LTL and increased frequency of rare TERT variants compared with younger controls without a family history of extreme longevity. Moreover, the authors reported that a TERT SNP (rs33954691) and three TERT haplotypes (rs2853669, rs2736098, rs33954691, and rs2853691) were associated with longevity, while one haplotype was also associated with a longer LTL. Accordingly, we examined the association of LTL and longevity with these TERC and TERT variants in a large sample of 58–100+ year-old Danish individuals.

Mette Soerensen, The Danish Aging Research Center, Epidemiology, Institute of Public Health, University of Southern Denmark, J.B. Winsloews Vej