title: Genetic variation in TERT and TERC and human leukocyte telomere length and longevity: a cross-sectional and longitudinal analysis.
abstract: 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 coefficient = -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 (AG + AA) = 1.31, P = 0.006]. No associations with longevity were observed for the TERT SNPs or haplotypes. Our study, thus, indicates that TERC is associated with both LTL and longevity in humans.
authors.affiliation: The Danish Aging Research Center, Epidemiology, Institute of Public Health, University of Southern Denmark, Odense C, Denmark. msoerensen@health.sdu.dk
authors.forename: Mette
authors.initials: M
authors.lastname: Soerensen
authors.forename: Mikael
authors.initials: M
authors.lastname: Thinggaard
authors.forename: Marianne
authors.initials: M
authors.lastname: Nygaard
authors.forename: Serena
authors.initials: S
authors.lastname: Dato
authors.forename: Qihua
authors.initials: Q
authors.lastname: Tan
authors.forename: Jacob
authors.initials: J
authors.lastname: Hjelmborg
authors.forename: Karen
authors.initials: K
authors.lastname: Andersen-Ranberg
authors.forename: Tinna
authors.initials: T
authors.lastname: Stevnsner
authors.forename: Vilhelm A
authors.initials: VA
authors.lastname: Bohr
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kimura
authors.forename: Abraham
authors.initials: A
authors.lastname: Aviv
authors.forename: Kaare
authors.initials: K
authors.lastname: Christensen
authors.forename: Lene
authors.initials: L
authors.lastname: Christiansen
mesh_terms: D000368:Aged; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007962:Leukocytes / Q000378:metabolism*; D008136:Longevity; D008137:Longitudinal Studies; D008297:Male; D012313:RNA / Q000235:genetics*; D019098:Telomerase / Q000235:genetics*; D016615:Telomere / Q000235:genetics*
chemical_list: C422952:telomerase RNA; D012313:RNA; D019098:Telomerase