Telomere Length, Mean Leukocyte

Description

Telomeres are special functional complexes at the ends of eukaryotic chromosomes involved in maintaining genetic stability and in regulation of cellular life span (Blackburn (2000, 2001); Blasco, 2003). Telomere homeostasis is relevant to normal aging and a wide range of disease states. Telomeres are made up of a variable number of tandem repeats (TTTAGGG in humans) that extend over several thousand basepairs. Telomere lengths are characteristic in each human individual and show wide interindividual variability (Slagboom et al., 1994; Jeanclos et al., 2000).

Other Features

Among 195 nondemented stroke (601367) survivors over age 75 years who were followed for 2 years for cognitive decline and 5 years for survival, Martin-Ruiz et al. (2006) found that longer telomeres in peripheral blood mononuclear cells were associated with decreased risk for death (p = 0.04) and dementia (p = 0.002) and with a smaller reduction in Mini-Mental State Examination score (p = 0.04). The authors suggested that peripheral leukocyte telomere length may serve as a biomarker for long-term stroke outcomes.

Inheritance

Twin and family studies (Slagboom et al., 1994; Jeanclos et al., 2000) yielded heritability values for mean telomere length in leukocytes of 78 to 84%.

In 130 individuals from 49 unrelated families, Nordfjall et al. (2005) determined telomere length in peripheral mononuclear cells and analyzed cultured Epstein-Barr virus-transformed lymphoblasts for the ability to maintain telomere length and for possible gender-linked inheritance of telomere length. They found a significant association between telomere lengths comparing father-son and father-daughter pairs (p = 0.011 and p = 0.005, respectively), but found no correlation between mother-daughter or mother-son pairs. The father-offspring correlation was highly significant (p less than 0.0001). Epstein-Barr virus cultures showed telomere preservation to be inversely related to initial mononuclear cell telomere length, with short telomeres displaying the most pronounced elongation. Nordfjall et al. (2005) concluded that telomere length is inherited and that there is evidence for father-to-offspring inheritance, whereas in vitro telomere length maintenance is dependent on initial telomere length.

In 3 families, comprising 6 parents and 9 offspring, Graakjaer et al. (2006) found a significant positive correlation of telomere length of allelic chromosome extremities transmitted from parent to child, suggesting heritability.

In a longitudinal study of 355 monozygotic and 297 dizygotic same-sex twins with an average follow-up of 12 years, Hjelmborg et al. (2015) found that the heritability of leukocyte telomere length at baseline was 64%, with 22% shared environmental effects. Heritability of age-dependent attrition rate was estimated at 28%. Individual unique environmental factors, estimated at 72%, affected attrition rate. Because attrition of leukocyte telomere length is slower in adults than in children, the findings suggested that heritability and early life environment are the main determinants of leukocyte telomere length throughout life.

Mapping

Linkage to Chromosome 3q26

Codd et al. (2010) conducted a genomewide association analysis of mean leukocyte telomere length in 2,917 individuals with follow-up in 9,492 individuals. They identified an association with telomere length on chromosome 3q26 (rs12696304, combined p = 3.72 x 10(-14)) at a locus that includes TERC (602322), which encodes the telomerase RNA component. Each copy of the minor allele (G) of rs12696304 was associated with an approximately 75-bp reduction in mean telomere length, equivalent to approximately 3.6 years of age-related telomere length attrition. The SNP rs12696304 is located 1.5 kb downstream of the TERC gene.

Linkage to Chromosome 12

Vasa-Nicotera et al. (2005) performed a QTL analysis of mean leukocyte telomere-restriction fragment lengths, measured by Southern blotting, in 383 adult subjects comprising 258 sib pairs. Heritability of mean TRF was 81.9% +/- 11.8%. There was significant linkage (lod = 3.20) of mean TRF length to a locus on chromosome 12, which explained 49% of the overall variability in mean TRF length. The interval on chromosome 12 indicated by the linkage studies spanned 13.2 Mb and contained 34 genes. Among these, the DNA helicase DDX11 (601150) emerged as a strong positional candidate to explain the effect on telomere length. Helicases unwind double-stranded DNA and RNA and are involved in a wide range of chromosome-related functions, including transcription, replication, segregation, and DNA repair. Many helicases have roles in the maintenance of telomeres and in telomere length control.

Andrew et al. (2006) pointed out that Vasa-Nicotera et al. (2005) used a random subsample of primarily male subjects from the British Heart Foundation (BHF) Family Heart Study, with probands originally selected for experience of heart disease, such as a heart attack, angina, or coronary bypass surgery, before age 65 years. Given that telomere length tends to be shorter among subjects with heart disease and among unaffected individuals, such an ascertainment scheme may have resulted in expression of different genes that influence telomere dynamics. By contrast, the data used in the study of Andrew et al. (2006) were from unselected healthy sisters. No evidence of linkage to chromosome 12 was found by Andrew et al. (2006).

In a study of mean leukocyte telomere length in 380 families with 520 sib pairs, including the study sample reported by Vasa-Nicotera et al. (2005), Mangino et al. (2008) confirmed linkage to the locus on chromosome 12 (maximum lod score of 4.3 at marker D12S345). Fine mapping identified a 51-kb region within intron 1 of the BICD1 gene (602204). The strongest association was with rs2630578 (p = 1.9 x 10(-5)), where the minor C allele (frequency 0.21) was associated with telomeres that were shorter by 604 (+/-204) base pairs, equivalent to approximately 15-20 years of age-related attrition in telomere length. Individuals carrying the C allele had 44% lower BICD1 mRNA levels in their leukocytes compared to GG homozygotes (p = 0.004), suggesting that the SNP has regulatory function. Since BICD1 is involved in Golgi-to-endoplasmic reticulum vacuolar transport, and studies have implicated vacuolar genes in telomere length homeostasis in yeast, Mangino et al. (2008) suggested that BICD1 may play a similar role in humans.

Linkage to Chromosome 14q

Andrew et al. (2006) performed a quantitative trait linkage (QTL) analysis of white blood cell mean terminal restriction fragment (TRF) links, measured by Southern blotting, for 2,050 adult female dizygotic twins comprising 1,025 twin pairs. The mean age for the twins was 47.8 +/- 12.4 years, with an age range of 18 to 80 years at the time of sample collection. For these cross-sectional data, Valdes et al. (2005) demonstrated linear age-related decrease in TRF length of approximately 27 +/- 1.5 bp per year. Andrew et al. (2006) determined that heritability of mean batch-adjusted TRF was 36% (95% confidence interval 18 to 48%), with a large common environmental effect of 49%. Significant linkage was observed on chromosome 14 (lod 3.9) at 14q23.2, and suggestive linkage at 10q26.13 (lod 2.4) and 3p26.1 (lod 2.7). This was said to be the first report of loci, mapped in a sample of healthy individuals, that influence mean telomere variation in humans.

Linkage to Chromosome 18q

In a genomewide association study of 1,625 adult women from the U.K. Adult Twin Register, Mangino et al. (2009) found an association between white cell telomere length and a region on chromosome 18q. The findings were replicated in 1,165 additional individuals of both genders from the U.K. Adult Twin Register. The joint analysis of genotyped data from the two cohorts yielded combined p values of 2.60 x 10(-6) at rs2162440 and 5.50 x 10(-6) at rs7235755 on 18q12.2. The G alleles of both SNPs were associated with shorter telomeres, extrapolating to an approximate 5 years of telomere erosion based on estimates of loss with age. The SNPs on chromosome 18q12.2 are located in a gene desert between the BRUNOL4 (612679) and PIK3C3 (602609) genes, the latter of which has been directly implicated in the pathway controlling telomere length variation in yeast.

Molecular Genetics

Associations Pending Confirmation

For discussion of a possible association between variation in the DCAF4 gene on chromosome 14q24 and leukocyte telomere length, see 616372.0001.

Animal Model

A locus determining telomere length in some mouse strains was mapped to chromosome 2 by Zhu et al. (1998).