Abstract
Various approaches exist to assess population differences in biological aging. Telomere length (TL) is one such measure, and is associated with disease, disability and early mortality. Yet, issues surrounding precision and reproducibility are a concern for TL measurement. An alternative method to estimate TL using DNA methylation (DNAmTL) was recently developed. Although DNAmTL has been characterized in adult and elderly cohorts, its utility in pediatric populations remains unknown. We examined the comparability of leukocyte TL measurements generated using qPCR (absolute TL; aTL) to those estimated using DNAmTL in a high-risk pediatric cohort (N = 269; age: 8–13 years, 83% investigated for maltreatment). aTL and DNAmTL measurements were correlated with one another (r = 0.20, p = 0.001), but exhibited poor measurement agreement and were significantly different in paired-sample t-tests (Cohen’s d = 0.77, p < 0.001). Shorter DNAmTL was associated with older age (r = −0.25, p < 0.001), male sex (β = −0.27, p = 0.029), and White race (β = −0.74, p = 0.008). By contrast, aTL was less strongly associated with age (r = −0.13, p = 0.040), was longer in males (β = 0.31, p = 0.012), and was not associated with race (p = 0.820). These findings highlight strengths and limitations of high-throughput measures of TL; although DNAmTL replicated hypothesized associations, aTL measurements were positively skewed and did not replicate associations with external validity measures. These results also extend previous research in adults and suggest that DNAmTL is a sensitive TL measure for use in pediatric populations.
Highlights
Telomeres are repetitive nucleoprotein regions at chromosome ends that prevent end to end fusions and maintain chromosome stability [1]
telomere length (TL) measurements estimated using qPCR were significantly longer than those estimated using DNA methylation in paired sample t-tests (Cohen’s d = 0.77, p < 0.001)
DNA methylation (DNAmTL) measurements fell within a narrower window, whereas absolute TL (aTL) tended to overestimate the longest telomeres (Figure 1)
Summary
Telomeres are repetitive nucleoprotein regions at chromosome ends that prevent end to end fusions and maintain chromosome stability [1]. The most common method to quantify TL in epidemiological research is quantitative-PCR (qPCR), which expresses telomeric content (T) relative to a single-copy gene (S) via a unitless metric known as the T/S ratio [15] This technique requires substantially less DNA than Southern blot and is high-throughput, capable of analyzing over 100 samples on a single assay. With a lifespan range of TL near 12.5 kb to 4.5 kb [25, 26], a low qPCR assay CV of 2% translates to measurement error of 90 bp-250 bp, possibly obscuring meaningful differences between groups Measurement error of this sort, combined with insufficient follow-up duration, may contribute to the telomere lengthening conundrum sometimes observed in longitudinal studies [27, 28], a finding counter to studies using larger samples or Southern Blot techniques that report decreases in TL on the scale of 20 bp-60 bp per year [2, 29,30,31]. We predicted that both shorter aTL and shorter DNAmTL will be associated with older age, male sex, White race, exposure to maltreatment, advanced pubertal development and younger paternal age
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