Genome-Wide Association Study of Relative Telomere Length

Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
PLoS ONE (Impact Factor: 3.23). 05/2011; 6(5):e19635. DOI: 10.1371/journal.pone.0019635
Source: PubMed


Telomere function is essential to maintaining the physical integrity of linear chromosomes and healthy human aging. The probability of forming proper telomere structures depends on the length of the telomeric DNA tract. We attempted to identify common genetic variants associated with log relative telomere length using genome-wide genotyping data on 3,554 individuals from the Nurses' Health Study and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial that took part in the National Cancer Institute Cancer Genetic Markers of Susceptibility initiative for breast and prostate cancer. After genotyping 64 independent SNPs selected for replication in additional Nurses' Health Study and Women's Genome Health Study participants, we did not identify genome-wide significant loci; however, we replicated the inverse association of log relative telomere length with the minor allele variant [C] of rs16847897 at the TERC locus (per allele β = -0.03, P = 0.003) identified by a previous genome-wide association study. We did not find evidence for an association with variants at the OBFC1 locus or other loci reported to be associated with telomere length. With this sample size we had >80% power to detect β estimates as small as ±0.10 for SNPs with minor allele frequencies of ≥0.15 at genome-wide significance. However, power is greatly reduced for β estimates smaller than ±0.10, such as those for variants at the TERC locus. In general, common genetic variants associated with telomere length homeostasis have been difficult to detect. Potential biological and technical issues are discussed.

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Available from: Sharon A Savage, Oct 01, 2015
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    • "The majority of our candidate genes were selected based on three prior studies of telomere-related genes (Mirabello et al., 2012, 2010; Nan et al., 2011b) and one study of arsenic exposure, telomere length, and gene expression (Li et al., 2012). We also included all 11 genes reported in recent genome-wide association studies of telomere length (Codd et al., 2010; Gu et al., 2011; Levy et al., 2010; Mangino et al., 2012, 2009; Prescott et al., 2011): ZNF676, CTC1, OBFC1, TERC, DHX35, WDR65, PELI2, KPNA5, SLC44A4, CXCR4 and CELF4 (BRUNOL4). In addition, we included 2 genes related to telomere biology (OGG1 and ERCC1) (Lu and Liu, 2010; Vannier et al., 2009) whose expression was reported to be associated with arsenic exposure among individuals in Inner Mongolia, China (Mo et al., 2009a, 2006). "
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    ABSTRACT: Inorganic arsenic is a carcinogen whose mode of action may involve telomere dysfunction. Recent epidemiological studies suggest that chronic arsenic exposure is associated with longer telomeres and altered expression of telomere-related genes in peripheral blood. In this study, we evaluated the association of urinary arsenic concentration with expression of telomere-related genes and telomere length in Bangladeshi individuals with a wide range of arsenic exposure through naturally contaminated drinking water. We used linear regression models to estimate associations between urinary arsenic and array-based expression measures for 69 telomere related genes using mononuclear cell RNA samples from 1799 individuals. Association between arsenic exposure and a qPCR-based telomere length measure was assessed among 167 individuals. Urinary arsenic was possitively associated with expression of WRN, and negatively associated with TERF2, DKC1, TERF2IP and OBFC1 (all P<0.00035, Bonferroni-corrected threshold). We detected interaction between urinary arsenic and arsenic metabolism efficiency in relation to expression of WRN (P for interaction =0.00008). In addition, we observed that very high arsenic exposure was associated with longer telomeres compared to very low exposure (P=0.02). Our findings suggest that arsenic's carcinogenic mode of action may involve alteration of telomere maintenance and/or telomere damage. This study extends our knowledge regarding the effect of arsenic on telomere length and expression of telomere-related genes. Copyright © 2014 Elsevier Inc. All rights reserved.
    Environmental Research 11/2014; 136C:462-469. DOI:10.1016/j.envres.2014.09.040 · 4.37 Impact Factor
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    • "Telomere dysfunction has also been pointed out as leading to chromosome instability [6], [7]. This fact is based on the finding that cancer predisposition syndromes lead to telomere dysfunction and chromosome instability [8]. "
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    ABSTRACT: Telomere length is considered to be a risk factor in adults due to its proved association with cancer incidence and mortality. Since newborn present a wide interindividual variation in mean telomere length, it is relevant to demonstrate if these differences in length can act also as an early risk indicator. To answer this question, we have measured the mean telomere length of 74 samples of cord blood from newborns and studied its association with the basal genetic damage, measured as the frequency of binucleated cells carrying micronuclei. In addition, we have challenged the cells of a subgroup of individuals (N = 35) against mitomycin-C (MMC) to establish their sensitivity to induced genomic instability. Results indicate that newborn with shorter telomeres present significantly higher levels of genetic damage when compared to those with longer telomeres. In addition, the cellular response to MMC was also significantly higher among those samples from subjects with shorter telomeres. Independently of the causal mechanisms involved, our results show for the first time that telomere length at delivery influence both the basal and induced genetic damage of the individual. Individuals born with shorter telomeres may be at increased risk, especially for those biological processes triggered by genomic instability as is the case of cancer and other age-related diseases.
    PLoS ONE 03/2014; 9(3):e91753. DOI:10.1371/journal.pone.0091753 · 3.23 Impact Factor
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    • "In humans, leukocyte telomere length (LTL) progressively shortens with age because of the inability of DNA polymerase to fully replicate the 3′ end of the DNA strand in mitotic division, and is frequently reported to be relatively shorter in aging-related diseases: such as Alzheimer's disease [2] and vascular dementia [3]. LTL varies among individuals with the same age, and is found to be inheritable in quantitative-trait linkage analyses of sib pairs, with heritability estimates ranging from 36% to 86% [4]–[7]. "
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    ABSTRACT: Leukocyte telomere length (LTL) is a predictor of aging and a number of age-related diseases. We performed genome-wide association studies of mean LTL in 2632 individuals,with a two-stage replication in 3917 individuals from Chinese populations. To further validate our findings, we get the results of 696 samples from a cohort of European ancestry. We identified two loci associated with LTL that map in telomerase reverse transcriptase (TERT; rs2736100, P = 1.93×10(-5)) on chromosome 5p15.33 and near keratin 80 (KRT80; rs17653722, P = 6.96×10(-6)) on 12q13.13. In Chinese population each C allele of rs2736100 and T allele of rs17653722 was associated with a longer mean telomere length of 0.026 and 0.059 T/S, respectively, equivalent to about 3 and 7 years of average age-related telomere attrition. Our findings provide new insights into telomere regulatory mechanism and even pathogenesis of age-related diseases.
    PLoS ONE 01/2014; 9(1):e85043. DOI:10.1371/journal.pone.0085043 · 3.23 Impact Factor
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