Shorter Relative Telomere Length Research Articles

Fructose intake and its association with relative telomere length: an exploratory study among healthy Lebanese adults.

Shorter relative telomere length (RTL) has been associated with increased incidence of morbidity. Although still disputed, available evidence suggests that dietary factors, including sugar-sweetened beverages (SSB) may be linked with shorter RTL. It was argued that the link between SSB and RTL may be explained by the sugar content of these beverages, and specifically fructose given its impact on oxidative stress and the inflammatory response. However, none of the existing studies have examined the specific link between fructose intake and RTL. This exploratory study aimed at (1) assessing the intake of dietary fructose (total, added and natural) in Lebanese healthy adults and (2) examining dietary fructose as a predictor of short telomere length. Following a cross-sectional design (n = 282), anthropometric and biochemical data were collected. RTL was assessed by utilizing real-time polymerase chain reaction (RT-qPCR) to amplify both telomere and single-copy gene segments. Dietary intake was evaluated using a culture-specific food frequency questionnaire (FFQ). Intakes of added fructose, naturally-occurring fructose, and total fructose were estimated. Mean intakes of added and natural fructose were of 39.03 ± 34.12 and 12.28 ± 8.59 g/day, respectively, representing 4.80 ± 3.56 and 1.78 ± 1.41% of total energy intake (EI). Mean total fructose intake was of 51.31 ± 35.55 g/day, contributing 6.58 ± 3.71% EI. Higher intakes of total and added fructose were significantly associated with shorter RTL 2nd RTL tertile as compared to the 3rd RTL tertile; relative risk ratio (RRR) = 3.10 [95% confidence interval (CI): 1.38, 6.94] and RRR = 2.33 (95% CI: 1.02, 5.36), respectively after adjustment for confounders identified using a directed acyclic graph (DAG). In conclusion, although we could not observe a dose-dependent relation between fructose intakes and RTL shortening and although the study is limited by its small sample size, the findings suggest that total and added dietary fructose intakes may be associated with shorter RTL. Larger studies, of longitudinal nature, are needed to further confirm the study findings.

Abstract 4220: Occupational pesticide use and relative leukocyte telomere length in the biomarkers of exposure and effect in agriculture study

Abstract Background: Previous epidemiologic studies have reported increased risks of certain cancers in relation to specific pesticide exposures, although the mechanisms underlying many of these associations remain poorly understood. Within the Biomarkers of Exposure and Effect in Agriculture (BEEA) study, a molecular epidemiologic investigation of pesticide applicators in Iowa and North Carolina, we examined whether occupational use of pesticides is associated with alterations in leukocyte telomere length. Telomeres are essential in maintaining chromosomal stability and altered telomere length has been linked to various malignancies. Methods: Relative telomere length (RTL) was measured using quantitative PCR in leukocytes from 1,539 male pesticide applicators ≥50 years of age. Using self-reported information on pesticide use, we characterized lifetime use of specific pesticides in terms of ever use and intensity-weighted lifetime days (IWLDs), a metric integrating total lifetime days of use and other factors influencing exposure. Multivariable linear regression models were used to estimate differences in geometric mean RTL (and corresponding 95% confidence intervals) by ever vs. never use of 48 pesticides and in exposure-response analyses for IWLDs of use of 46 pesticides, adjusting for age, state of residence, race/ethnicity, body mass index, and cigarette smoking status and pack-years. Results: Among ever users of the insecticides lindane and aldicarb, mean RTL was significantly longer compared to never users (p=0.01 and 0.03, respectively); in exposure-response analyses, we also observed a suggestive but non-statistically significant trend between increasing IWLDs of lindane use and longer RTL (p-trend=0.07). Higher IWLDs of use of the insecticide diazinon was also associated with longer RTL (p-trend=0.03) while increasing IWLDs of the insecticide heptachlor and the herbicide 2,4,5-TP were associated with shorter RTL (p-trends=0.04 and 0.03, respectively). Conclusions: This is, to our knowledge, the largest investigation of occupational pesticide use and RTL to date. Our findings provide novel evidence suggesting that use of certain pesticides could be associated with altered leukocyte telomere length. Notably, diazinon and lindane have previously been associated with increased risks of lung and lymphoid malignancies, respectively, and longer leukocyte telomere length has been implicated in the development of these cancers. Citation Format: Patricia A. Erickson, Vicky C. Chang, Casey L. Dagnall, Kedest Teshome, Mitchell J. Machiela, Kathryn H. Barry, Shahinaz M. Gadalla, Laura E. Beane Freeman, Gabriella Andreotti, Jonathan N. Hofmann. Occupational pesticide use and relative leukocyte telomere length in the biomarkers of exposure and effect in agriculture study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4220.

The relationship between relative telomere length and anti-tuberculosis drug-induced hepatitis : A case-control study

Anti-tuberculosis drug-induced hepatitis (AT-DIH) is a common and serious adverse drug reaction of tuberculosis treatment. Evidence demonstrated that many factors could affect the occurrence of AT-DIH, such as ageing, smoking, alcohol, oxidative stress, etc., while these factors could also promote telomere shortening. Therefore, relative telomere length (RTL) is indirectly related to the occurrence of AT-DIH. The present study aimed to explore and validate this relationship in Chinese tuberculosis patients. A 1:4 matched case-control study was undertaken using 202 AT-DIH cases and 808 controls. Logistic regression models were used to estimate the association between RTL and AT-DIH with odds ratios (ORs) and 95% confidence intervals (CIs). The area under receiver operating characteristic curve (AUC) was calculated to estimate the discriminative performance for distinguishing AT-DIH cases from controls. The average RTL in AT-DIH cases was significantly shorter than that in controls (1.24 vs. 1.46, P=0.002). Patients with longer RTL were at a reduced risk of AT-DIH (OR=0.79, 95% CI: 0.66-0.94, P=0.009), and a dose-response relationship also existed between RTL and lower AT-DIH risk (P for trend=0.012). Under the optimal RTL cut-off value of 1.22, the corresponding AUCs were 0.57 (95% CI: 0.53-0.62, P=0.001) in the univariate model and 0.62 (95% CI: 0.57-0.66, P<0.001) in the multivariate model. This study showed that the shorter the RTL, the higher the risk of AT-DIH during an anti-tuberculosis treatment. The short RTL could potentially serve as a risk factor or a predictive test of the hepatotoxic risk associated with anti-tuberculosis treatments.

Concomitant use of relative telomere length, biological health score and physical/social statuses in the biological aging evaluation of mustard-chemical veterans

Sulfur mustard (SM) is a toxic gas that has been used as a chemical weapon in wars. After many years, SM-exposed people are still suffering from its side effects such as biological and premature aging. This study was aimed to evaluate biological aging rate via involving biological health scoring (BHS), relative telomere length (TL) and different physical/social variables i.e. marital and smoking statuses, body mass index, salary and educational levels. BHS was calculated according to measurement of 18 biomarkers related to function of four physiological systems (endocrine, inflammatory, cardiovascular and metabolic systems) and two organs (liver and kidney). The volunteers were 442 individuals exposed to SM gas in 1987 and 119 healthy individuals as non-exposed group. Each group was divided based on leukocyte relative TL (short, intermediate and long). Our data showed an inverse correlation between BHS and relative TL in two groups. The BHS was significantly higher in SM-exposed group than non-exposed group, especially in the participants with short and intermediate TL. The BHS had also a positive correlation with smoking and BMI parameters, and a negative correlation with salary and educational levels in the participants with shorter telomeres; and SM strengthened these correlations in the shorter telomeres. It is concluded that the higher BHS along with shorter relative TL that are indices for lower health quality and biological aging, could be used in the health evaluation of non- and SM-exposed people; and involving of BHS, TL and physical/social covariates could be useful to make this evaluation more accurate.

Long-Term Follow-Up of Newborns with 22q11 Deletion Syndrome and Low TRECs

BackgroundPopulation-based neonatal screening using T-cell receptor excision circles (TRECs) identifies infants with profound T lymphopenia, as seen in cases of severe combined immunodeficiency, and in a subgroup of infants with 22q11 deletion syndrome (22q11DS).PurposeTo investigate the long-term prognostic value of low levels of TRECs in newborns with 22q11DS.MethodsSubjects with 22q11DS and low TRECs at birth (22q11Low, N=10), matched subjects with 22q11DS and normal TRECs (22q11Normal, N=10), and matched healthy controls (HC, N=10) were identified. At follow-up (median age 16 years), clinical and immunological characterizations, covering lymphocyte subsets, immunoglobulins, TRECs, T-cell receptor repertoires, and relative telomere length (RTL) measurements were performed.ResultsAt follow-up, the 22q11Low group had lower numbers of naïve T-helper cells, naïve T-regulatory cells, naïve cytotoxic T cells, and persistently lower TRECs compared to healthy controls. Receptor repertoires showed skewed V-gene usage for naïve T-helper cells, whereas for naïve cytotoxic T cells, shorter RTL and a trend towards higher clonality were found. Multivariate discriminant analysis revealed a clear distinction between the three groups and a skewing towards Th17 differentiation of T-helper cells, particularly in the 22q11Low individuals. Perturbations of B-cell subsets were found in both the 22q11Low and 22q11Normal group compared to the HC group, with larger proportions of naïve B cells and lower levels of memory B cells, including switched memory B cells.ConclusionsThis long-term follow-up study shows that 22q11Low individuals have persistent immunologic aberrations and increased risk for immune dysregulation, indicating the necessity of lifelong monitoring.Clinical ImplicationsThis study elucidates the natural history of childhood immune function in newborns with 22q11DS and low TRECs, which may facilitate the development of programs for long-term monitoring and therapeutic choices.

Shorter Leukocyte Telomere Length Is Associated with Worse Survival of Patients with Bladder Cancer and Renal Cell Carcinoma.

Simple SummaryIntrinsic telomere shortening promotes tumorigenesis in cells with impaired DNA damage repair mechanisms, as dysfunctional telomeres lead to chromosomal instability. More recent data show that the telomere length of peripheral blood leukocyte (PBL) cells can be a prognostic marker for survival of patients with solid tumors. However, reports on bladder cancer (BC) and renal cell carcinoma (RCC) are not consistent and partly contradictory. Our results show, first, that telomere length is shorter in patients with BC or RCC compared to patients without malignant disease. More importantly, the relative telomere length (RTL) of PBL cells is associated with survival of patients with BC and RCC. Thus, telomere length in PBL cells could be an auxiliary prognostic marker in BC and RCC.Background: Telomeres are protein–DNA complexes at the tips of linear chromosomes. They protect the DNA from end-to-end fusion and exonucleolytic degradation. Shortening of telomeric DNA during aging can generate dysfunctional telomeres, promoting tumorigenesis. More recent data indicate that both short and long telomeres of peripheral blood leukocyte (PBL) cells can serve as prognostic biomarkers for cancer risk and may be associated with survival of patients with solid cancers. Telomere length in PBL cells could also be a potential prognostic biomarker for survival in bladder cancer (BC) or renal cell carcinoma (RCC). Methods: The relative telomere length (RTL) of PBL cells was assessed in patients with BC (n = 144) and RCC (n = 144) by using qPCR. A control population of patients without malignant disease (NC, n = 73) was included for comparison. The correlation and association of RTL with histopathological parameters and overall survival (OS) were evaluated. Results: Patients with BC and RCC had significantly shorter telomeres compared to patients without malignant disease. Within the cancer cohorts, multivariate analysis revealed that short RTL is an independent predictor of worse survival in BC (p = 0.039) and RCC (p = 0.041). Conclusion: Patients with BC and RCC had significantly shorter telomeres compared to the normal population. Shorter RTL in BC and RCC was an independent predictor of reduced survival.

The correlation of salivary telomere length and single nucleotide polymorphisms of the ADIPOQ, SIRT1 and FOXO3A genes with lifestyle-related diseases in a Japanese population.

It has been reported that genetic factors are associated with risk factors and onset of lifestyle-related diseases, but this finding is still the subject of much debate. The aim of the present study was to investigate the correlation of genetic factors, including salivary telomere length and three single nucleotide polymorphisms (SNPs) that may influence lifestyle-related diseases, with lifestyle-related diseases themselves. In one year at a single facility, relative telomere length and SNPs were determined by using monochrome multiplex quantitative polymerase chain reaction and TaqMan SNP Genotyping Assays, respectively, and were compared with lifestyle-related diseases in 120 Japanese individuals near our university. In men and all participants, age was inversely correlated with relative telomere length with respective p values of 0.049 and 0.034. In men, the frequency of hypertension was significantly higher in the short relative telomere length group than in the long group with unadjusted p value of 0.039, and the difference in the frequency of hypertension between the two groups was of borderline statistical significance after adjustment for age (p = 0.057). Furthermore, in men and all participants, the sum of the number of affected lifestyle-related diseases, including hypertension, was significantly higher in the short relative telomere length group than in the long group, with p values of 0.004 and 0.029, respectively. For ADIPOQ rs1501299, men's ankle brachial index was higher in the T/T genotype than in the G/G and G/T genotypes, with p values of 0.001 and 0.000, respectively. For SIRT1 rs7895833, men's body mass index and waist circumference and all participants' brachial-ankle pulse wave velocity were higher in the A/G genotype than in the G/G genotype, with respective p values of 0.048, 0.032 and 0.035. For FOXO3A rs2802292, women's body temperature and all participants' saturation of peripheral oxygen were lower in the G/T genotype than in the T/T genotype, with respective p values of 0.039 and 0.032. However, relative telomere length was not associated with physiological or anthropometric measurements except for height in men (p = 0.016). ADIPOQ rs1501299 in men, but not the other two SNPs, was significantly associated with the sum of the number of affected lifestyle-related diseases (p = 0.013), by genotype. For each SNPs, there was no significant difference in the frequency of hypertension or relative telomere length by genotype. Relative telomere length and the three types of SNPs determined using saliva have been shown to be differentially associated with onset of and measured risk factors for lifestyle-related diseases consisting mainly of cardiovascular diseases and cancer.

A Novel Association between YKL-40, a Marker of Structural Lung Disease, and Short Telomere Length in 10-Year-Old Children with Bronchopulmonary Dysplasia.

Extremely preterm infants are born with immature lungs and are exposed to an inflammatory environment as a result of oxidative stress. This may lead to airway remodeling, cellular aging and the development of bronchopulmonary dysplasia (BPD). Reliable markers that predict the long-term consequences of BPD in infancy are still lacking. We analyzed two biomarkers of cellular aging and lung function, telomere length and YKL-40, respectively, at 10 years of age in children born preterm with a history of BPD (n = 29). For comparison, these markers were also evaluated in sex-and-age-matched children born at term with childhood asthma (n = 28). Relative telomere length (RTL) was measured in whole blood with qPCR and serum YKL-40 with ELISA, and both were studied in relation to gas exchange and the regional ventilation/perfusion ratio using three-dimensional V/Q-scintigraphy (single photon emission computer tomography, SPECT) in children with BPD. Higher levels of YKL-40 were associated with shorter leukocyte RTL (Pearson’s correlation: −0.55, p = 0.002), but were not associated with a lower degree of matching between ventilation and perfusion within the lung. Serum YKL-40 levels were significantly higher in children with BPD compared to children with asthma (17.7 vs. 13.2 ng/mL, p < 0.01). High levels of YKL-40 and short RTLs were associated to the need for ventilatory support more than 1 month in the neonatal period (p < 0.01). The link between enhanced telomere shortening in childhood and structural remodeling of the lung, as observed in children with former BPD but not in children with asthma at the age of 10 years, suggests altered lung development related to prematurity and early life inflammatory exposure. In conclusion, relative telomere length and YKL-40 may serve as biomarkers of altered lung development as a result of early-life inflammation in children with a history of prematurity.

Telomere length in relation to colour polymorphism across life stages in the tawny owl

Telomere erosion has been proposed to be tightly associated with senescence, environmental stressors and life history trade‐offs. How telomere dynamics vary across life stages and especially in relation to (heritable) phenotypic traits is still unclear. The tawny owl Strix aluco display a highly heritable melanin‐based colour polymorphism, a grey and a brown morph, linked to several fitness traits including morph‐specific telomere dynamics. As adults, brown tawny owls have shorter relative telomere length (RTL) and exhibit faster telomere shortening rate than grey owls. Here we test if these morph‐specific telomere dynamics emerge already during growth, or if they are induced only in adult life through differential physiological costs associated with the life history of the morphs. We analysed RTL from 287 tawny owl offspring and 81 first breeding adults to evaluate at what life stage morph‐specific patterns emerge. We found no differences in RTL between the two morphs during the nestling period nor at the first breeding attempt. Sex, brood size or size rank in the nest did not affect offspring RTL. Among first‐breeders, females had shorter telomeres than males suggesting a sampling‐time dependent difference in reproductive costs between sexes, due to the prominent sex roles in tawny owls in the early nestling period. The probability to return to breed after the first breeding attempt was not affected by RTL, sex or colour morph. The lack of morph‐specific difference in RTL among nestlings and first breeders suggests that previously observed morph‐specific differences in RTL dynamics in adults emerge at the onset of the breeding career and is likely due to different physiological profiles and life‐history strategies adopted by adults. We conclude that different telomere dynamics and senescence patterns among highly heritable phenotypes (colour morphs) are likely to be a result of differential costs of reproduction and self‐maintenance.

The effect of environmental Bisphenol A exposure on breast cancer associated with obesity

Bisphenol A (BPA) is a widely used endocrine disrupter. Its environmental exposure is a causative factor of cell aging via decreasing telomerase activity, thus leading to shortening of telomere length. Epidemiological studies confirm positive associations between BPA exposure and the incidence of obesity and type 2 diabetes (T2DM). Increased urinary BPA levels in obese females are both significantly correlated with shorter relative telomere length and T2DM. BPA is a critically effective endocrine disrupter leading to poor prognosis via the obesity-inflammation-aromatase axis in breast cancer. Environmental BPA exposure contributes to the progression of both estrogen dependent and triple negative breast cancers. BPA is a positive regulator of human telomerase reverse transcriptase (hTERT) and it increases the expression of hTERT mRNA in breast cancer cells. BPA exposure can lead to tamoxifen resistance. Among patients treated with chemotherapy, those with persistent high telomerase activity due to BPA are at higher risk of death.

Telomere length and its relationships with lifestyle and behavioural factors: variations by sex and race/ethnicity.

Adherence to healthy lifestyles/behaviours promotes healthy ageing. However, little is known about whether age, sex and/or race/ethnicity moderate associations of lifestyle/behavioural factors with relative telomere length (RTL), a potential biomarker of ageing. We included 749 midlife to older non-Hispanic White (n = 254), Black (n = 248) and Hispanic (n = 247) US participants [mean (standard deviation) age = 69.3 (7.2) years; women: 50.5%]. We extracted genomic DNA from peripheral leucocytes. RTL was assayed using real-time quantitative polymerase chain reaction. Multivariable regression was used to examine associations between lifestyle/behavioural exposures (i.e. physical activity, alcohol consumption, smoking and depression) with RTL. Increasing chronological age was associated with shorter RTL (P < 0.01). Higher physical activity was associated with longer RTL (P-trend = 0.03); daily versus never/rare alcohol consumption and 30+ versus <5 smoking pack-year were associated with shorter RTLs (P-trend = 0.02). Associations varied significantly by sex and race/ethnicity. The association between physical activity and longer RTL appeared strongest among non-Hispanic Whites (P-interaction = 0.01). Compared to men, women had stronger associations between heavy smoking and shorter RTLs (P-interaction = 0.03). Light/moderate alcohol consumption (monthly/weekly) was associated with longer RTL among non-Hispanic Whites, while daily consumption was related to shorter RTLs among Blacks and Hispanics (P-interactions < 0.01). Associations of daily alcohol and heavy smoking with shorter RTLs were particularly apparent among Black women. We observed novel variations by sex and race/ethnicity in associations between lifestyle/behavioural factors and RTL. Further work is needed to replicate these findings and to address potential public health implications for modifying strategies by sex or across racial/ethnic groups to optimise lifestyles/behaviours for healthy ageing.

Telomere shortening is associated with poor physical performance in knee osteoarthritis.

Telomere length is a hallmark characteristic of ageing and age-related diseases. Osteoarthritis (OA) is the most common cause of joint pain and physical disability in the elderly. Previous studies have revealed the role of telomere shortening in OA; however, the relationship between telomere length, muscle strength and physical performance in knee OA patients remains unknown. The aim of the present study was to investigate the association of telomere length and physical performance in patients with knee OA. A total of 202 patients with knee OA and 60 healthy controls were enrolled in the study. The quality of life was assessed using Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index and Short Form Health Survey. The skeletal muscle mass was examined using bioelectrical impedance analysis, while the muscle strength was analyzed using hand grip force and isometric knee extension force. The physical performance of patients with knee OA was also investigated using gait speed, Timed up and go test (TUGT), Sit to stand test and 6-min walk test (6MWT). Blood leukocyte relative telomere length (RTL) was assessed using real time quantitative PCR. The mean blood leukocyte RTL in knee OA subjects was significantly lower compared with healthy controls (P<0.001). Knee OA patients with RTL values in the lowest quartile had a slow gait speed (P=0.006) and prolonged TUGT time (P=0.03). Multivariate regression analyses and multiple logistic regression analyses adjusted for age, sex, waist circumference, body mass index, fat mass, skeletal muscle index and the total WOMAC demonstrated that gait speed, TUGT and 6MWT were associated with longer RTL (P-trend<0.05). These findings suggested that poorer physical performance was associated with shorter RTL. Therefore, leukocyte telomere length and physical performance tests, especially gait speed, TUGT and 6MWT, could predict the health status and quality of life in patients with knee OA.

Short Dysfunctional Telomere Is Highly Predictive of Dismal Outcome in MDS but Not in AML Patients.

Background: A trigger for initiation the clonal hematopoietic stem cells disorders could be short telomere length probably due to chromosomal instability. The relationship between relative telomere length (RTL) and the two linked hematological stem cell disorders, myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) is still unclear. Materials and Methods: We evaluated the role of RTL in MDS (n=96) and AML (n=130) at the time of diagnosis using a real time quantitative polymerase chain reaction (RT-PCR) technique. The median value of RTL (1) was set as the cutoff for statistical comparison. Overall survival (OS) is defined as the time from diagnosis to death or last follow-up. Results: RTL was significantly longer in both MDS and AML cases versus control (p<0.0001) and was significantly longer in MDS versus AML cases (p =0.03). RTL correlated negatively with age in MDS (p <0.0001) but not in AML cases. RTL was also significantly shorter in MDS cases with pancytopenia and poor risk cytogenetics (p < 0.0001 for each) and short RTL was significantly associated with inferior survival (p = 0.007), while RTL showed no significant impact on OS in AML cases. Moreover, short RTL retained independent prognostic value in multivariate analysis (HR= 3.42 [95% CI, 8.97-19.35], p = 0.004). Conclusion: RTL showed an association with both AML and MDS; however, short RTL was an independent poor prognostic factor in MDS patients only.

Telomere Length and Glutathione Level as Potential Biomarkers for Autism

Oxidative stress is a common feature in nearly all neurodegenerative disorders including autism spectrum disorder (ASD). ASD is behaviorally defined disorder associated with abnormalities in social communication, behavior, language and perception. Chronic exposure to different common stress factors like immune inflammation, malnutrition, alcohol, abuse and drugs induce congenital and behavioral impairment. To the best of our knowledge this study is the first exploring the rate of oxidative stress and its effect on telomere length simultaneously in Egyptian autistic children. In this study we investigated the effect of oxidative stress associated with ASD. Patients were selected based on full clinical and neurological examination and the severity of autism evaluated using childhood autism rating scale (CARS) and Autism Diagnostic Interview–Revised (ADI™-R). Expectedly we found the majority of autism affected children were males, and consanguinity rate between the ASD families was ~ 27% while it was completely absent in the control subjects. We found a highly significant correlation between ASD and low levels of total glutathione (P&lt;0.001) compared to controls. We reported a remarkable highly significant correlation between ASD children and shorter relative telomere length (P&lt;0.001). Moreover we identified a correlation between telomere length and behavioral characteristics in autistic children represented by social interaction impairment (ADI-R 1st domain) (r= - 0.354, P = 0.025). Here we conclude that oxidative stress represented by low glutathione level is an early sign of autism, and is affecting the telomere length that protecting the genetic material. Behavioral abnormalities associated with autism are dependent on telomere length

Genetic variations associated with telomere length affect the risk of gastric carcinoma.

This study aimed to further understand the role of relative telomere length (RTL) in susceptibility to gastric carcinoma (GC) and investigate the association between genetic polymorphisms in the telomere length related genes and GC risk.RTL was measured using the real-time quantitative polymerase chain reaction from 1000 patients and 1100 healthy controls. Genotyping was performed using the Agena MassARRAY platform. The statistical analysis was performed using the chi-square/ Welch T tests, Mann-Whitney U test, and logistic regression analysis.The association analysis of telomere length and GC showed that the RTL in the case group was shorter than in the controls, and the shorter RTL was associated with an increased risk of GC. The association analysis between telomere length related genes polymorphisms and genetic susceptibility to GC indicated that: In the allele models and genetic models, TERT (rs10069690, rs2242652 and rs2853676) and TN1F1 (rs7708392 and rs10036748) were significantly associated with an increased risk of GC. In addition, the haplotype 'Grs10069690Crs2242652" of TERT and the haplotype 'Grs7708392Trs10036748" of TNIP1 were associated with an increased risk of GCOur results suggested that shorter RTL was associated with an increased risk of GC; The association analysis have identified that the TERT (rs10069690, rs2242652 and rs2853676) and TN1P1 (rs7708392 and rs10036748) were associated with GC risk.

Leukocyte telomere length as a diagnostic biomarker for anti-tuberculosis drug-induced liver injury

Despite being relatively rare, anti-tuberculosis drug-induced liver injury (ATDILI) is a leading cause of acute liver failure and a major reason for treatment discontinuation, because of no specific and selective markers for ATDILI. Herein, this study aimed to investigate whether telomere length, a biological indicator of age-related diseases, is associated with ATDILI outcomes and could serve as an early ATDILI biomarker. Relative telomere length (RTL) in blood leukocyte of 100 age- and gender-matched healthy controls, 49 tuberculosis patients with ATDILI, and 53 tuberculosis patients with non-ATDILI was quantified using real-time polymerase chain reaction. Both tuberculosis patients with and without ATDILI had significantly shorter RTL than healthy controls. Compared with tuberculosis patients with non-ATDILI, RTL in those with ATDILI was significantly increased. Longer RTL was found to be significantly associated with increased susceptibility to ATDILI. Multivariate linear regression analysis showed that an increment in RTL was independently correlated with elevated values of aspartate aminotransferase and alanine aminotransferase assessed within 60 days after anti-tuberculosis treatment. Kaplan-Meier curve analysis demonstrated that longer RTL was associated with elevated rates of hepatotoxicity in tuberculosis patients. Receiver-operating characteristic curve analysis unveiled a diagnostic accuracy of RTL as a novel indicator for ATDILI progression (AUC = 0.73), which yielded more sensitive and specific values than traditional liver biomarkers including serum enzyme activities of aminotransferases measured within 7 days after treatment with anti-tuberculosis regimens. Collectively, aberrant RTL in blood leukocyte would reflect hepatotoxicity induced by anti-tuberculosis agents and might have a potential biomarker for early ATDILI progression.

Discriminating association of a common telomerase reverse transcriptase promoter polymorphism with telomere parameters in non-small cell lung cancer with or without epidermal growth factor receptor mutation

BackgroundThe role of epidermal growth factor receptor (EGFR) pathways in regulating telomerase is increasingly being recognised. We analysed the impact of rs2853669 single nucleotide polymorphism (SNP) on telomere parameters and its prognostic value for non-small cell lung cancer (NSCLC) with or without EGFR mutation. MethodsThe association of rs2853669 with telomerase reverse transcriptase (TERT) mRNA level and relative telomere length (RTL) was analysed using resected tumour samples from 250 NSCLC patients. We also investigated the patients’ clinical outcomes with a median follow-up of 57 months (2–99 months). ResultsThe rs2853669 T/C allele was significantly associated with lower TERT mRNA expression (versus C/C and versus T/T; p < 0.001 for both) and shorter RTL (versus C/C and versus T/T; p = 0.039 and 0.023) in patients without EGFR mutation. Such difference was not observed in their counterparts harbouring EGFR mutation. When considering the cohort as a whole, T/C allele was significantly associated with shortest overall survival compared with T/T or C/C allele (mean: 61.8, 80.9 and 88.7 months, plog-rank < 0.001) and disease-free survival (mean: 78.3, 87.9 and 91.5 months, plog-rank = 0.019). Stratification analyses showed that the negative prognostic effect of T/C on OS was constrained in patients without EGFR mutation. ConclusionOur study revealed significant associations of a common SNP within TERT promoter region on telomere parameters and survival in NSCLC patients without EGFR mutation. The result may help providing instruction for therapeutic interventions targeting telomerase and evidence for investigation of TERT-EGFR interacting mechanism in telomere biology.

Pre-transplant short telomeres are associated with high mortality risk after unrelated donor haematopoietic cell transplant for severe aplastic anaemia.

Telomeres are essential for chromosomal stability and markers of biological age. We evaluated the effect of pre-transplant short (<10th percentile-for-age) or very short (<5th or <1st percentile-for-age) leucocyte telomere length on survival after unrelated donor haematopoietic cell transplantation (HCT) for acquired severe aplastic anaemia (SAA). Patient pre-transplant blood samples and clinical data were available at the Center for International Blood and Marrow Transplant Research. We used quantitative real time polymerase chain reaction to measure relative telomere length (RTL) in 490 SAA patients who received HCT between 1990 and 2013 (median age=20years). One hundred and twelve patients (22·86%) had pre-HCT RTL <10th percentile-for-age, with the majority below the 5th percentile (N=80, 71·43%). RTL <10th percentile-for-age was associated with a higher risk of post-HCT mortality (hazard ratio [HR]=1·78, 95% confidence interval [CI]=1·18-2·69, P=0·006) compared with RTL ≥50th percentile; no survival differences were noted in longer RTL categories (P>0·10). Time-dependent effects for post-HCT mortality were only observed in relation to very short RTL; HR comparing RTL <5th versus ≥5th percentile=1·38, P=0·15 for the first 12months after HCT, and HR=3·91, P<0·0001, thereafter, P-heterogeneity=0·008; the corresponding HRs for RTL <1st versus ≥1st percentile=1·29, P=0·41, and HR=5·18, P<0·0001, P-heterogeneity=0·005. The study suggests a potential role for telomere length in risk stratification of SAA patients in regard to their HCT survival.

Hazardous air pollutants and telomere length in the Sister Study.

Telomeres are vital for genomic integrity and telomere length has been linked to many adverse health outcomes. Some hazardous air pollutants, or air toxics, increase oxidative stress and inflammation, two possible determinants of shortened telomere length. No studies have examined air toxic-telomere length associations in a non-occupational setting. This study included 731 Sister Study participants (enrolled 2003-2007) who were randomly selected to assess telomere length in baseline blood samples. Multiplex qPCR was used to determine telomere to single copy gene (T/S) ratios. Census tract concentration estimates of 29 air toxics from the 2005 National Air Toxics Assessment were linked to baseline residential addresses. Air toxics were classified into tertile-based categories of the exposure. Multivariable linear regression was used to estimate β coefficients and 95% confidence intervals (CI) in single pollutant models. Multipollutant groups were identified with regression trees. The average T/S ratio was 1.24. Benzidine (T3vsT1 β= -0.08; 95% CI: -0.14, -0.01) and 1,4-dioxane (T3vsT1 β= -0.06; 95% CI: -0.13, 0.00) in particular, as well as carbon tetrachloride, chloroprene, ethylene dibromide, and propylene dichloride, were associated with shorter relative telomere length. Benzidine (p=0.02) and 1,4-dioxane (p=0.06) demonstrated some evidence of a monotonic trend. The regression tree identified age, BMI, physical activity, ethylene oxide, acrylonitrile, ethylidene dichloride, propylene dichloride, and styrene in multipollutant groups related to telomere length. In this first study of air toxics and telomere length in a non-occupational setting, several air toxics, particularly 1,4-dioxane and benzidine, were associated with shorter relative telomere length.

Telomere length in peripheral blood leukocytes and risk of renal cell carcinoma.

BackgroundTelomeres are essential for chromosomal stability and may play a key role in carcinogenesis. Telomere length is suggested as a tentative biomarker of risk for renal cell carcinoma (RCC). However, results of previous association studies between telomere length and risk for RCC are inconsistent.MethodsWe evaluated RCC risk in relation to peripheral blood leukocyte telomere length using a hospital-based case–control study of 169 RCC cases and 189 controls. Cases were histologically-confirmed RCC patients who were treated at the Moffitt Cancer Center (Tampa, FL). Controls with no history of cancer underwent a screening exam at the Lifetime Cancer Screening Center at Moffitt Cancer Center to rule out the presence of cancer. Relative telomere length (RTL) was measured by quantitative real-time polymerase chain reaction (PCR) using peripheral blood leukocyte DNA. Logistic regression was used to determine the association between RTL and RCC risk.ResultsAs expected, increasing age was inversely correlated with RTL (Pearson r=−0.213, P=0.003) among controls but not cases. Average RTL was significantly shorter in cases as compared with controls [mean ± standard deviation (SD): 3.18±1.50 and 4.39±1.99, respectively, P<0.001]. In contrast, average RTL was not significantly different by gender, race, smoking status among controls or by clinical stages among RCC cases. In regression analysis, we observed that shorter RTL is significantly associated with RCC risk [odds ratio (OR) =1.48; 95% confidence interval (CI): 1.27–1.71] after adjustment for covariates.ConclusionsWe found that shorter RTL is associated with an increased risk for RCC. Our findings suggest that telomere length may be involved in the development of RCC.