Leukocyte telomere length in relation to the risk of Barrett's esophagus and esophageal adenocarcinoma.

Chronic inflammation and oxidative damage caused by obesity, cigarette smoking, and chronic gastroesophageal reflux disease (GERD) are major risk factors associated with Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). EAC has been increasing the past few decades, and early discovery and treatment are crucial for survival. Telomere shortening due to cell division and oxidative damage may reflect the impact of chronic inflammation and could possibly be used as predictor for disease development. We examined the prevalence of shorter leukocyte telomere length (LTL) among individuals with GERD, BE, or EAC using a pooled analysis of studies from the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON). Telomere length was measured in leukocyte DNA samples by Q-PCR. Participants included 1173 patients (386 with GERD, 384 with EAC, 403 with BE) and 736 population-based controls. The association of LTL (in tertiles) along the continuum of disease progression from GERD to BE to EAC was calculated using study-specific odds ratios (ORs) and 95% confidence intervals (CIs) from logistic regression models adjusted for potential confounders. Shorter LTL were less prevalent among GERD patients (OR 0.57; 95% CI: 0.35-0.93), compared to population-based controls. No statistically significant increased prevalence of short/long LTL among individuals with BE or EAC was observed. In contrast to some earlier reports, our findings add to the evidence that leukocyte telomere length is not a biomarker of risk related to the etiology of EAC. The findings do not suggest a relationship between LTL and BE or EAC.

Telomere length attrition and chronic periodontitis: an ARIC Study nested case-control study.

AIM: This nested case-control study sought to determine whether an accelerated rate of leukocyte telomere length (LTL) shortening over 6 years was associated with chronic periodontitis. MATERIALS AND METHODS: We sampled cases (n = 178) with severe chronic periodontitis and controls (n = 178) with no/mild chronic periodontitis from the Atherosclerosis Risk in Communities study. Controls were frequency-matched to cases by study site, age, sex and race. Age ranged from 53 to 73 years. Severe chronic periodontitis was defined using the CDC-AAP case classification. LTL was measured from DNA collected at two time points, 6 years apart, with quantitative polymerase chain reaction relative to a single-copy control gene. Multiple linear regression evaluated associations between LTL measured at baseline, follow-up and change scores with severe chronic periodontitis, adjusting for potential confounders. RESULTS: Cases had shorter LTL than controls at baseline (p = 0.03) and follow-up (p = 0.04) after adjusting for confounding. Overall there was a net reduction in LTL over time (p = 0.02). The rate of LTL did not differ between cases and controls (p = 0.80). CONCLUSIONS: Leukocyte telomere length shortening occurred at the same rate among adults with and without severe chronic periodontitis. This suggests that LTL shortening may have occurred earlier in the life course.

DNA damage accumulation and TRF2 degradation in atypical Werner syndrome fibroblasts with LMNA mutations.

Segmental progeroid syndromes are groups of disorders with multiple features suggestive of accelerated aging. One subset of adult-onset progeroid syndromes, referred to as atypical Werner syndrome, is caused by mutations in the LMNA gene, which encodes a class of nuclear intermediate filaments, lamin A/C. We previously described rapid telomere attrition and accelerated replicative senescence in cultured fibroblasts overexpressing mutant lamin A. In this study, we investigated the cellular phenotypes associated with accelerated telomere shortening in LMNA mutant primary fibroblasts. In early passage primary fibroblasts with R133L or L140R LMNA mutations, shelterin protein components were already reduced while cells still retained telomere lengths comparable to those of controls. There was a significant inverse correlation between the degree of abnormal nuclear morphology and the level of TRF2, a shelterin subunit, suggesting a potential causal relationship. Stabilization of the telomeres via the introduction of the catalytic subunit of human telomerase, hTERT (human telomerase reverse transcriptase), did not prevent degradation of shelterin components, indicating that reduced TRF2 in LMNA mutants is not mediated by short telomeres. Interestingly, γ-H2AX foci (reflecting double strand DNA damage) in early passage LMNA mutant primary fibroblasts and LMNA mutant hTERT fibroblasts were markedly increased in non-telomeric regions of DNA. Our results raise the possibility that mutant lamin A/C causes global genomic instability with accumulation of non-telomeric DNA damage as an early event, followed by TRF2 degradation and telomere shortening.