Leucocyte telomere length and risk of cardiovascular disease: systematic review and meta-analysis.

OBJECTIVE: To assess the association between leucocyte telomere length and risk of cardiovascular disease. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Studies published up to March 2014 identified through searches of Medline, Web of Science, and Embase. ELIGIBILITY CRITERIA: Prospective and retrospective studies that reported on associations between leucocyte telomere length and coronary heart disease (defined as non-fatal myocardial infarction, coronary heart disease death, or coronary revascularisation) or cerebrovascular disease (defined as non-fatal stroke or death from cerebrovascular disease) and were broadly representative of general populations--that is, they did not select cohort or control participants on the basis of pre-existing cardiovascular disease or diabetes. RESULTS: Twenty four studies involving 43,725 participants and 8400 patients with cardiovascular disease (5566 with coronary heart disease and 2834 with cerebrovascular disease) were found to be eligible. In a comparison of the shortest versus longest third of leucocyte telomere length, the pooled relative risk for coronary heart disease was 1.54 (95% confidence interval 1.30 to 1.83) in all studies, 1.40 (1.15 to 1.70) in prospective studies, and 1.80 (1.32 to 2.44) in retrospective studies. Heterogeneity between studies was moderate (I(2) = 64%, 41% to 77%, Phet<0.001) and was not significantly explained by mean age of participants (P = 0.23), the proportion of male participants (P = 0.45), or distinction between retrospective versus prospective studies (P = 0.32). Findings for coronary heart disease were similar in meta-analyses restricted to studies that adjusted for conventional vascular risk factors (relative risk 1.42, 95% confidence interval 1.17 to 1.73); studies with ≥ 200 cases (1.44, 1.20 to 1.74); studies with a high quality score (1.53, 1.22 to 1.92); and in analyses that corrected for publication bias (1.34, 1.12 to 1.60). The pooled relative risk for cerebrovascular disease was 1.42 (1.11 to 1.81), with no significant heterogeneity between studies (I(2) = 41%, 0% to 72%, Phet = 0.08). Shorter telomeres were not significantly associated with cerebrovascular disease risk in prospective studies (1.14, 0.85 to 1.54) or in studies with a high quality score (1.21, 0.83 to 1.76). CONCLUSION: Available observational data show an inverse association between leucocyte telomere length and risk of coronary heart disease independent of conventional vascular risk factors. The association with cerebrovascular disease is less certain

Leucocyte telomere length and risk of type 2 diabetes mellitus: new prospective cohort study and literature-based meta-analysis.

Short telomeres have been linked to various age-related diseases. We aimed to assess the association of telomere length with incident type 2 diabetes mellitus (T2DM) in prospective cohort studies.Leucocyte relative telomere length (RTL) was measured using quantitative polymerase chain reaction in 684 participants of the prospective population-based Bruneck Study (1995 baseline), with repeat RTL measurements performed in 2005 (n = 558) and 2010 (n = 479). Hazard ratios for T2DM were calculated across quartiles of baseline RTL using Cox regression models adjusted for age, sex, body-mass index, smoking, socio-economic status, physical activity, alcohol consumption, high-density lipoprotein cholesterol, log high-sensitivity C-reactive protein, and waist-hip ratio. Separate analyses corrected hazard ratios for within-person variability using multivariate regression calibration of repeated measurements. To contextualise findings, we systematically sought PubMed, Web of Science and EMBASE for relevant articles and pooled results using random-effects meta-analysis.Over 15 years of follow-up, 44 out of 606 participants free of diabetes at baseline developed incident T2DM. The adjusted hazard ratio for T2DM comparing the bottom vs. the top quartile of baseline RTL (i.e. shortest vs. longest) was 2.00 (95% confidence interval: 0.90 to 4.49; P = 0.091), and 2.31 comparing the bottom quartile vs. the remainder (1.21 to 4.41; P = 0.011). The corresponding hazard ratios corrected for within-person RTL variability were 3.22 (1.27 to 8.14; P = 0.014) and 2.86 (1.45 to 5.65; P = 0.003). In a random-effects meta-analysis of three prospective cohort studies involving 6,991 participants and 2,011 incident T2DM events, the pooled relative risk was 1.31 (1.07 to 1.60; P = 0.010; I2 = 69%).Low RTL is independently associated with the risk of incident T2DM. To avoid regression dilution biases in observed associations of RTL with disease risk, future studies should implement methods correcting for within-person variability in RTL. The causal role of short telomeres in T2DM development remains to be determined

Study flow diagram of the literature-based meta-analysis.

<p>The figure is based on the 2009 PRISMA flow diagram template (available from <a href="http://www.prisma-statement.org/statement.htm" target="_blank">http://www.prisma-statement.org/statement.htm</a>).</p

Association of leucocyte relative telomere length an risk of type 2 diabetes mellitus in the Bruneck Study (n = 606, 44 events over follow-up 1995–2010).

<p>Cox models were adjusted for age, sex, body mass index, smoking, socio-economic status, physical activity, alcohol consumption, high density lipoprotein cholesterol, log high-sensitivity C-reactive protein, and waist-hip ratio. Abbreviations: CI, confidence interval; HR, hazard ratio; RTL, relative telomere length; T2DM, type 2 diabetes mellitus.</p

Description and meta-analysis of published data from three prospective cohort studies on the association of short telomeres and risk of type 2 diabetes mellitus.

<p>Published relative risks were pooled by random-effects meta-analysis. In the Bruneck Study and the Strong Heart Family Study, type 2 diabetes was defined according to the 1997 American Diabetes Association criteria. In the WHI Observational Study, diabetes was defined based on self-report and hospitalisation for type 2 diabetes. All three studies measured telomere length with a quantitative polymerase chain reaction technique. *Reported relative risks were additionally adjusted for two variables in the Bruneck Study (HDL cholesterol and log hsCRP), three variables in the Strong Heart Family Study (age², fasting glucose, total triglycerides), and three variables in the Women's Health Initiative Observational Study (date of blood collection, clinical centre, hormone therapy). †Max. ‡Mean. $The Women's Health Initiative Observational Study involved postmenopausal women who proved to be ineligible or unwilling to be randomised as part of the Women's Health Initiative Clinical Trial. Abbreviations: CI, confidence interval; NOS, Newcastle-Ottawa Scale for assessing the quality of nonrandomised studies in meta-analyses; T2DM, type 2 diabetes mellitus; WHI, Women's Health Initiative.</p

Distribution of baseline leucocyte relative telomere length in the Bruneck Study according to different disease states (1995, n = 684).

<p>Abbreviations: RTL, relative telomere length; T2DM, type 2 diabetes mellitus. There were 390 participants with normoglycaemia, 216 participants with impaired fasting glucose, and 78 participants with a clinical diagnosis of T2DM.</p

Baseline characteristics of the Bruneck Study population and their cross-sectional association with leucocyte relative telomere length (1995, n = 684).

<p>Standardised mean differences in leucocyte relative telomere length were adjusted for age and sex. Asterisks indicate level of statistical significance: *P≤0.05; **P≤0.01; ***P≤0.001. The mean (SD) of HbA1c was 5.8% (3.7%) in DCCT-derived units and 40 mmol/mol (17 mmol/mol) in SI units. Abbreviations: ApoB, apolipoprotein B; ApoB-IC, apoB-immune complexes; CI, confidence interval; Cu-OxLDL, copper-oxidised low-density lipoprotein; HbA1c, glycated haemoglobin; HDL, high-density lipoprotein; HOMA-IR, homeostatic model assessment of insulin resistance; hsCRP, high-sensitivity C-reactive protein; IgG, immunoglobulin G; IgM, immunoglobulin M; LDL, low-density lipoprotein; RTL, relative telomere length; MDA, malondialdehyde; OxPL/apoB, oxidised phospholipids on apolipoprotein B-100; SD, standard deviation; RLU, relative light unit; SMD, standardised mean difference; WHR, waist-hip ratio.</p

Association of leucocyte relative telomere length with incident type 2 diabetes mellitus in the Bruneck Study (n = 606, 44 events).

<p>Asterisks indicate level of statistical significance: *P≤0.05; **P≤0.01; ***P≤0.001. Abbreviations: BMI, body mass index; HDL-C, high density lipoprotein cholesterol; hsCRP; high-sensitivity C-reactive protein; RTL, relative telomere length; SES, socio-economic status; T2DM, type 2 diabetes mellitus; WHR, waist-hip ratio. Participants with a baseline history of type 2 diabetes mellitus were excluded from the analysis (n = 78).</p><p>Association of leucocyte relative telomere length with incident type 2 diabetes mellitus in the Bruneck Study (n = 606, 44 events).</p