Association Of Leukocyte Telomere Length Research Articles

Association of leukocyte telomere length with cardiac conduction disease and sick sinus syndrome

Abstract Background Cardiac conduction disease (CCD) and sick sinus syndrome (SSS) may be related to a degenerative process. Leukocyte telomere length (LTL) is associated with the aging process and age-related degenerative diseases. We aimed to investigate the association between LTL and the risks of CCD/SS, and to explore whether LTL is related with cardiovascular imaging and electrocardiographic (ECG) changes. Methods This is a population-based cross-sectional study of UK Biobank participants without history of CCD/SSS recruited from 2006 to 2010. LTL was measured using a quantitative polymerase chain reaction method. Cardiovascular measurements were derived from cardiovascular magnetic resonance using machine learning. The median (IQR) duration of follow-up was 12.0 (11.3-12.7) years. The associations of LTL with imaging and ECG measurements and incident CCD/SSS were evaluated by multivariable regression models. Results Among the 412,452 white participants, 188,891 (45.8%) were male, with a mean age of 57.3 years. Longer LTL was independently associated with positive cardiac remodeling, including higher left ventricular mass, larger atrial volume, and increased atrial stroke volumes. However, no significant associations were observed with ECG findings including PR interval and P-wave duration. 11991 (2.6%) participants developed CCD and 984 (0.2%) developed SSS. Longer LTL was not associated with younger age. However, longer LTL was not associated with a lower risk of incident CCD (LTL fourth quartile vs. first quartile: hazard ratio, 0.98; 95% CI, 0.97-1.0; P = 0.057) or SSS (LTL fourth quartile vs. first quartile: hazard ratio, 0.98; 95% CI, 0.92-1.05; P = 0.554). Conclusions In this cross-sectional study, longer LTL was associated with a larger atrial size with better atrial function in middle age, but not with ECG changes. However, longer LTL was not associated with a lower risk of incident CCD and SSS.

Causal association and shared genetics between telomere length and COVID-19 outcomes: new evidence from the latest large-scale summary statistics

BackgroundObservational studies suggested that leukocyte telomere length (LTL) is shortened in COVID-19 patients. However, the genetic association and causality remained unknown. MethodsBased on the genome-wide association of LTL (N = 472,174) and COVID-19 phenotypes (N = 1,086,211-2,597,856), LDSC and SUPERGNOVA were used to estimate the genetic correlation. Cross-trait GWAS meta-analysis, colocalization, fine-mapping analysis and transcriptome-wide association study were conducted to explore the shared genetic etiology. Mendelian randomization (MR) was utilized to infer the causality. Upstream and downstream two-step MR was performed to investigate the potential mediating effects. ResultsLDSC identified a significant genetic association between LTL and all COVID-19 phenotypes (rG < 0, p < 0.05). Six significant regions were observed for LTL and COVID-19 susceptibility and hospitalization, respectively. Colocalization analysis found rs144204502, rs34517439, and rs56255908 were shared causal variants between LTL and COVID-19 phenotypes. Numerous biological pathways associated with LTL and COVID-19 outcomes were identified, mainly involved in immune related pathways. MR showed that longer LTL was significantly associated with a lower risk of COVID-19 severity (OR [95% CI] = 0.81 [0.71-0.92], p = 1.24×10-3) and suggestively associated with lower risks of COVID-19 susceptibility (OR [95% CI] = 0.96 [0.92-1.00], p = 3.44×10-2) and COVID-19 hospitalization (OR [95% CI] = 0.89 [0.80-0.98], p = 1.89×10-2). LTL partially mediated the effects of BMI, smoking, and education on COVID-19 outcomes. Furthermore, six proteins partially mediated the causality of LTL on COVID-19 outcomes, including BNDF, QPCT, FAS, MPO, SFTPB, and APOF. ConclusionsOur findings suggested that shorter LTL was genetically associated with higher risk of COVID-19 phenotypes, with shared genetic etiology and potential causality.

The association of leukocyte telomere length with exceptional longevity among older women.

The association of leukocyte telomere length (LTL) with survival to late life with intact mobility has not been adequately studied. This prospective cohort study consisted of 1451 postmenopausal women from a Women's Health Initiative ancillary study, who were eligible, because of birth year, to survive to age 90 as of March 6, 2021. LTL was measured by Southern blot at baseline (1993-1998). Associations between LTL and survival to age 90 were evaluated using logistic regression models adjusted for socio-demographic characteristics, health factors, and lifestyle factors. Multinominal logistic regression was utilized to examine associations of LTL with survival to age 90 with or without intact mobility. Mediation analysis examined the extent to which incident coronary heart disease and stroke-mediated the association between LTL and longevity. Overall, 76.7% of women were White, and 23.3% were Black; average age at baseline was 70.4±3.5 years. Relative to death before age 90, the odds of survival to age 90 were 60% higher (OR, 1.60; 95% CI, 1.28-2.01), the odds of survival to age 90 with mobility limitation were 72% higher (OR, 1.72; 95% CI, 1.33-2.21), and the odds of survival to age 90 with intact mobility were 44% higher (OR, 1.44; 95% CI, 1.06-1.95) for every one kilobase longer LTL. Absence of CHD, stroke, or CHD/stroke mediated the association of LTL with survival to age 90 by 11.1%, 37.4%, and 31.3%, respectively; however, these findings were not significant. Longer LTL was associated with higher odds of survival to age 90 among older women.

A sex-specific association of leukocyte telomere length with thigh muscle mass.

Telomeres are DNA-protein complexes at the ends of linear chromosomes that protect against DNA degradation. Telomeres shorten during normal cell divisions and therefore, telomere length is an indicator of mitotic-cell age. In humans, telomere shortening is a potential biomarker for disease risk, progression and premature death. Physical activity has been associated with longer leukocyte telomere length (LTL) in some studies. In the current study the relationship between LTL, thigh muscle mass and adipose tissue distribution was explored. We performed anthropometric measurements and magnetic resonance imaging (MRI) measurements of the thigh in 149 healthy subjects (77 male, 72 female). LTL was measured using qPCR. Additionally, the subjects answered a questionnaire concerning their training behaviour. In male subjects, LTL was significantly associated with thigh muscle mass, independent of age and body mass index (p=0.006). In addition, a slight association of LTL with weekly endurance units in the male group was found. These relations could not be observed in females. In conclusion, we observed a sex-specific association of LTL and thigh muscle mass in healthy males. The reason of this sex-specific association is currently unclear, but could be related to different training effects and/or hormonal pathways in men and women.

Association of leukocyte telomere attrition in coronary artery disease in Pakistani population: A case-control study with meta-analysis

BackgroundCoronary arteries disease (CAD) is one of the primary causes of mortality worldwide. Genetic, epigenetic and environmental factors have been hypothesized in the pathogenesis of CAD. Leukocyte telomere length (LTL) has been proposed as a potential biomarker for early detection of atherosclerosis. Telomere is the DNA-Protein structure that maintains stability and integrity of chromosomes and is associated with the aging-related cellular mechanisms. This study is designed to investigate the association of LTL with CAD pathogenesis. Material and MethodThis prospective case-control study included 100 patients and 100 control individuals. DNA was extracted from the peripheral blood samples, and LTL was measured using real-time PCR. Data were normalized with single copy gene and presented as relative telomere length T/S ratio. Comprehensive meta-analysis was conducted to ascertain the pivotal role of telomere length in CAD pathology across multiple populations. ResultsOur results showed shorter telomere length in CAD patients as compared to control. The correlation analysis revealed a significant (P-value <0.01) negative correlation between telomere length with basal metabolic index (BMI), total cholesterol, and low-density lipoprotein cholesterol (LDL-C) and a positive correlation with high-density lipoprotein cholesterol (HDL-C). Meta-analysis results indicated a significantly shorter telomere length in the Asian population and a non-significant shorter telomere length in other populations. Receiver operator curve (ROC) analysis demonstrated an area under the curve (AUC) of 0.814 with cut-off value of 0.691 exhibited sensitivity of 72.2%, and specificity of 79.1%, for the diagnosis of CAD. ConclusionIn conclusion, LTL is associated with the onset of CAD and could be used as a diagnostic predictor to screen individuals with CAD.

Assessing the association of leukocyte telomere length with ankylosing spondylitis and rheumatoid arthritis: A bidirectional Mendelian randomization study.

Telomere length shortening can cause senescence and apoptosis in various immune cells, resulting in immune destabilization and ageing of the organism. In this study, we aimed to systematically assess the causal relationship of leukocyte telomere length (LTL) with ankylosing spondylitis (AS) and rheumatoid arthritis (RA) using a Mendelian randomization study. LTL (n=472174) was obtained from the UK Biobank genome-wide association study pooled data. AS (n=229640), RA (n=212472) were obtained from FinnGen database. MR-Egger, inverse variance weighting, and weighted median methods were used to estimate the effects of causes. Cochran's Q test, MR Egger intercept test, MR-PRESSO, leave-one-out analysis, and funnel plots were used to look at sensitivity, heterogeneity, and multiple effects. Forward MR analysis considered LTL as the exposure and AS, RA as the outcome. Reverse MR analysis considered AS, RA as the exposure and LTL as the outcome. In the forward MR analysis, inverse variance-weighted and weighted median analysis results indicated that longer LTL might be associated with increased risk of AS (IVW: OR = 1.55, 95% CI: 1.14-2.11, p = 0.006). MR Egger regression analysis showed no pleiotropy between instrumental variables (IVs) (Egger intercept= 0.008, p = 0.294). The leave-one-out analysis showed that each single nucleotide polymorphism (SNP) of AS was robust to each outcome. No significant causal effects were found between AS, RA and LTL in the reverse MR analysis. Longer LTL may be related with an increased risk of developing AS, and these findings provide a foundation for future clinical research on the causal association between LTL and AS.

Telomere length associates with chronological age and mortality across racially diverse pulmonary fibrosis cohorts

Pulmonary fibrosis (PF) is characterized by profound scarring and poor survival. We investigated the association of leukocyte telomere length (LTL) with chronological age and mortality across racially diverse PF cohorts. LTL measurements among participants with PF stratified by race/ethnicity were assessed in relation to age and all-cause mortality, and compared to controls. Generalized linear models were used to evaluate the age-LTL relationship, Cox proportional hazards models were used for hazard ratio estimation, and the Cochran–Armitage test was used to assess quartiles of LTL. Standardized LTL shortened with increasing chronological age; this association in controls was strengthened in PF (R = −0.28; P < 0.0001). In PF, age- and sex-adjusted LTL below the median consistently predicted worse mortality across all racial groups (White, HR = 2.21, 95% CI = 1.79–2.72; Black, HR = 2.22, 95% CI = 1.05–4.66; Hispanic, HR = 3.40, 95% CI = 1.88–6.14; and Asian, HR = 2.11, 95% CI = 0.55–8.23). LTL associates uniformly with chronological age and is a biomarker predictive of mortality in PF across racial groups.

Independent and Joint Association of Leukocyte Telomere Length and Lifestyle Score With Incident Stroke.

HomeStrokeAhead of PrintIndependent and Joint Association of Leukocyte Telomere Length and Lifestyle Score With Incident Stroke No AccessLetterRequest AccessAboutView PDFSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialNo AccessLetterRequest AccessIndependent and Joint Association of Leukocyte Telomere Length and Lifestyle Score With Incident Stroke Haiqing Zhang, PhD, Xuefeng Lai, PhD, Qin Fang, PhD, Lin Ma, MM, Miao Liu, PhD, Huihua Yang, PhD, Wenting Guo, PhD, Meian He, PhD, Liangle Yang, PhD and Xiaomin Zhang, PhD Haiqing ZhangHaiqing Zhang https://orcid.org/0000-0001-6652-6417 Department of Occupational and Environmental Health, Ministry of Education Key Laboratory of Environment and Health, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China. *H. Zhang and X. Lai contributed equally. Search for more papers by this author , Xuefeng LaiXuefeng Lai Department of Occupational and Environmental Health, Ministry of Education Key Laboratory of Environment and Health, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China. *H. Zhang and X. Lai contributed equally. Search for more papers by this author , Qin FangQin Fang Department of Occupational and Environmental Health, Ministry of Education Key Laboratory of Environment and Health, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China. Search for more papers by this author , Lin MaLin Ma Department of Occupational and Environmental Health, Ministry of Education Key Laboratory of Environment and Health, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China. Search for more papers by this author , Miao LiuMiao Liu Department of Occupational and Environmental Health, Ministry of Education Key Laboratory of Environment and Health, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China. Search for more papers by this author , Huihua YangHuihua Yang Department of Occupational and Environmental Health, Ministry of Education Key Laboratory of Environment and Health, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China. Search for more papers by this author , Wenting GuoWenting Guo Department of Occupational and Environmental Health, Ministry of Education Key Laboratory of Environment and Health, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China. Search for more papers by this author , Meian HeMeian He Department of Occupational and Environmental Health, Ministry of Education Key Laboratory of Environment and Health, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China. Search for more papers by this author , Liangle YangLiangle Yang https://orcid.org/0000-0001-9751-1904 Department of Occupational and Environmental Health, Ministry of Education Key Laboratory of Environment and Health, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China. Search for more papers by this author and Xiaomin ZhangXiaomin Zhang Correspondence to: Xiaomin Zhang, PhD, Department of Occupational and Environmental Health, Ministry of Education Key Laboratory of Environment and Health, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd, Wuhan 430030, Hubei, China. Email E-mail Address: [email protected] https://orcid.org/0000-0003-3877-5242 Department of Occupational and Environmental Health, Ministry of Education Key Laboratory of Environment and Health, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Hubei, China. Search for more papers by this author Originally published28 Feb 2023https://doi.org/10.1161/STROKEAHA.122.041126Stroke. 2023;0"Independent and Joint Association of Leukocyte Telomere Length and Lifestyle Score With Incident Stroke." Stroke, , pp. –Footnotes*H. Zhang and X. Lai contributed equally.For Sources of Funding and Disclosures, see page xxx.Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.122.041126.Correspondence to: Xiaomin Zhang, PhD, Department of Occupational and Environmental Health, Ministry of Education Key Laboratory of Environment and Health, and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Rd, Wuhan 430030, Hubei, China. Email [email protected]com Previous Back to top Next FiguresReferencesRelatedDetails Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/STROKEAHA.122.041126PMID: 36852686 Originally publishedFebruary 28, 2023 KeywordsstrokelifestylehabitsagingtelomerePDF download Advertisement SubjectsCerebrovascular Disease/StrokeEpidemiologyLifestyle

Leukocyte telomere length and mitochondrial DNA copy number association with colorectal cancer risk in an aging population

In this study, we evaluated the association of blood leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNA-CN) with the risk of incident colorectal cancer (CRC). We studied and followed-up a cohort of Russian men and women (aged 45 – 69 years, n = 9360, 54% female) from the HAPIEE study for 15 years. Using the nested case-control design, we selected cases with incident CRC among those free from any baseline cancer (n = 146) and sex- and age-stratified controls among those free from baseline cancer and cardiovascular disease and alive at the end of the follow-up (n = 799). We employed multivariable-adjusted logistic regression to estimate the odds ratios (ORs) of CRC per 1 decile of LTL or mtDNA-CN. We observed an inverse association of LTL and mtDNA-CN baseline values with the 15-year risk of incident CRC. Carriers of shorter telomeres had an increased 15-year risk of incident CRC with adjusted OR 3.2 (95% CI: 2.56 – 3.87, P &lt; 0.001) per 1 decile decrease in LTL, independent of baseline age, sex, smoking, body mass index, blood pressure, lipid levels, and education. Similarly, lower mtDNA-CN was associated with the higher risk of incident CRC with adjusted OR 1.7 (95% CI: 1.12 – 1.89, P &lt; 0.001) per 1 decile decrease in mtDNA-CN, independent of the aforementioned factors. Using the modified values of LTL and mtDNA-CN adjusted for multiple factors and their interactions with a case–control status, the ORs of CRC were 2.53 and 1.52 per 1 decile decrease in adjusted baseline LTL and mtDNA-CN, respectively. In conclusion, LTL and mtDNA-CN were independent inverse predictors of the 15-year risk of CRC in the Russian cohort. These findings highlight the relevance for subsequent research to exploit the mechanisms through which LTL and mtDNA-CN may reflect human health.

Association of leukocyte telomere length with perceived physical fatigability

BackgroundLeukocyte telomere length (LTL) is a potential genomic marker of biological aging, but its relation to fatigability, a prognostic indicator of phenotypic aging (e.g., functional decline) is unknown. We hypothesized shorter LTL would predict greater perceived physical fatigability, but that this association would be attenuated by adjusting for chronological age. MethodsTwo generations of participants (N = 1997; 309 probands, 1688 offspring) were from the Long Life Family Study (age = 73.7 ± 10.4, range 60–108, 54.4 % women), a longitudinal cohort study of aging. LTL was assayed at baseline. Perceived physical fatigability was measured 8.0 ± 1.1 years later using the validated, self-administered 10-item Pittsburgh Fatigability Scale (PFS, 0–50, higher scores = greater fatigability). Generalized estimating equations were generated to model the association between LTL and PFS Physical scores. ResultsPrevalence of greater physical fatigability (PFS scores≥15) was 41.9 %. Using generalized estimating equations, a one kilobase pair shorter LTL was associated with higher PFS Physical scores (β = 1.8, p < .0001), accounting for family structure, and adjusting for field center, follow-up time, sex, and follow-up body mass index, physical activity, and chronic health conditions. When age was included as a covariate, the association was fully attenuated (β = 0.1, p = .78). ConclusionLTL may provide an alternative method for estimating an individual's lifetime exposure to chronic stressors, but does not appear to provide additional information not captured by chronological age. Further research is needed to characterize the interaction between age, LTL, and perceived fatigability, and develop a method of identifying individuals at risk for deleterious aging.

Genetic association of leukocyte telomere length with Graves' disease in Biobank Japan: A two-sample Mendelian randomization study.

BackgroundTelomere length (TL) has been recognized to be fundamental to the risk of autoimmune disorders. However, the role of leukocyte TL in Graves’ disease has not yet been fully elucidated. In the study, we exploited the two-sample Mendelian randomization (MR) design to evaluate the causal effect of leukocyte TL on the risk of Graves’ disease.MethodsGenome-wide association study (GWAS) data of leukocyte TL from the Singapore Chinese Health Study (SCHS) cohort and Graves’ disease from Biobank Japan (BBJ, 2176 cases and 210,277 controls) were analyzed. Nine single nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs) for TL. We used the inverse variance weighted (IVW) approach as the main estimator and MR-Egger regression, weighted median, simple mode, and weighed mode methods as complementary estimators. Horizontal pleiotropy was assessed using the intercept from MR-Egger.ResultsThe analysis demonstrated that genetically predicted longer leukocyte TL was causally associated with a lower risk of Graves’ disease using the IVW method (odds ratio [OR]: 1.64, 95% confidence interval [CI]: 1.23-2.17, P=2.27e-04, and other complementary MR approaches achieved similar results. The intercept from the MR-Egger analysis provided no noticeable evidence of horizontal pleiotropy (β=0.02, P=0.641). MR-PRESSO method reported no outliers (P=0.266).ConclusionsOur results provided evidence to support a genetic predisposition to shorter leukocyte TL with an increased risk of Graves’ disease. Further studies are warranted to explore the mechanism underlying the association.

Associations of cord blood leukocyte telomere length with adiposity growth from infancy to adolescence.

Leukocyte telomere length (LTL) may be a biomarker for chronic disease susceptibility, but no work has tested this hypothesis directly. Our study investigated associations of LTL at birth with markers of adiposity growth that are linked with cardiometabolic health later in life. Participants were 375 children in Project Viva (48% female, 71% White). Body mass index (BMI) trajectories from birth to 18 years were tracked using repeated measures of BMI collected in physical examinations and via medical records, then used to predict age (months) and magnitude (kg/m2 ) of BMI peak and rebound. LTL was measured from cord blood via duplex quantitative PCR. A binary variable indicating LTL shorter than the reference population average was the primary exposure. LTL was unrelated to BMI at peak or rebound, but associations were apparent with the timing of BMI growth milestones. Short LTL was related to a later age of peak for females (β=0.99, 95% CI=0.16, 1.82; psex interaction =0.015) and an earlier age of rebound for both males and females (βcombined =-5.26, 95% CI=-9.44, -1.08). LTL at birth may be an early biomarker of altered adiposity growth. Newborn telomere biology may shed new insight into the developmental origins of health and disease.

Telomere length and brain aging: A systematic review and meta-analysis.

The current evidence on the association of leukocyte telomere length (LTL) with age-related structural and cognitive changes in the brain is mixed. Herein conforming to PRISMA 2020 guidelines, we performed a systematic review and meta-analysis using data from 27 observational studies in non-demented individuals. We used effect size and p-value based meta-analysis methods considering marked heterogeneity among studies. We found that the longer LTL was associated with higher brain volume (β=0.43, 95%CI: 0.36-0.50%, p=0.008, N=1102) and with higher global cognition (β=0.01; 95%CI: 0.00-0.02, p=0.03, N=19609) by effect size based meta-analysis and with brain volume, hippocampal volume, global cognition, cognitive domains of attention/speed as well as executive functions by p-value based meta-analysis. No significant association of LTL with brain white matter hyperintensities was detected. Furthermore, the evidence strongly suggests a subgroup-specific canonical effect of telomeres, notably in older individuals and females. In conclusion, we provide meta-analytic evidence on the beneficial effect of telomeres on brain structure as well as cognition and advocate for a beneficial subgroup-specific effect that warrants further attention.

Association between COVID-19 and telomere length: A bidirectional Mendelian randomization study.

Several traditional observational studies suggested an association between COVID‐19 and leukocyte telomere length (LTL), a biomarker for biological age. However, whether there was a causal association between them remained unclear. We aimed to investigate whether genetically predicted COVID‐19 is related to the risk of LTL, and vice versa. We performed bidirectional Mendelian randomization (MR) study using summary statistics from the genome‐wide association studies of critically ill COVID‐19 (n = 1 388 342) and LTL (n = 472 174) of European ancestry. The random‐effects inverse‐variance weighted estimation method was applied as the primary method with several other estimators as complementary methods. Using six single‐nucleotide polymorphisms (SNPs) of genome‐wide significance as instrumental variables for critically ill COVID‐19, we did not find a significant association of COVID‐19 on LTL (β = 0.0075, 95% confidence interval [CI]: −0.018 to 0.021, p = 0.733). Likewise, using 97 SNPs of genome‐wide significance as instrumental variables for LTL, we did not find a significant association of LTL on COVID‐19 (odds ratio = 1.00, 95% CI: 0.79–1.28, p = 0.973). Comparable results were obtained using MR‐Egger regression, weighted median, and weighted mode approaches. We did not find evidence to support a causal association between COVID‐19 and LTL in either direction.

Longer leukocyte telomere length is associated with myeloid inflammation and increased mortality after transcatheter aortic valve replacement.

AimsInflammatory activation of leukocytes may limit prognosis of patients (pts) with severe aortic valve stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). Leukocyte telomere length (LTL) is a marker of proliferative capacity and inflammatory responsiveness but the impact of LTL on the prognosis in AS remains elusive. The aim of this study was to analyse the association of LTL with inflammatory markers and prognosis of pts undergoing TAVR.Methods and resultsLTL was analysed using quantitative real-time PCR in 285 consecutive pts (median age 82 years) undergoing TAVR and correlated with 18-month all-cause mortality. C-reactive protein was significantly elevated in pts with the longest LTL (P = 0.017), paralleled by increased procalcitonin (PCT) serum levels (P = 0.0006). This inflammatory reaction was accompanied by increased myeloid cells in the highest LTL tertile, mainly a rise in circulating neutrophils (P = 0.0025) and monocytes (P = 0.01). Multivariate analysis revealed LTL (HR 2.6, 95%CI 1.4–5.1, P= 0.004) and PCT levels (HR 4.3, 95%CI 1.7–11.0, P = 0.003) as independent predictors of mortality.ConclusionsLonger LTL is associated with increased mortality after TAVR. This might be explained by enhanced proliferative capacity of cells resulting in myeloid and systemic inflammation. Our findings suggest that targeting the specific inflammation pathways could present a novel strategy to augment survival in selected patients with degenerative aortic stenosis.

Exploring the Association of Leukocyte Telomere Length and Hearing Threshold Shifts of Adults in the United States.

BackgroundAlthough telomere length has a significant relationship with various age-related diseases, studies on its relationship with hearing status in adults are limited and equivocal. This study investigated the associations between mean telomere length (MTL) and low-, speech-, and high-frequency hearing threshold shifts of adults in the United States.MethodsA total of 2,027 adults, aged 20-69 years, from the National Health and Nutrition Examination Surveys (NHANES, 1999–2002) were included in the analytic sample. The quantitative polymerase chain reaction method was used for the MTL assay, and MTL was expressed using the telomere-to-single copy gene (T/S) ratio. Hearing loss was defined as a pure-tone average (PTA) for the better ear at ≥ 20 dB HL at frequencies 500, 1,000, 2,000, and 4,000 Hz. Univariate and multivariate linear regression analyses and smooth curve fittings were conducted to evaluate the correlation between MTL and low-, speech-, and high-frequency hearing levels.ResultsThe mean age of the participants was 40.60 ± 12.76 years, including 952 men (weighted, 48.67%) and 303 (weighted, 12.88%) participants with hearing loss. After adjusting for potential confounders in the multivariate linear regression model, the relationship between MTL and hearing thresholds was not statistically significant. Smooth curve fittings indicated a non-linear relationship between MTL and high-frequency PTA hearing threshold shifts. MTL was inversely related to high-frequency PTA to the turning point (T/S ratio = 0.82) (adjusted β−21.45, 95% CI −37.28, −5.62; P = 0.008). When the T/S ratio exceeded0.82, MTL was not associated with high-frequency PTA (adjusted β0.18, 95% CI −2.21, 2.57; P = 0.8809).ConclusionOur findings revealed that MTL was associated with high-frequency PTA hearing threshold shifts of adults in the United States in a non-linear manner.

323-OR: Associations of Leukocyte Telomere Length and Related Allelic Variations with the Risk of Coronary Events in People with Long-Standing Type 1 Diabetes

Backgrounds and Aims: Leukocyte telomere length (LTL) is associated with cardiovascular risk. We evaluated associations between LTL, allelic variations (SNPs) in LTL-related genes (associated with LTL in the literature) and the incidence of coronary artery disease (CAD) in adults with long-standing type 1 diabetes. Participants and Methods: LTL was measured by real-time PCR in 260 participants of the GENEDIAB cohort (males 60%, age 45±12 years, duration of diabetes 29±years at baseline, mean±SD) . Thirty-three SNPs in LTL-associated genes were genotyped in 826 participants from GENEDIAB and GENESIS cohorts (males 55%, age 43±12 years, duration of diabetes 27±9 years at baseline) . The risk for CAD (myocardial infarction or coronary artery revascularization) during follow-up was analyzed using Cox models according to LTL (expressed in tertiles of distribution) and SNPs. Results: The cumulative incidence of CAD in GENEDIAB (11±7-year follow-up) was 21.2%. The incidence of CAD by LTL tertiles was 27.6% (shorter LTL) , 23.3% (intermediate LTL) and 12.6% (longer LTL) . Hazard ratio (HR) for shorter vs. longer LTL was 1.63 (95%CI 1.15-2.37) , p=0.005, unadjusted model, and 1.58 (95%CI 1.08-2.39) , p=0.02, after adjustment on sex, age, duration of diabetes, blood pressure, kidney function and history of CAD at baseline. The cumulative incidence of CAD in GENEDIAB and GENESIS pooled data (followed by 11±6 years) was 15.1%. Six SNPs located in three genes (TERC, NAF1 and TNKS) were significantly associated with the incidence of CAD. Discussion: Shorter LTL at baseline was associated with an increased risk of CAD during the follow-up in adults with long-standing type 1 diabetes. Allelic variations in LTL-related genes were also associated with coronary risk in these subjects. Disclosure M.Sanchez: None. G.Velho: None. L.Potier: Board Member; Boehringer Ingelheim International GmbH, Lilly, Novo Nordisk, Consultant; AstraZeneca, Sanofi. N.Venteclef: None. F.Fumeron: None. A.Scheen: Advisory Panel; AstraZeneca, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk. J.Gautier: Other Relationship; Novo Nordisk, Sanofi, Speaker's Bureau; Eli Lilly and Company. M.Marre: Board Member; AstraZeneca, Consultant; Novo Nordisk. R.Roussel: None. K.Mohammedi: Board Member; Lilly, Novo Nordisk, Sanofi, Research Support; Cyclerion Therapeutics, Inc., Speaker's Bureau; Abbott, AstraZeneca.

Modifiable traits, healthy behaviours, and leukocyte telomere length: a population-based study in UK Biobank

SummaryBackgroundTelomere length is associated with risk of several age-related diseases and cancers. We aimed to investigate the extent to which telomere length might be modifiable through lifestyle and behaviour, and whether such modification has any clinical consequences.MethodsIn this population-based study, we included participants from UK Biobank who had leukocyte telomere length (LTL) measurement, ethnicity, and white blood cell count data. We investigated associations of LTL with 117 potentially modifiable traits, as well as two indices of healthy behaviours incorporating between them smoking, physical activity, diet, maintenance of a healthy bodyweight, and alcohol intake, using both available and imputed data. To help interpretation, associations were summarised as the number of equivalent years of age-related change in LTL by dividing the trait β coefficients with the age β coefficient. We used mendelian randomisation to test causality of selected associations. We investigated whether the associations of LTL with 22 diseases were modified by the number of healthy behaviours and the extent to which the associations of more healthy behaviours with greater life expectancy and lower risk of coronary artery disease might be mediated through LTL.Findings422 797 participants were available for the analysis (227 620 [53·8%] were women and 400 036 [94·6%] were White). 71 traits showed significant (p<4·27 × 10–4) associations with LTL but most were modest, equivalent to less than 1 year of age-related change in LTL. In multivariable analyses of 17 traits with stronger associations (equivalent to ≥2 years of age-related change in LTL), oily fish intake, educational attainment, and general health status retained a significant association of this magnitude, with walking pace and current smoking being additionally significant at this level of association in the imputed models. Mendelian randomisation analysis suggested that educational attainment and smoking behaviour causally affect LTL. Both indices of healthy behaviour were positively and linearly associated with LTL, with those with the most healthy behaviours having longer LTL equivalent to about 3·5 years of age-related change in LTL than those with the least heathy behaviours (p<0·001). However, healthy behaviours explained less than 0·2% of the total variation in LTL and did not significantly modify the association of LTL with risk of any of the diseases studied. Neither the association of more healthy behaviours on greater life expectancy or lower risk of coronary artery disease were substantially mediated through LTL.InterpretationAlthough several potentially modifiable traits and healthy behaviours have a quantifiable association with LTL, at least some of which are likely to be causal, these effects are not of a sufficient magnitude to substantially alter the association between LTL and various diseases or life expectancy. Attempts to change telomere length through lifestyle or behavioural changes might not confer substantial clinical benefit.FundingUK Medical Research Council, UK Biotechnology and Biological Sciences Research Council, and British Heart Foundation.

The association of leukocyte telomere length and intermediate coronary lesions-a retrospective study.

Intermediate coronary lesions (40-70% stenosis) present a higher risk for future cardiovascular events for instability of plaques. Shortened telomere is an indicator of cellular senescence, which is associated with age-related diseases. However, the relationship between telomere length and severity of intermediate coronary lesions remains largely unknown. A total of 121 lesions of 121 patients with intermediate coronary disease that underwent intravascular optical coherence tomography were enrolled. These patients were retrospectively divided into two groups according to whether accept percutaneous coronary intervention (PCI) treatment: non-PCI group and PCI group. Leukocyte telomere length (LTL) in patients of PCI group were significantly shorter (12.54±2.70 vs. 15.32±3.72 kb, P<0.001) than non-PCI group. The PCI group had longer lipid length (17.17±9.94 vs. 12.21±10.15 mm, P=0.01) and greater lipid index (4,286.82±3,012.54 vs. 2,444.87±2,677.59 °*mm, P<0.001). There was a significant difference in the prevalence of thin-cap fibroatheroma (36.6% vs. 16.0%, P=0.013), macrophages (56.3% vs. 38.0%, P=0.047), plaque rupture (23.9% vs. 6.0%, P=0.009), cholesterol crystal (49.3% vs. 30.0%, P=0.034), dissection (23.9% vs. 4.0%, P=0.003) between PCI and non-PCI group. Logistic regression revealed that LTL was independently associated with PCI after adjusting for confounding factors (OR 0.952, CI: 0.930-0.974, per 1unit increase, P<0.001). Receiver operating characteristic (ROC) analysis revealed a LTL area under the ROC curve (AUC) of 0.714 (95% CI: 0.619-0.808, P<0.001) in the study population. Furthermore, LTL was inversely correlated with lipid length (r =-0.190, P=0.037), lipid arc (r =-0.301, P=0.001), lipid index (r =-0.182, P=0.046), and positive correlation with FCT (r =0.213, P=0.034). LTL was independently associated with possibility of receiving PCI in intermediate coronary lesion patients and LTL is also significantly related to plaque instability features that evaluated by optical coherence tomography. LTL may be as an indicator to assess the necessity of PCI in intermediate coronary lesion patients.

Body mass index and shortened telomere length in middle-aged female and male RUNNING HEAD: Middle-aged and shortened telomere length

Obesity is a risk factor associated with age-related disorders that accelerate aging, and it increases the risk of metabolic diseases. Therefore, this study was conducted to investigate the association of leukocyte telomere length (LTL) with the presence of higher body weight in middle-aged females and males. The study subjects comprised 160 (80 control and 80 higher body mass index BMI groups) with ranging ages of 30-50 years included and stratified for BMI. The physio-biochemical analysis was measured using enzymatic determination. Mean telomere length was determined by using the southern blotting technique. The association analysis revealed a significant variance (P &lt; 0.01) in biochemical parameters between higher BMI groups and control including waist, lipid profile, and the level of estradiol, testosterone, follicle-stimulating hormone, and luteinizing hormone. Mean telomere length was shorter in middle-aged males compared to the females of higher BMI groups and control groups for both age groups. LTL was shorter in the overweight and obese patients compared with the control group, and these differences in LTL obese group were shorter compared to the overweight group. In conclusion, shorter telomere length was observed in middle-aged males associated with higher body weight and lipid abnormalities. Lipid/lipoprotein abnormalities can be used as a predictor for the shortened telomere length and the reduction in adiposity indices can improvement the telomere length in both overweight and obese subjects.