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BMJ (Clinical Research Ed.) Jul 2014To assess the association between leucocyte telomere length and risk of cardiovascular disease. (Meta-Analysis)
Meta-Analysis Review
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.
Topics: Cardiovascular Diseases; Humans; Leukocytes; Models, Statistical; Odds Ratio; Regression Analysis; Risk Factors; Telomere Shortening
PubMed: 25006006
DOI: 10.1136/bmj.g4227 -
Public Health Genomics 2017The goal of this systematic review and meta-analysis is to determine the effect of diet on telomere length. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The goal of this systematic review and meta-analysis is to determine the effect of diet on telomere length.
METHODS
We searched the following databases: MEDLINE, Embase, LILACS, CINAHL, ISI Web of Science, and Scopus, as well as the Cochrane Central Register of Controlled Trials and the National Institutes of Health, from inception to December 2016. Articles that assessed effects of diet on telomere length were included.
RESULTS
A total of 2,128 studies were identified, 30 were read in full, and 7 were systematically reviewed. Five RCTs were included in the meta-analysis, covering 9 diets; a total of 533 participants were included. Study heterogeneity (I2) was 89%, and differences were not identified regarding average telomere lengths (mean difference 1.06; 95% CI -1.53 to 3.65).
CONCLUSION
The available evidence suggests that there is no effect of diet on telomere length, but the strong heterogeneity in the type and duration of dietary interventions does not allow any final statement on the absence of an effect of diet on telomere length.
Topics: Aged; Diet; Female; Humans; Life Expectancy; Male; Middle Aged; Statistics as Topic; Telomere; Telomere Shortening
PubMed: 29439273
DOI: 10.1159/000486586 -
Human Reproduction Update Nov 2020Studies in non-human mammals suggest that environmental factors can influence spermatozoal DNA methylation, and some research suggests that spermatozoal DNA methylation...
BACKGROUND
Studies in non-human mammals suggest that environmental factors can influence spermatozoal DNA methylation, and some research suggests that spermatozoal DNA methylation is also implicated in conditions such as subfertility and imprinting disorders in the offspring. Together with an increased availability of cost-effective methods of interrogating DNA methylation, this premise has led to an increasing number of studies investigating the DNA methylation landscape of human spermatozoa. However, how the human spermatozoal DNA methylome is influenced by environmental factors is still unclear, as is the role of human spermatozoal DNA methylation in subfertility and in influencing offspring health.
OBJECTIVE AND RATIONALE
The aim of this systematic review was to critically appraise the quality of the current body of literature on DNA methylation in human spermatozoa, summarize current knowledge and generate recommendations for future research.
SEARCH METHODS
A comprehensive literature search of the PubMed, Web of Science and Cochrane Library databases was conducted using the search terms 'semen' OR 'sperm' AND 'DNA methylation'. Publications from 1 January 2003 to 2 March 2020 that studied human sperm and were written in English were included. Studies that used sperm DNA methylation to develop methodologies or forensically identify semen were excluded, as were reviews, commentaries, meta-analyses or editorial texts. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) criteria were used to objectively evaluate quality of evidence in each included publication.
OUTCOMES
The search identified 446 records, of which 135 were included in the systematic review. These 135 studies were divided into three groups according to area of research; 56 studies investigated the influence of spermatozoal DNA methylation on male fertility and abnormal semen parameters, 20 studies investigated spermatozoal DNA methylation in pregnancy outcomes including offspring health and 59 studies assessed the influence of environmental factors on spermatozoal DNA methylation. Findings from studies that scored as 'high' and 'moderate' quality of evidence according to GRADE criteria were summarized. We found that male subfertility and abnormal semen parameters, in particular oligozoospermia, appear to be associated with abnormal spermatozoal DNA methylation of imprinted regions. However, no specific DNA methylation signature of either subfertility or abnormal semen parameters has been convincingly replicated in genome-scale, unbiased analyses. Furthermore, although findings require independent replication, current evidence suggests that the spermatozoal DNA methylome is influenced by cigarette smoking, advanced age and environmental pollutants. Importantly however, from a clinical point of view, there is no convincing evidence that changes in spermatozoal DNA methylation influence pregnancy outcomes or offspring health.
WIDER IMPLICATIONS
Although it appears that the human sperm DNA methylome can be influenced by certain environmental and physiological traits, no findings have been robustly replicated between studies. We have generated a set of recommendations that would enhance the reliability and robustness of findings of future analyses of the human sperm methylome. Such studies will likely require multicentre collaborations to reach appropriate sample sizes, and should incorporate phenotype data in more complex statistical models.
Topics: DNA Methylation; Female; Humans; Infertility, Male; Male; Pregnancy; Pregnancy Outcome; Reproducibility of Results; Semen; Spermatozoa
PubMed: 32790874
DOI: 10.1093/humupd/dmaa025 -
Ageing Research Reviews Sep 2019Telomere shortening has been proposed as a potentially useful biomarker of human ageing and age-related morbidity and mortality. We performed a systematic review and... (Meta-Analysis)
Meta-Analysis
Telomere shortening has been proposed as a potentially useful biomarker of human ageing and age-related morbidity and mortality. We performed a systematic review and meta-analysis to summarize results from individual studies on the telomere length according to the frailty status and frailty index in older adults. We searched the PubMed, SCOPUS and Web of Science databases to identify studies that evaluated the telomere length in frail and non-frail older adults and the relationship between telomere length and frailty index score. We used the base pairs (bp) as a measure of the telomere length. Summary estimates were calculated using random-effects models. Nine studies were included in the present systematic review and a total of 10,079 older adults were analyzed. We found that the frail older adults (n = 355) had shorter telomeres than the non-frail (n = 1894) (Standardized Mean Difference [SMD] -0.41; 95% CI -0.73 to -0.09; P = 0.01; I = 82%). Significant differences in telomere length between frail and non-frail older adults were identified in Hispanic (SMD -1.31; 95% CI -1.71 to -0.92; P < 0.0001; I = 0%) but not in Non-Hispanic countries (SMD -0.13; 95% CI -0.26 to 0.00; P = 0.06; I = 0%). Similar results were found in the adjusted meta-analysis (SMD -0.56; 95% -1.12 to 0.00; P = 0.05; I = 85%). A significant but weak relationship was found between telomere length and frailty index analyzing 8244 individuals (SMD -0.06; 95% IC -0.10 to 0.01; P = 0.01; I = 0%). The current available evidence suggests that telomere length may be not a meaningful biomarker for frailty. Because the potential influence of ethnicity in shortening of telomeres and decline in physiologic reserves associated with aging, additional multiethnic studies are needed.
Topics: Aged; Aging; Biomarkers; Female; Frail Elderly; Frailty; Humans; Male; Telomere Shortening
PubMed: 31170457
DOI: 10.1016/j.arr.2019.100914 -
Frontiers in Oncology 2022DNA replication is a process fundamental in all living organisms in which deregulation, known as replication stress, often leads to genomic instability, a hallmark of...
DNA replication is a process fundamental in all living organisms in which deregulation, known as replication stress, often leads to genomic instability, a hallmark of cancer. Most malignant tumors sustain persistent proliferation and tolerate replication stress increasing reliance to the replication stress response. So whilst replication stress induces genomic instability and tumorigenesis, the replication stress response exhibits a unique cancer-specific vulnerability that can be targeted to induce catastrophic cell proliferation. Radiation therapy, most used in cancer treatment, induces a plethora of DNA lesions that affect DNA integrity and, in-turn, DNA replication. Owing to radiation dose limitations for specific organs and tumor tissue resistance, the therapeutic window is narrow. Thus, a means to eliminate or reduce tumor radioresistance is urgently needed. Current research trends have highlighted the potential of combining replication stress regulators with radiation therapy to capitalize on the high replication stress of tumors. Here, we review the current body of evidence regarding the role of replication stress in tumor progression and discuss potential means of enhancing tumor radiosensitivity by targeting the replication stress response. We offer new insights into the possibility of combining radiation therapy with replication stress drugs for clinical use.
PubMed: 35875060
DOI: 10.3389/fonc.2022.838637 -
Environmental Research Oct 2017Cigarette smoking is a risk factor for ageing-related disease, but its association with biological ageing, indicated by telomere length, is unclear. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Cigarette smoking is a risk factor for ageing-related disease, but its association with biological ageing, indicated by telomere length, is unclear.
METHODS
We systematically reviewed evidence evaluating association between smoking status and telomere length. Searches were performed in MEDLINE (Ovid) and EMBASE (Ovid) databases, combining variation of keywords "smoking" and "telomere". Data was extracted for study characteristics and estimates for association between smoking and telomere length. Quality of studies was assessed with a risk of bias score, and publication bias was assessed with a funnel plot. I test was used to observe heterogeneity. Meta-analysis was carried out to compare mean difference in telomere length by smoking status, and a dose-response approach was carried out for pack-years of smoking and telomere length. A sensitivity analysis was carried out to examine sources of heterogeneity.
RESULTS
A total of 84 studies were included in the review, and 30 among them were included in our meta-analysis. Potential bias was addressed in half of included studies, and there was little evidence of small study bias. Telomere length was shorter among ever smokers compared to never smokers (summary standard mean difference [SMD]: -0.11 (95% CI -0.16 to -0.07)). Similarly, shorter telomere length was found among smokers compared to non-smokers, and among current smokers compared to never or former smokers. Dose-response meta-analysis suggested an inverse trend between pack-years of smoking and telomere length. However, heterogeneity among some analyses was observed.
CONCLUSION
Shorter telomeres among ever smokers compared to those who never smoked may imply mechanisms linking tobacco smoke exposure to ageing-related disease.
Topics: Humans; Risk Factors; Smoking; Telomere Homeostasis; Telomere Shortening; Tobacco Smoke Pollution
PubMed: 28704792
DOI: 10.1016/j.envres.2017.06.038 -
Cancer Epidemiology, Biomarkers &... Jan 2017Telomeres ensure genome integrity during replication. Loss of telomeric function leads to cell immortalization and accumulation of genetic alterations. The association... (Review)
Review
Telomeres ensure genome integrity during replication. Loss of telomeric function leads to cell immortalization and accumulation of genetic alterations. The association of telomere length (TL) with breast cancer prognosis is examined through a systematic review. Electronic databases (MEDLINE, EMBASE, CENTRAL), from inception to December 2015, and relevant reviews were searched. Studies that evaluated TL (blood and/or tumor) in association with breast cancer survival or prognostic factor were included. Thirty-six studies met inclusion criteria. Overall risk of bias was critical. Eight studies reported survival outcomes. Overall, there was a trend toward an association of longer telomeres with better outcomes (tumor, not blood). Of the 33 studies reporting associations with prognostic factors, nine adjusted for potential confounders. Among the latter, shorter telomeres were associated with older age (blood, not tumor), higher local recurrence rates (normal tissue), higher tumor grade (tumor), and lower physical activity (blood), which were reported in one study each. TL was not associated with molecular subtype (blood, one study), family history (tumor, one study), chemotherapy (blood, three of four studies), and stress reduction interventions (blood, two of two studies). Although major methodologic differences preclude from drawing conclusive results, TL could be a valuable breast cancer prognostic marker. Cancer Epidemiol Biomarkers Prev; 26(1); 3-10. ©2016 AACR.
Topics: Breast Neoplasms; Female; Genetic Markers; Humans; Observational Studies as Topic; Predictive Value of Tests; Prognosis; Retrospective Studies; Telomere; Telomere Shortening; Treatment Outcome
PubMed: 27677729
DOI: 10.1158/1055-9965.EPI-16-0343 -
Innovation (Cambridge (Mass.)) May 2021COVID-19 has spread globally to over 200 countries with more than 40 million confirmed cases and one million deaths as of November 1, 2020. The SARS-CoV-2 virus, leading... (Review)
Review
COVID-19 has spread globally to over 200 countries with more than 40 million confirmed cases and one million deaths as of November 1, 2020. The SARS-CoV-2 virus, leading to COVID-19, shows extremely high rates of infectivity and replication, and can result in pneumonia, acute respiratory distress, or even mortality. SARS-CoV-2 has been found to continue to rapidly evolve, with several genomic variants emerging in different regions throughout the world. In addition, despite intensive study of the spike protein, its origin, and molecular mechanisms in mediating host invasion are still only partially resolved. Finally, the repertoire of drugs for COVID-19 treatment is still limited, with several candidates still under clinical trial and no effective therapeutic yet reported. Although vaccines based on either DNA/mRNA or protein have been deployed, their efficacy against emerging variants requires ongoing study, with multivalent vaccines supplanting the first-generation vaccines due to their low efficacy against new strains. Here, we provide a systematic review of studies on the epidemiology, immunological pathogenesis, molecular mechanisms, and structural biology, as well as approaches for drug or vaccine development for SARS-CoV-2.
PubMed: 33997827
DOI: 10.1016/j.xinn.2021.100116 -
Role of human DNA2 (hDNA2) as a potential target for cancer and other diseases: A systematic review.DNA Repair Nov 2017DNA nuclease/helicase 2 (DNA2), a multi-functional protein protecting the high fidelity of genomic transmission, plays critical roles in DNA replication and repair... (Review)
Review
DNA nuclease/helicase 2 (DNA2), a multi-functional protein protecting the high fidelity of genomic transmission, plays critical roles in DNA replication and repair processes. In the maturation of Okazaki fragments, DNA2 acts synergistically with other enzymes to cleave the DNA-RNA primer flaps via different pathways. DNA2 is also involved in the stability of mitochondrial DNA and the maintenance of telomeres. Moreover, DNA2 potentially participates in controlling the cell cycle by repairing the DNA replication faults at main checkpoints. In addition, previous evidences demonstrated that DNA2 also functions in the repair process of DNA damages, such as base excision repair (BER). Currently, large studies revealed the structures and functions of DNA2 in prokaryotes and unicellular eukaryotes, such as bacteria and yeast. However, the studies that highlighted the functions of human DNA2 (hDNA2) and the relationships with other multifunctional proteins are still elusive, and more precise investigations are immensely needed. Therefore, this review mainly encompasses the key functions of DNA2 in human cells with various aspects, especially focusing on the genome integrity, and also generalizes the recent insights to the mechanisms related to the occurrence of cancer and other diseases potentially linked to the mutations in DNA2.
Topics: DNA Helicases; DNA Repair; DNA Replication; DNA, Neoplasm; Humans; Mutation; Neoplasms
PubMed: 28903076
DOI: 10.1016/j.dnarep.2017.09.001 -
Frontiers in Genetics 2021The triad of drug efficacy, toxicity and resistance underpins the risk-benefit balance of all therapeutics. The application of pharmacogenomics has the potential to...
The triad of drug efficacy, toxicity and resistance underpins the risk-benefit balance of all therapeutics. The application of pharmacogenomics has the potential to improve the risk-benefit balance of a given therapeutic via the stratification of patient populations based on DNA variants. A growth in the understanding of the particulars of the mitochondrial genome, alongside the availability of techniques for its interrogation has resulted in a growing body of literature examining the impact of mitochondrial DNA (mtDNA) variation upon drug response. To critically evaluate and summarize the available literature, across a defined period, in a systematic fashion in order to map out the current landscape of the subject area and identify how the field may continue to advance. A systematic review of the literature published between January 2009 and December 2020 was conducted using the PubMed database with the following key inclusion criteria: reference to specific mtDNA polymorphisms or haplogroups, a core objective to examine associations between mtDNA variants and drug response, and research performed using human subjects or human models. Review of the literature identified 24 articles reporting an investigation of the association between mtDNA variant(s) and drug efficacy, toxicity or resistance that met the key inclusion criteria. This included 10 articles examining mtDNA variations associated with antiretroviral therapy response, 4 articles examining mtDNA variants associated with anticancer agent response and 4 articles examining mtDNA variants associated with antimicrobial agent response. The remaining articles covered a wide breadth of medications and were therefore grouped together and referred to as "other." Investigation of the impact of mtDNA variation upon drug response has been sporadic to-date. Collective assessment of the associations identified in the articles was inconclusive due to heterogeneous methods and outcomes, limited racial/ethnic groups, lack of replication and inadequate statistical power. There remains a high degree of idiosyncrasy in drug response and this area has the potential to explain variation in drug response in a clinical setting, therefore further research is likely to be of clinical benefit.
PubMed: 34484295
DOI: 10.3389/fgene.2021.698825