scholarly journals Telomeres and Telomere Length: A General Overview

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 558 ◽  
Author(s):  
Nalini Srinivas ◽  
Sivaramakrishna Rachakonda ◽  
Rajiv Kumar
Keyword(s):  
Environmental Factors ◽  
Telomere Length ◽  
Replicative Senescence ◽  
Association Studies ◽  
Epidemiological Data ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Telomere Attrition ◽  
Age Related ◽  
The Impact

Telomeres are highly conserved tandem nucleotide repeats that include proximal double-stranded and distal single-stranded regions that in complex with shelterin proteins afford protection at chromosomal ends to maintain genomic integrity. Due to the inherent limitations of DNA replication and telomerase suppression in most somatic cells, telomeres undergo age-dependent incremental attrition. Short or dysfunctional telomeres are recognized as DNA double-stranded breaks, triggering cells to undergo replicative senescence. Telomere shortening, therefore, acts as a counting mechanism that drives replicative senescence by limiting the mitotic potential of cells. Telomere length, a complex hereditary trait, is associated with aging and age-related diseases. Epidemiological data, in general, support an association with varying magnitudes between constitutive telomere length and several disorders, including cancers. Telomere attrition is also influenced by oxidative damage and replicative stress caused by genetic, epigenetic, and environmental factors. Several single nucleotide polymorphisms at different loci, identified through genome-wide association studies, influence inter-individual variation in telomere length. In addition to genetic factors, environmental factors also influence telomere length during growth and development. Telomeres hold potential as biomarkers that reflect the genetic predisposition together with the impact of environmental conditions and as targets for anti-cancer therapies.

scholarly journals RAD51B (rs8017304 and rs2588809), TRIB1 (rs6987702, rs4351379, and rs4351376), COL8A1 (rs13095226), and COL10A1 (rs1064583) Gene Variants with Predisposition to Age-Related Macular Degeneration

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Alvita Vilkeviciute ◽  
Loresa Kriauciuniene ◽  
Romanas Chaleckis ◽  
Vytenis Pranas Deltuva ◽  
Rasa Liutkeviciene
Keyword(s):  
Macular Degeneration ◽  
Association Studies ◽  
Strong Association ◽  
Age Related Macular Degeneration ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Exudative Amd ◽  
Age Related ◽  
Significant Difference ◽  
The Impact

Background. Age-related macular degeneration (AMD) is a progressive neurodegenerative disease of a central part of the neural retina (macula) and a leading cause of blindness in elderly people. While it is known that the AMD is a multifactorial disease, genetic factors involved in lipid metabolism, inflammation, and neovascularization are currently being widely studied in genome-wide association studies (GWAS). The aim of our study was to evaluate the impact of new single nucleotide polymorphisms (SNPs) in RAD51B, TRIB1, COL8A1, and COL10A1 genes on AMD development. Methods. Case-control study involved 254 patients diagnosed with early AMD, 244 patients with exudative AMD, and 942 control subjects. The genotyping of RAD51B (rs8017304 and rs2588809), TRIB1 (rs6987702, rs4351379, and rs4351376), COL8A1 (rs13095226), and COL10A1 (rs1064583) was carried out using TaqMan assays by a real-time polymerase chain reaction (RT-PCR) method. Results. Statistically significant difference was found in genotype (TT, TC, and CC) distribution of COL8A1 rs13095226 between exudative AMD and control groups (60.2%, 33.6%, and 6.1% vs. 64.9%, 32.3%, and 2.9%, respectively, p=0.036). Also, comparing with TT+TC, rs13095226 CC genotype was associated with 3.5-fold increased odds of exudative AMD development (OR = 3.540; 95% CI: 1.415-8.856; p=0.007). Conclusion. Our study revealed a strong association between a variant in COL8A1 (rs13095226) and exudative AMD development.

scholarly journals Novel genetic determinants of telomere length from a trans-ethnic analysis of 109,122 whole genome sequences in TOPMed

2019 ◽  
Author(s):  
Margaret A Taub ◽  
Matthew P Conomos ◽  
Rebecca Keener ◽  
Kruthika R Iyer ◽  
Joshua S Weinstock ◽  
...  
Keyword(s):  
Telomere Length ◽  
Association Studies ◽  
P Value ◽  
Genome Wide Association Studies ◽  
Whole Genome ◽  
Genetic Determinants ◽  
Age Related ◽  
Genome Wide ◽  
Variant Genotype ◽  
Effect Heterogeneity

ABSTRACTTelomeres shorten in replicating somatic cells, and telomere length (TL) is associated with age-related diseases 1,2. To date, 17 genome-wide association studies (GWAS) have identified 25 loci for leukocyte TL 3–19, but were limited to European and Asian ancestry individuals and relied on laboratory assays of TL. In this study from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, we used whole genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of TL in n=109,122 trans-ethnic (European, African, Asian and Hispanic/Latino) individuals. We identified 59 sentinel variants (p-value <5×10−9) from 36 loci (20 novel, 13 replicated in external datasets). There was little evidence of effect heterogeneity across populations, and 10 loci had >1 independent signal. Fine-mapping at OBFC1 indicated the independent signals colocalized with cell-type specific eQTLs for OBFC1 (STN1). We further identified two novel genes, DCLRE1B (SNM1B) and PARN, using a multi-variant gene-based approach.

Clinical implication of telomere length-related polymorphisms in gastric cardia adenocarcinoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15502-e15502
Author(s):  
Nasha Zhang ◽  
Ming Yang
Keyword(s):  
Telomere Length ◽  
Genetic Variants ◽  
Association Studies ◽  
Gastric Cardia ◽  
Candidate Snps ◽  
Gastric Cardia Adenocarcinoma ◽  
Genome Wide Association Studies ◽  
Critical Feature ◽  
Increased Risk ◽  
The Impact

e15502 Background: Aberrant telomere lengthening is a critical feature of malignant cells. Short leukocyte telomere length (LTL) confers elevated risk of gastric cardia adenocarcinoma (GCA). Multiple genome-wide association studies (GWAS) identified various single nucleotide polymorphisms (SNPs) associated with LTL in different ethnic populations. However, it remains largely unexplored how these genetic variants are involved in GCA susceptibility. Methods: We systematically screened GWAS-identified candidate SNPs and tested the impact of thirty polymorphisms in genes associated with interindividual LTL variation on GCA using two-stage case-control comparisons consisting of 1,024 GCA patients and 1,118 controls. Results: We observed that CXCR4 rs6430612, TERT rs10069690 and rs2853676 as well as VPS34 rs2162440 are significantly associated with GCA development. A 0.64-fold decreased risk of GCA is associated with the CXCR4 rs6430612 CT genotype compared with the CC genotype ( P= 0.002). On the contrary, the TERT rs10069690 TT genotype carriers had a 1.83-fold increased risk to develop GCA compared to the CC genotype carriers ( P= 5.8×10-6). We also detected a 2.17-fold increased OR for GCA that was associated with the TERT rs2853676 TT genotype ( P= 2.6×10-6). In addition, the odds of having the VPS34 rs2162440 GA genotype in GCA patients was 1.35 compared with the GG genotype ( P= 0.002). In stratified analyses, the association between TERT rs10069690 polymorphism and GCA was more pronounced in nonsmokers ( Pinteraction=9.7×10-5) and nondrinkers ( Pinteraction= 4.6×10-5). Conclusions: Our results highlight the importance of both LTL and LTL-related genetic variants to GCA predisposition.

scholarly journals Genome-wide association study of telomere length among South Asians identifies a second RTEL1 association signal

2017 ◽  
Vol 55 (1) ◽  
pp. 64-71 ◽  
Author(s):  
Dayana A Delgado ◽  
Chenan Zhang ◽  
Lin S Chen ◽  
Jianjun Gao ◽  
Shantanu Roy ◽  
...  
Keyword(s):  
Telomere Length ◽  
South Asian ◽  
Genome Wide Association Study ◽  
Association Studies ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Age Related ◽  
Genome Wide ◽  
Potential Biomarker

BackgroundLeucocyte telomere length (TL) is a potential biomarker of ageing and risk for age-related disease. Leucocyte TL is heritable and shows substantial differences by race/ethnicity. Recent genome-wide association studies (GWAS) report ~10 loci harbouring SNPs associated with leucocyte TL, but these studies focus primarily on populations of European ancestry.ObjectiveThis study aims to enhance our understanding of genetic determinants of TL across populations.MethodsWe performed a GWAS of TL using data on 5075 Bangladeshi adults. We measured TL using one of two technologies (qPCR or a Luminex-based method) and used standardised variables as TL phenotypes.ResultsOur results replicate previously reported associations in the TERC and TERT regions (P=2.2×10−8 and P=6.4×10−6, respectively). We observed a novel association signal in the RTEL1 gene (intronic SNP rs2297439; P=2.82×10−7) that is independent of previously reported TL-associated SNPs in this region. The minor allele for rs2297439 is common in South Asian populations (≥0.25) but at lower frequencies in other populations (eg, 0.07 in Northern Europeans). Among the eight other previously reported association signals, all were directionally consistent with our study, but only rs8105767 (ZNF208) was nominally significant (P=0.003). SNP-based heritability estimates were as high as 44% when analysing close relatives but much lower when analysing distant relatives only.ConclusionsIn this first GWAS of TL in a South Asian population, we replicate some, but not all, of the loci reported in prior GWAS of individuals of European ancestry, and we identify a novel second association signal at the RTEL1 locus.

scholarly journals The role of polymorphic ERAP1 in autoinflammatory disease

2018 ◽  
Vol 38 (4) ◽  
Author(s):  
Emma Reeves ◽  
Edward James
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Autoinflammatory Disease ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Genetic Associations ◽  
Single Nucleotide ◽  
Cell Functions ◽  
The Impact

Autoimmune and autoinflammatory conditions represent a group of disorders characterized by self-directed tissue damage due to aberrant changes in innate and adaptive immune responses. These disorders possess widely varying clinical phenotypes and etiology; however, they share a number of similarities in genetic associations and environmental influences. Whilst the pathogenic mechanisms of disease remain poorly understood, genome wide association studies (GWAS) have implicated a number of genetic loci that are shared between several autoimmune and autoinflammatory conditions. Association of particular HLA alleles with disease susceptibility represents one of the strongest genetic associations. Furthermore, recent GWAS findings reveal strong associations with single nucleotide polymorphisms in the endoplasmic reticulum aminopeptidase 1 (ERAP1) gene and susceptibility to a number of these HLA-associated conditions. ERAP1 plays a major role in regulating the repertoire of peptides presented on HLA class I alleles at the cell surface, with the presence of single nucleotide polymorphisms in ERAP1 having a significant impact on peptide processing function and the repertoire of peptides presented. The impact of this dysfunctional peptide generation on CD8+ T-cell responses has been proposed as a mechanism of pathogenesis diseases where HLA and ERAP1 are associated. More recently, studies have highlighted a role for ERAP1 in innate immune-mediated pathways involved in inflammatory responses. Here, we discuss the role of polymorphic ERAP1 in various immune cell functions, and in the context of autoimmune and autoinflammatory disease pathogenesis.

scholarly journals Prioritization of Cancer-Related Genomic Variants by SNP Association Network

2015 ◽  
Vol 14s2 ◽  
pp. CIN.S17288
Author(s):  
Changning Liu ◽  
Zhenyu Xuan
Keyword(s):  
Association Studies ◽  
Age Related Macular Degeneration ◽  
Chromatin Interaction ◽  
Reference Database ◽  
Genome Wide Association Studies ◽  
Association Network ◽  
Nucleotide Polymorphisms ◽  
Gwas Study ◽  
Snp Association ◽  
Age Related

We have developed a general framework to construct an association network of single nucleotide polymorphisms (SNPs) (SNP association network, SAN) based on the functional interactions of genes located in the flanking regions of SNPs. SAN, which was constructed based on protein-protein interactions in the Human Protein Reference Database (HPRD), showed significantly enriched signals in both linkage disequilibrium (LD) and long-range chromatin interaction (Hi-C). We used this network to further develop two methods for predicting and prioritizing disease-associated genes from genome-wide association studies (GWASs). We found that random walk with restart (RWR) using SAN (RWR-SAN) can greatly improve the prediction of lung-cancer-associated genes by comparing RWR with the use of network in HPRD (AUC 0.81 vs 0.66). In a reanalysis of the GWAS dataset of age-related macular degeneration (AMD), SAN could identify more potential AMD-associated genes that were previously ranked lower in the GWAS study. The interactions in SAN could facilitate the study of complex diseases.

scholarly journals Separating the contributions of SLC26A9 and CFTR to anion secretion in primary human bronchial epithelia (HBE)

2021 ◽  
Author(s):  
Mads B Larsen ◽  
Jeannie J Choi ◽  
Xiaohui Wang ◽  
Michael M Myerburg ◽  
Raymond A Frizzell ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Association Studies ◽  
Primary Source ◽  
Airway Disease ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Anion Secretion ◽  
Anion Transporter ◽  
Bronchial Epithelia ◽  
The Impact

Aberrant anion secretion across the bronchial epithelium is associated with airway disease, most notably in cystic fibrosis. While the cystic fibrosis transmembrane conductance regulator (CFTR) is recognized as the primary source of airway anion secretion, alternative anion transport mechanisms play a contributing role. An alternative anion transporter of growing interest is SLC26A9, a constitutively active chloride channel which has been shown to interact with CFTR and may also contribute to bicarbonate secretion. Interest in SLC26A9 has been fueled by genome-wide association studies which suggest it is a significant modifier of CF disease severity. In spite of this growing evidence that SLC26A9 plays an important role in the airway, its presence and function in bronchial epithelia remains poorly understood, in part because its activity is difficult to separate from the activity of CFTR. Here we present results using primary, human bronchial epithelia (HBE) from multiple patient sources to confirm that SLC26A9 mRNA is present in HBE, and that its constitutive channel activity is unaffected by knock down of CFTR. Furthermore, SLC26A9 and CFTR show differential responses to common inhibitors of anion secretion. Finally, we assess the impact of bicarbonate on the activity of SLC26A9 and CFTR. These results confirm that SLC26A9 is the primary source of constitutive anion secretion across HBE, and should inform future studies focused on activation of SLC26A9 as an alternative anion channel in CF. These results should provide a strong foundation to investigate how single nucleotide polymorphisms in SLC26A9 modulate airway disease.

scholarly journals Bayesian network analysis of plasma microRNA sequencing data in patients with venous thrombosis

2020 ◽  
Vol 22 (Supplement_C) ◽  
pp. C34-C45 ◽  
Author(s):  
Florian Thibord ◽  
Gaëlle Munsch ◽  
Claire Perret ◽  
Pierre Suchon ◽  
Maguelonne Roux ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Association Studies ◽  
Statistical Significance ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Sequencing Data ◽  
New Associations ◽  
Significance Threshold ◽  
The Impact ◽  
Plasma Mirna

Abstract MicroRNAs (miRNAs) are small regulatory RNAs participating to several biological processes and known to be involved in various pathologies. Measurable in body fluids, miRNAs have been proposed to serve as efficient biomarkers for diseases and/or associated traits. Here, we performed a next-generation-sequencing based profiling of plasma miRNAs in 344 patients with venous thrombosis (VT) and assessed the association of plasma miRNA levels with several haemostatic traits and the risk of VT recurrence. Among the most significant findings, we detected an association between hsa-miR-199b-3p and haematocrit levels (P = 0.0016), these two markers having both been independently reported to associate with VT risk. We also observed suggestive evidence for association of hsa-miR-370-3p (P = 0.019), hsa-miR-27b-3p (P = 0.016) and hsa-miR-222-3p (P = 0.049) with VT recurrence, the observations at the latter two miRNAs confirming the recent findings of Wang et al. Besides, by conducting Genome-Wide Association Studies on miRNA levels and meta-analyzing our results with some publicly available, we identified 21 new associations of single nucleotide polymorphisms with plasma miRNA levels at the statistical significance threshold of P &lt; 5 × 10−8, some of these associations pertaining to thrombosis associated mechanisms. In conclusion, this study provides novel data about the impact of miRNAs’ variability in haemostasis and new arguments supporting the association of few miRNAs with the risk of recurrence in patients with venous thrombosis.

scholarly journals Bcl11b/Ctip2 in Skin, Tooth, and Craniofacial System

2020 ◽  
Vol 8 ◽  
Author(s):  
Marie-Thérèse Daher ◽  
Pedro Bausero ◽  
Onnik Agbulut ◽  
Zhenlin Li ◽  
Ara Parlakian
Keyword(s):  
Association Studies ◽  
Regulatory Region ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Tooth Formation ◽  
Skin Development ◽  
Cell Proliferation And Differentiation ◽  
Genome Wide ◽  
Dual Action ◽  
The Impact

Ctip2/Bcl11b is a zinc finger transcription factor with dual action (repression/activation) that couples epigenetic regulation to gene transcription during the development of various tissues. It is involved in a variety of physiological responses under healthy and pathological conditions. Its role and mechanisms of action are best characterized in the immune and nervous systems. Furthermore, its implication in the development and homeostasis of other various tissues has also been reported. In the present review, we describe its role in skin development, adipogenesis, tooth formation and cranial suture ossification. Experimental data from several studies demonstrate the involvement of Bcl11b in the control of the balance between cell proliferation and differentiation during organ formation and repair, and more specifically in the context of stem cell self-renewal and fate determination. The impact of mutations in the coding sequences of Bcl11b on the development of diseases such as craniosynostosis is also presented. Finally, we discuss genome-wide association studies that suggest a potential influence of single nucleotide polymorphisms found in the 3’ regulatory region of Bcl11b on the homeostasis of the cardiovascular system.

scholarly journals Genetically Increased Telomere Length and Aging-Related Traits in the U.K. Biobank

2019 ◽  
Vol 76 (1) ◽  
pp. 15-22
Author(s):  
Kathryn Demanelis ◽  
Lin Tong ◽  
Brandon L Pierce
Keyword(s):  
Blood Pressure ◽  
Telomere Length ◽  
Simulated Data ◽  
Forced Expiratory Volume ◽  
Nucleotide Polymorphisms ◽  
Middle Aged ◽  
Standard Deviation Increase ◽  
Age Related ◽  
Potential Biomarker ◽  
The Impact

Abstract Telomere length (TL) shortens over time in most human cell types and is a potential biomarker of aging. However, the causal association of TL on physical and cognitive traits that decline with age has not been extensively examined in middle-aged adults. Using a Mendelian randomization (MR) approach, we utilized genetically increased TL (GI-TL) to estimate the impact of TL on aging-related traits among U.K. Biobank (UKB) participants (age 40–69 years). We manually curated 53 aging-related traits from the UKB and restricted to unrelated participants of British ancestry (n = 337,522). We estimated GI-TL as a linear combination of nine TL-associated single nucleotide polymorphisms (SNPs), each weighted by its previously-reported association with leukocyte TL. Regression models were used to assess the associations between GI-TL and each trait. We obtained MR estimates using the two-sample inverse variance weighted (IVW) approach. We identified six age-related traits associated with GI-TL (Bonferroni-corrected threshold p &lt; .001): pulse pressure (PP) (p = 5.2 × 10-14), systolic blood pressure (SBP) (p = 2.9 × 10-15), diastolic blood pressure (DBP) (p = 5.5 × 10-6), hypertension (p = 5.5 × 10-11), forced expiratory volume (FEV1) (p = .0001), and forced vital capacity (FVC) (p = 3.8 × 10-6). Under MR assumptions, one standard deviation increase in TL (~1,200 base pairs) increased PP, SBP, and DBP by 1.5, 2.3, and 0.8 mmHg, respectively, while FEV1 and FVC increased by 34.7 and 52.2 mL, respectively. The observed associations appear unlikely to be due to selection bias based on analyses including inverse probability weights and analyses of simulated data. These findings suggest that longer TL increases pulmonary function and blood pressure traits among middle-aged UKB participants.

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