Variation In Telomere Length Research Articles

Effect of polygenic scores of telomere length alleles on telomere length in newborns and parents.

In adults, polygenic scores (PGSs) of telomere length (TL) alleles explain about 4.5% of the variance in TL, as measured by quantitative polymerase chain reaction (qPCR). Yet, these PGSs strongly infer a causal role of telomeres in aging-related diseases. To better understand the determinants of TL through the lifespan, it is essential to examine to what extent these PGSs explain TL in newborns. This study investigates the effect of PGSs on TL in both newborns and their parents, with TL measured by Southern blotting and expressed in base-pairs (bp). Additionally, the study explores the impact of PGSs related to transmitted or non-transmitted alleles on TL in newborns. For parents and newborns, the PGS effects on TL were 172 bp (p = 2.03 × 10-15) and 161 bp (p = 3.06 × 10-8), explaining 6.6% and 5.2% of the TL variance, respectively. The strongest PGS effect was shown for maternally transmitted alleles in newborn girls, amounting to 214 bp (p = 3.77 × 10-6) and explaining 7.8% of the TL variance. The PGS effect of non-transmitted alleles was 56 bp (p = 0.0593) and explained 0.6% of the TL variance. Our findings highlight the importance of TL genetics in understanding early-life determinants of TL. They point to the potential utility of PGSs composed of TL alleles in identifying susceptibility to aging-related diseases from birth and reveal the presence of sexual dimorphism in the effect of TL alleles on TL in newborns. Finally, we attribute the higher TL variance explained by PGSs in our study to TL measurement by Southern blotting.

Genetic and telomeric variability: Insights from a tropical avian hybrid zone.

Telomere lengths and telomere dynamics can correlate with lifespan, behaviour and individual quality. Such relationships have spurred interest in understanding variation in telomere lengths and their dynamics within and between populations. Many studies have identified how environmental processes can influence telomere dynamics, but the role of genetic variation is much less well characterized. To provide a novel perspective on how telomeric variation relates to genetic variability, we longitudinally sampled individuals across a narrow hybrid zone (n = 127 samples), wherein two Manacus species characterized by contrasting genome-wide heterozygosity interbreed. We measured individual (n = 66) and population (n = 3) differences in genome-wide heterozygosity and, among hybrids, amount of genetic admixture using RADseq-generated SNPs. We tested for population differences in telomere lengths and telomere dynamics. We then examined how telomere lengths and telomere dynamics covaried with genome-wide heterozygosity within populations. Hybrid individuals exhibited longer telomeres, on average, than individuals sampled in the adjacent parental populations. No population differences in telomere dynamics were observed. Within the parental population characterized by relatively low heterozygosity, higher genome-wide heterozygosity was associated with shorter telomeres and higher rates of telomere shortening-a pattern that was less apparent in the other populations. All of these relationships were independent of sex, despite the contrasting life histories of male and female manakins. Our study highlights how population comparisons can reveal interrelationships between genetic variation and telomeres, and how naturally occurring hybridization and genome-wide heterozygosity can relate to telomere lengths and telomere dynamics.

Understanding seasonal telomere length dynamics in hibernating species

Oxidative stress is thought to be one of the main causes of ageing as it progressively damages cell components throughout life, eventually causing cellular failure and apoptosis. In many organisms, telomeres shorten throughout life under the effect of, amongst other factors, oxidative stress, and are therefore commonly used as marker of biological ageing. However, hibernators, which are regularly exposed to acute oxidative stress when rewarming from torpor, are unexpectedly long-lived. In this review, we explore the causes of oxidative stress associated with hibernation and its impact on telomere dynamics in different taxa, focussing on hibernating rodents. We then speculate on the adaptive mechanisms of hibernators to compensate for the effects of oxidative stress, which may explain their increased longevity. Because winter hibernation appears to be associated with high oxidative stress, hibernators, particularly rodents, may periodically invest in repair mechanisms and antioxidant defences, resulting in seasonal variations in telomere lengths. This research shows how species with a slow life-history strategy deal with large changes in oxidative stress, unifying evolutionary and physiological theories of ageing. Because of the marked seasonal variation in telomere length, we also draw attention when using telomeres as markers for biological aging in seasonal heterotherms and possibly in other highly seasonal species.

Whole exome sequencing analyses reveal novel genes in telomere length and their biomedical implications.

Telomere length is a putative biomarker of aging and is associated with multiple age-related diseases. There are limited data on the landscape of rare genetic variations in telomere length. Here, we systematically characterize the rare variant associations with leukocyte telomere length (LTL) through exome-wide association study (ExWAS) among 390,231 individuals in the UK Biobank. We identified 18 robust rare-variant genes for LTL, most of which estimated effects on LTL were significant (> 0.2 standard deviation per allele). The biological functions of the rare-variant genes were associated with telomere maintenance and capping and several genes were specifically expressed in the testis. Three novel genes (ASXL1, CFAP58, and TET2) associated with LTL were identified. Phenotypic association analyses indicated significant associations of ASXL1 and TET2 with cancers, age-related diseases, blood assays, and cardiovascular traits. Survival analyses suggested that carriers of ASXL1 or TET2 variants were at increased risk for cancers; diseases of the circulatory, respiratory, and genitourinary systems; and all-cause and cause-specific deaths. The CFAP58 carriers were at elevated risk of deaths due to cancers. Collectively, the present whole exome sequencing study provides novel insights into the genetic landscape of LTL, identifying novel genes associated with LTL and their implications on human health and facilitating a better understanding of aging, thus pinpointing the genetic relevance of LTL with clonal hematopoiesis, biomedical traits, and health-related outcomes.

Longer prostate stromal cell telomere length is associated with increased risk of death from other cancers.

Telomeres are located at chromosomal termini and function to maintain genomic integrity. Telomere dysfunction is a well-recognized contributor to aging and age-related diseases, such as prostate cancer. Since telomere length is highly heritable, we postulate that stromal cell telomere length in the tissue of a particular solid organ may generally reflect constitutive stromal cell telomere length in other solid organs throughout the body. Even with telomere loss occurring with each round of cell replication, in general, telomere length in prostate stromal cells in mid-life would still be correlated with the telomere length in stromal cells in other organs. Thus, we hypothesize that prostate stromal cell telomere length and/or telomere length variability is a potential indicator of the likelihood of developing future solid cancers, beyond prostate cancer, and especially lethal cancer. To explore this hypothesis, we conducted a cohort study analysis of 1,175 men who were surgically treated for prostate cancer and were followed for death, including from causes other than their prostate cancer. In this cohort study with a median follow-up of 19 years, we observed that longer prostate stromal cell telomere length measured in tissue microarray spots containing prostate cancer was associated with an increased risk of death from other solid cancers. Variability in telomere length among these prostate stromal cells was possibly positively associated with risk of death from other solid cancers. Studying the link between stromal cell telomere length and cancer mortality may be important for guiding the development of cancer interception and prevention strategies.

Breaking down causes, consequences, and mediating effects of telomere length variation on human health

BackgroundTelomeres form repeated DNA sequences at the ends of chromosomes, which shorten with each cell division. Yet, factors modulating telomere attrition and the health consequences thereof are not fully understood. To address this, we leveraged data from 326,363 unrelated UK Biobank participants of European ancestry.ResultsUsing linear regression and bidirectional univariable and multivariable Mendelian randomization (MR), we elucidate the relationships between leukocyte telomere length (LTL) and 142 complex traits, including diseases, biomarkers, and lifestyle factors. We confirm that telomeres shorten with age and show a stronger decline in males than in females, with these factors contributing to the majority of the 5.4% of LTL variance explained by the phenome. MR reveals 23 traits modulating LTL. Smoking cessation and high educational attainment associate with longer LTL, while weekly alcohol intake, body mass index, urate levels, and female reproductive events, such as childbirth, associate with shorter LTL. We also identify 24 traits affected by LTL, with risk for cardiovascular, pulmonary, and some autoimmune diseases being increased by short LTL, while longer LTL increased risk for other autoimmune conditions and cancers. Through multivariable MR, we show that LTL may partially mediate the impact of educational attainment, body mass index, and female age at childbirth on proxied lifespan.ConclusionsOur study sheds light on the modulators, consequences, and the mediatory role of telomeres, portraying an intricate relationship between LTL, diseases, lifestyle, and socio-economic factors.

Effects of Age and Biological Age-Determining Factors on Telomere Length in Type 2 Diabetes Mellitus Patients.

Background and Objectives: Telomere length (TL) undergoes attrition over time, indicating the process of aging, and is linked to a higher risk of diabetes mellitus type 2 (DM-2). This molecular epidemiological study investigated the correlation between leukocyte TL variations and determinants of molecular aging in 121 Pakistani DM-2 patients. Materials and Methods: The ratio of telomere repeats to the SCG copy number was calculated to estimate the TL in each sample through qPCR assays. Results: In this study, smaller mean TLs were observed in 48.8% of males (6.35 ± 0.82 kb), 3.3% of underweight patients (5.77 ± 1.14 kb), 61.2% of patients on regular medication (6.50 ± 0.79 kb), 9.1% with very high stress levels (5.94 ± 0.99 kb), 31.4% of smokers (5.83 ± 0.73 kb), 40.5% of patients with low physical activity (6.47 ± 0.69 kb), 47.9% of hypertensive patients (5.93 ± 0.64 kb), 10.7% of patients with DM-2 for more than 15 years, and 3.3% of patients with a delayed onset of DM-2 (6.00 ± 0.93 kb). Conclusion: This research indicated a significant negative correlation (R2 = 0.143) between TL and the age of DM-2 patients. This study demonstrated that the correlation of telomere length with age in DM-2 patients was also influenced by various age-determining factors, including hypertension and smoking habits, with significant strong (R2 = 0.526) and moderate (R2 = 0.299) correlations, respectively; sex, obesity, the stress level and age at the onset of diabetes with significant weak correlations (R2 = 0.043, 0.041, 0.037, and 0.065, respectively), and no significant correlations of medication routine, rate of physical activity, and the durations of DM-2 with age-adjusted telomere length. These results challenge TL as the sole marker of aging, thus highlighting the need for further research to understand underlying factors and mitigate the effect of aging or premature aging on diabetic patients.

Abstract 3461: Shorter leukocyte telomere length and higher risk of primary liver cancer in a prospective cohort study

Abstract Background: Telomeres are conserved tandem repeats at chromosome ends that are vital to maintaining chromosomal stability and preventing degradation. Shorter telomere lengths (TL) are typically associated with older biological age or poor health status and can activate programmed cell death, whereas longer telomere lengths can be indicative of younger age or abnormal replication processes with oncogenic mutations. Previous research has identified a link between telomere length and carcinogenesis, but relatively few studies have investigated TL and primary liver cancer (PLC) risk despite it being one of the leading causes of cancer worldwide. The goal of this analysis was to study this association in a large prospective cohort. Methods: Data was extracted from the Singapore Chinese Cohort Health Study, a cohort of 63,257 men and women aged 45-74 years at enrollment during 1993-1998. Telomere length was measured in peripheral leukocytes of 26,540 participants who provided baseline blood samples, using a validated quantitative polymerase chain reaction (qPCR) method. PLC incidence and death among cohort participants was annually surveilled using the nationwide Singapore Cancer Registry and the National Birth and Death Registry from study enrollment to 2015. For statistical analysis, a t test was performed to examine the differences in TL between participants who developed incident PLC and those who remained free of PLC. Cox proportional hazard method was used to estimate the hazard ratios (HRs) and their 95% confidence interval (CI) of PLC incidence according to TL quartiles. Results: Over a 12-year follow-up, 199 participants developed incident PLC. The relative TL was significantly lower in participants with incident PLC than those without (-6.7%, p < 0.001). Multivariate Cox regression model showed an inverse association between TL quartile and risk of PLC (p for trend = 0.009). Compared with the lowest quartile, HRs (95% CIs) of PLC for the 2nd, 3rd, and highest quartile of TL were 0.78 (0.54-1.12), 0.75 (0.51-1.11), and 0.57 (0.37-0.88), respectively, after adjustment for age, sex, alcohol use, body mass index, and smoking status. Conclusion: The present analysis demonstrated a statistically significant association between shorter telomere length and increased risk of PLC in a large prospective cohort of Singaporean Chinese. This inverse association for PLC is different from those for other cancer types in the same cohort. These results warrant further studies such as using Mendelian randomization to quantify genetic variation in TL with PLC development. Citation Format: Sindhu Karnam, Kathryn Demanelis, Kenneth B. Beckman, Renwei Wang, Jennifer Adams-Haduch, Woon-Puay Koh, Jian-Min Yuan. Shorter leukocyte telomere length and higher risk of primary liver cancer in a prospective cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3461.

Telomere length and micronuclei trajectories in APP/PS1 mouse model of Alzheimer's disease: Correlating with cognitive impairment and brain amyloidosis in a sexually dimorphic manner.

Although studies have demonstrated that genome instability is accumulated in patients with Alzheimer's disease (AD), the specific types of genome instability linked to AD pathogenesis remain poorly understood. Here, we report the first characterization of the age- and sex-related trajectories of telomere length (TL) and micronuclei in APP/PS1 mice model and wild-type (WT) controls (C57BL/6). TL was measured in brain (prefrontal cortex, cerebellum, pituitary gland, and hippocampus), colon and skin, and MN was measured in bone marrow in 6- to 14-month-old mice. Variation in TL was attributable to tissue type, age, genotype and, to a lesser extent, sex. Compared to WT, APP/PS1 had a significantly shorter baseline TL across all examined tissues. TL was inversely associated with age in both genotypes and TL shortening was accelerated in brain of APP/PS1. Age-related increase of micronuclei was observed in both genotypes but was accelerated in APP/PS1. We integrated TL and micronuclei data with data on cognition performance and brain amyloidosis. TL and micronuclei were linearly correlated with cognition performance or Aβ40 and Aβ42 levels in both genotypes but to a greater extent in APP/PS1. These associations in APP/PS1 mice were dominantly driven by females. Together, our findings provide foundational knowledge to infer the TL and micronuclei trajectories in APP/PS1 mice during disease progression, and strongly support that TL attrition and micronucleation are tightly associated with AD pathogenesis in a female-biased manner.

Shorter telomeres are associated with shell anomalies in a long‐lived tortoise

AbstractAge‐related telomere length (TL) variation is relatively well‐described for mammals, birds and other model organisms. Nevertheless, it remains largely unknown in ectotherms, especially turtles and tortoises, which are extremely long‐lived species with slow or negligible senescence. In this study, we described TL dynamics in wild spur‐thighed tortoises (Testudo graeca), one of the chelonian species with the lowest aging rates. By combining cross‐sectional (single) and longitudinal (capture–recapture) samplings, we assessed the relationship between TL and individual characteristics (sex, age, individual growth rate, body condition index, presence of shell anomalies). We did not find any association between TL and sex, individual growth rate, or body condition. However, the relationship with age remains uncertain, likely due to the complex dynamics of TL over time. Interestingly, shorter telomeres correlated significantly with shell anomalies, which are usually assumed as a fitness proxy for reptiles. Overall, our results suggest TL as a potential indicator for ontogenetic studies on tortoises, while its utility as a marker of biological age appears limited.

Cross-tissue comparison of telomere length and quality metrics of DNA among individuals aged 8 to 70 years.

Telomere length (TL) is an important biomarker of cellular aging, yet its links with health outcomes may be complicated by use of different tissues. We evaluated within- and between-individual variability in TL and quality metrics of DNA across five tissues using a cross-sectional dataset ranging from 8 to 70 years (N = 197). DNA was extracted from all tissue cells using the Gentra Puregene DNA Extraction Kit. Absolute TL (aTL) in kilobase pairs was measured in buccal epithelial cells, saliva, dried blood spots (DBS), buffy coat, and peripheral blood mononuclear cells (PBMCs) using qPCR. aTL significantly shortened with age for all tissues except saliva and buffy coat, although buffy coat was available for a restricted age range (8 to 15 years). aTL did not significantly differ across blood-based tissues (DBS, buffy coat, PBMC), which had significantly longer aTL than buccal cells and saliva. Additionally, aTL was significantly correlated for the majority of tissue pairs, with partial Spearman's correlations controlling for age and sex ranging from ⍴ = 0.18 to 0.51. We also measured quality metrics of DNA including integrity, purity, and quantity of extracted DNA from all tissues and explored whether controlling for DNA metrics improved predictions of aTL. We found significant tissue variation: DNA from blood-based tissues had high DNA integrity, more acceptable A260/280 and A260/230 values, and greater extracted DNA concentrations compared to buccal cells and saliva. Longer aTL was associated with lower DNA integrity, higher extracted DNA concentrations, and higher A260/230, particularly for saliva. Model comparisons suggested that incorporation of quality DNA metrics improves models of TL, although relevant metrics vary by tissue. These findings highlight the merits of using blood-based tissues and suggest that incorporation of quality DNA metrics as control variables in population-based studies can improve TL predictions, especially for more variable tissues like buccal and saliva.

Exposure to Ambient Particulate Matter during Pregnancy: Implications for Infant Telomere Length

Background: Growing evidence suggests that air pollution may influence fetal development, with potential consequences for later health. Alteration of telomere length (TL) is one possible mediating mechanism for the link between fetal exposure to air pollution and the development of disease. However, the few studies exploring associations between prenatal pollution and infant TL have assessed varied trimesters of pregnancy and shown mixed results. The aim of this study was to examine the differential relationships between prenatal exposure to air pollutant PM2.5 during the first, second, and third trimesters of pregnancy with infant TL at one month of age. Methods: Women (n = 74) were recruited in obstetric clinics during their third trimester. Data on PM2.5 exposure for each woman’s residential area during each trimester was acquired from the regional Air Quality Management District. At one month postnatal, a salivary sample was collected from the infant, which provided DNA for the telomere assay. Women completed questionnaires about stressors in their lives, perceived stress, depression, and sociodemographics for inclusion as covariates. Multiple linear regression was used to analyze the results. Results: PM2.5 exposure during the second (β = 0.31, p = 0.003) and third (β = 0.24, p = 0.02) trimesters was associated with longer infant TL. Exposure in the first trimester was not related to TL. Covariates of maternal depression and age and infant female sex were also associated with longer TL. Variables in the model contributed to 34% of the variance in TL (F = 10.58, p = 0.000). Discussion: Fetal programming of longer telomeres in response to pollution may have adaptive value in preparing the neonate for a postnatal environment that is less than optimal in terms of air quality. Alternatively, longer telomeres may forecast later health risks, considering established links between longer TL and diseases such as cancer. Future research needs to address how prenatal pollution interacts with TL to influence health over time.

On the distribution and diversity of tissue-specific somatic mutations in honey bee (Apis mellifera) drones

Somatic mutations originate from both exogenous (e.g. UV radiation, chemical agents) and endogenous (e.g., DNA replication, defective DNA repair) sources and can have significant impacts on an animal’s reproductive success. This may be especially true for haploid organisms that are susceptible to any deleterious alleles inherited from their parent and any that arise over their lifetime. Unfortunately, little is known about the rate of somatic mutation accumulation across individuals and tissues of haplodiploid animal populations, the functional processes through which they arise, and their distribution across tissues and the genome. Here, we generated short-read whole-genome sequencing data for four tissues of haploid honey bee males. We paired this with estimates of telomere length and tissue-specific DNA content to address three major questions: is there variance in somatic mutational load across haploid individuals and specific tissues therein, does increased DNA content in a tissue contribute to somatic mutational load, and does telomere length correlate with mutational load? Our results suggest that variance in somatic mutational load is better captured across individuals than across tissues, that tissue-specific DNA content is not associated with somatic mutation load, and that variance in telomere length does not correlate with somatic mutation loads across tissues. To our knowledge, this is the first observational study on somatic mutational load in Apoidea and likely Hymenoptera. It serves as a useful advent for additional studies understanding the processes through which haploids tolerate or repair somatic mutations.

Telomere Length Variation in Model Bryophytes.

The ends of linear chromosomes of most eukaryotes consist of protein-bound DNA arrays called telomeres, which play essential roles in protecting genome integrity. Despite general evolutionary conservation in function, telomeric DNA is known to drastically vary in length and sequence between different eukaryotic lineages. Bryophytes are a group of early diverging land plants that include mosses, liverworts, and hornworts. This group of ancient land plants recently emerged as a new model for important discoveries in genomics and evolutionary biology, as well as for understanding plant adaptations to a terrestrial lifestyle. We measured telomere length in different ecotypes of model bryophyte species, including Physcomitrium patens, Marchantia polymorpha, Ceratodon purpureus, and in Sphagnum isolates. Our data indicate that all analyzed moss and liverwort genotypes have relatively short telomeres. Furthermore, all analyzed ecotypes and isolates of model mosses and liverworts display evidence of substantial natural variation in telomere length. Interestingly, telomere length also differs between male and female strains of the dioecious liverwort M. polymorpha and dioecious moss C. purpureus. Given that bryophytes are extraordinarily well adapted to different ecological niches from polar to tropical environments, our data will contribute to understanding the impact of natural telomere length variation on evolutionary adaptations in this ancient land plant lineage.

Potential roles of telomeres and telomerase in neurodegenerative diseases

Telomeres, essential DNA-protein complexes located at chromosome ends, play a critical role in preventing chromosome fusion, recombination, and degradation, thus ensuring genomic stability. When telomeres reach a limiting shortened length, they will activate DNA damage checkpoints, stop cell division and trigger replicative senescence. Telomerase is composed of RNA and protein, which can synthesize telomeres repeat sequences, and elongate telomeres. Studies have shown that telomere length (TL) and telomerase activity are closely involved in aging, aging-related degenerative diseases, and tumors. Neurodegenerative diseases (NDDs) are one of the major aging-related diseases caused by both genetic and environmental factors, characterized by insidious onset, difficult diagnosis, irreversible disease progression, and lack of effective treatments, which brings a heavy burden to society and families. Currently, many studies have noted variations in leukocyte telomere length (LTL) and telomerase activity in NDDs, suggesting a vital role for telomeres and telomerase in NDD pathogenesis. This review explores the relationship between TL and NDDs, examines telomerase as a potential therapeutic target, and discusses emerging biomarkers and intervention strategies for NDD diagnosis and treatment.

Polygenic Modifiers of Expressivity in Telomere Biology Disorders

Telomere biology disorders (TBDs) are caused by pathogenic germline variants in genes involved in telomere maintenance resulting in very short telomeres for age and high risks of bone marrow failure, certain cancers, as well as pulmonary and liver disease. Interestingly, some pathogenic TBD mutations have variable expressivity and incomplete penetrance, even within families. Variant carriers can present with early manifestations such as the mucocutaneous triad and bone marrow failure or may not manifest until later in life with adult-onset idiopathic pulmonary fibrosis or liver disease, or have no associated clinical phenotype. The underlying causes of this heterogeneity are poorly understood. We hypothesized that common genetic variants contributing to inter-individual variation in telomere length in the general population may combine with the effects of monogenic TBD-causing variants to underlie variable clinical manifestations in TBDs. To examine this, we developed polygenic scores (PGS) to predict telomere length using genome-wide SNPs from the UK Biobank. We then applied the most predictive polygenic score to the out-of-sample All of Us cohort, as well as the National Cancer Institute's longitudinal cohort of individuals with inherited bone marrow failure syndromes, including those with TBDs (ClinicalTrials.gov Identifier: NCT00027274). If monogenic mutations and polygenic predisposition to short telomeres both contribute to the clinical severity of TBDs and likelihood of early-onset manifestations, the distribution of genetically predicted telomere length in this ascertained cohort would be shifted towards shorter telomeres compared with the population average. Consistent with this, individuals with TBDs enriched for early-onset bone marrow failure phenotypes (n = 92) have a median polygenic score 0.32 standard deviations (SDs) shorter than the UK Biobank (p=0.002), and 0.31 SDs shorter than the external All of Us cohort (p=0.003) ( Figure). Individuals with TBDs also have shorter genetically predicted telomeres compared to individuals with Fanconi anemia (n = 45) and Diamond Blackfan anemia (n = 49) (p=0.008), indicating that this phenomenon is specific to TBDs. We binned the PGS into quintiles and show that the lowest quintile is associated with an odds ratio of TBD of 1.89 [1.19,2.86], while being in the highest quintile is associated with an odds ratio of 0.54 [0.29,1.02]. Interestingly, TBD cases with no identified mutation have a median PGS 0.1 SDs towards shorter telomeres than patients with a known mutation. Collectively, these results indicate that common, genome-wide determinants of telomere length are significant modifiers of the early-onset manifestations of TBDs. We hypothesized that the converse should also be true: TBD causal variants should be present in adult population cohorts, and adult individuals with a pathogenic variant who avoided the severe childhood-onset manifestations of TBDs, should not have polygenically predicted short telomere length. To test this hypothesis, we filtered the UK Biobank for TBD causal variants annotated in ClinVar, and identified 71 putative pathogenic cases. Importantly, among these cases there were no individuals with bone marrow failure, but these individuals did have shorter telomeres compared with the UK Biobank. Interestingly, these 71 putative cases had a population-normal telomere length PGS, and significantly longer PGS predicted telomere length than the NCI cohort (p=0.025). We also find that being classified as among these pathogenic cases is associated with an odds ratio for developing pulmonary fibrosis of 10.79 [4.34,26.8]. In summary, despite normal PGS and absence of bone marrow failure, these putative cases have short telomeres and increased risk of adult manifestations of TBDs, consistent with the idea that the pathogenic mutations and common genetic variation affecting telomere length combine to impact expressivity. Collectively, these findings indicate that polygenic effects on telomere length can modify the impacts of monogenic mutations in TBD-associated genes. These results have implications not only for clinical risk assessment in patients with TBDs, but also for our general understanding and interpretation of variable penetrance/expressivity in presumed monogenic disorders.

Sperm production is negatively associated with muscle and sperm telomere length in a species subjected to strong sperm competition.

Life-history theory suggests that ageing is one of the costs of reproduction. Accordingly, a higher reproductive allocation is expected to increase the deterioration of both the somatic and the germinal lines through enhanced telomere attrition. In most species, males' reproductive allocation mainly regards traits that increase mating and fertilization success, that is sexually selected traits. In this study, we tested the hypothesis that a higher investment in sexually selected traits is associated with a reduced relative telomere length (RTL) in the guppy (Poecilia reticulata), an ectotherm species characterized by strong pre- and postcopulatory sexual selection. We first measured telomere length in both the soma and the sperm over guppies' lifespan to see whether there was any variation in telomere length associated with age. Second, we investigated whether a greater investment in pre- and postcopulatory sexually selected traits is linked to shorter telomere length in both the somatic and the sperm germinal lines, and in young and old males. We found that telomeres lengthened with age in the somatic tissue, but there was no age-dependent variation in telomere length in the sperm cells. Telomere length in guppies was significantly and negatively correlated with sperm production in both tissues and life stages considered in this study. Our findings indicate that telomere length in male guppies is strongly associated with their reproductive investment (sperm production), suggesting that a trade-off between reproduction and maintenance is occurring at each stage of males' life in this species.

Associations between telomere attrition, genetic variants in telomere maintenance genes, and non-small cell lung cancer risk in the Jammu and Kashmir population of North India

BackgroundTelomeres are repetitive DNA sequences located at the ends of chromosomes, playing a vital role in maintaining chromosomal integrity and stability. Dysregulation of telomeres has been implicated in the development of various cancers, including non-small cell lung cancer (NSCLC), which is the most common type of lung cancer. Genetic variations within telomere maintenance genes may influence the risk of developing NSCLC. The present study aimed to evaluate the genetic associations of select variants within telomere maintenance genes in a population from Jammu and Kashmir, North India, and to investigate the relationship between telomere length and NSCLC risk.MethodsWe employed the cost-effective and high-throughput MassARRAY MALDI-TOF platform to assess the genetic associations of select variants within telomere maintenance genes in a population from Jammu and Kashmir, North India. Additionally, we used TaqMan genotyping to validate our results. Furthermore, we investigated telomere length variation and its relation to NSCLC risk in the same population using dual-labeled fluorescence-based qPCR.ResultsOur findings revealed significant associations of TERT rs10069690 and POT1 rs10228682 with NSCLC risk (adjusted p-values = 0.019 and 0.002, respectively), while TERF2 rs251796 and rs2975843 showed no significant associations. The TaqMan genotyping validation further substantiated the associations of TERT rs10069690 and rs2242652 with NSCLC risk (adjusted p-values = 0.02 and 0.003, respectively). Our results also demonstrated significantly shorter telomere lengths in NSCLC patients compared to controls (p = 0.0004).ConclusionThis study highlights the crucial interplay between genetic variation in telomere maintenance genes, telomere attrition, and NSCLC risk in the Jammu and Kashmir population of North India. Our findings suggest that TERT and POT1 gene variants, along with telomere length, may serve as potential biomarkers and therapeutic targets for NSCLC in this population. Further research is warranted to elucidate the underlying mechanisms and to explore the potential clinical applications of these findings.

0466 Effect of Obstructive Sleep Apnea and CPAP on Telomere Length and its Associated Mechanisms

Abstract Introduction Growing evidence suggests the contribution of obstructive sleep apnea (OSA) in the molecular pathways of aging related to the maintenance of telomere length. The present study aimed to investigate the effect of OSA and its treatment with continuous positive airway pressure (CPAP) on the variation of telomere length and its associated mechanisms. Methods For this, a 6-month randomized, double-blind and sham-controlled clinical trial was conducted. Participants were randomized to CPAP or sham-CPAP and attended 7 visits, in which they underwent clinical assessment and had their blood collected to determine mean leukocyte telomere length (LTL) and the dosage of metabolic and inflammatory markers. Results Among 127 individuals that we contacted, 46 met the inclusion criteria. At baseline, individuals in both groups were homogeneous, including LTL (p=0.106). Adherence during the intervention was 5.29 ± 1.09 in the sham-CPAP group and 5.71 ± 0.19 in the CPAP group. After 6 months of intervention, we observed a statistically significant effect of the treatment (p=0.001) on LTL, in which the sham-CPAP group (1.0117 ± 0.1552, 0.9457 ± 0.0747, 0.8482 ± 0.2163) showed a more significant reduction than the CPAP group (1.0960 ± 0.1122, 1.0521 ± 0.1094, 1.0675 ± 0.1225). Furthermore, we found a negative correlation between delta LTL and dela TNF-α at Visit 7 and Visit 1 (rho=-0.216, p=0.003) due to the sham-CPAP intervention (rho=-0.383, p=0.009) in relation to the use of CPAP (rho=0.021, p=0.800). Conclusion We can conclude that CPAP, when compared to sham-CPAP placebo, caused an effect on LTL stability, potentially by the modulation of TNF-α. Support (if any) Our studies are supported by Associação Fundo de Incentivo à Pesquisa (AFIP), Fundação de Amparo à Pesquisa de São Paulo (FAPESP), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Conselho Nacional de Desenvolvimento Científico Tecnológico (V.A. and S.T. received CNPq fellowships).

Association between leukocyte telomere length and COVID-19 severity

BackgroundInter-individual variations in the clinical manifestations of SARS-CoV-2 infection are among the challenging features of COVID-19. The known role of telomeres in cell proliferation and immune competency highlights their possible function in infectious diseases. Variability in telomere length is an invaluable parameter in the heterogeneity of the clinical presentation of diseases.ResultIn this study, our aim was to investigate the possible association between leukocyte telomere length (LTL) and COVID-19 severity. LTL was measured in 100 patients with moderate and severe forms of COVID-19 using the quantitative PCR (q-PCR) method. Statistical analysis confirmed a strong inverse correlation between relative LTL and COVID-19 severity.ConclusionsThese findings suggest that LTL can be a useful parameter for predicting disease severity in patients, as individuals with short telomeres may have a higher risk of developing severe COVID-19.