Polygenic basis and biomedical consequences of telomere length variation

Wang, Qingning; Allara, Elias; Musicha, Crispin; Kaptoge, Stephen; Stoma, Svetlana; Jiang, Tao; Hamby, Stephen E.; Braund, Peter S.; Bountziouka, Vasiliki; Budgeon, Charley; Denniff, Matthew; Swinfield, Chloe; Papakonstantinou, Manolo; Sheth, Shilpi; Nanus, Dominika E; Warner, Sophie C; Wang, Minxian; Khera, Amit V.; Eales, James; Ouwehand, Willem H.; Thompson, John R.; Angelantonio, Emanuele Di; Wood, Angela; Butterworth, Adam S.; Danesh, John; Nelson, Christopher P.; Samani, Nilesh J.

doi:10.1101/2021.03.23.21253516

Cited by 36 publications

(79 citation statements)

References 66 publications

(72 reference statements)

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“…This probably reflects a combination of the low overall prevalence of frailty in the studied population and the relatively low strength of the genetic instruments, which explain less than 5% of the variation in LTL. 12 Therefore, we cannot exclude the possibility that the observed association between shorter LTL and increased risk of frailty is due to residual confounding which we have not accounted for.…”

Section: Discussionmentioning

confidence: 94%

“…We have previously characterised the association of LTL with 123 diseases, identified using hospital admissions, operations, death registry and self-report data as described elsewhere. 12 To assess the extent to which any association of LTL with frailty is independent of any association of LTL with these diseases at baseline, we conducted regression modelling using standardised residuals after regressing LTL on indicators of history of the 123 diseases.…”

Section: Discussionmentioning

confidence: 99%

“…10 Shorter mean leucocyte telomere length (LTL) has been associated with risk of several age-associated diseases with causal inference analyses suggesting that some of the associations are primary. 11,12 However, it should be noted that the relationship between LTL and disease is complex and longer LTL can also be associated with disease risk, most notably for several cancers. [11][12][13] Current evidence on whether inter-individual variation in LTL is associated with higher risk of frailty is inconclusive.…”

Section: Introductionmentioning

confidence: 99%

“…11,12 However, it should be noted that the relationship between LTL and disease is complex and longer LTL can also be associated with disease risk, most notably for several cancers. [11][12][13] Current evidence on whether inter-individual variation in LTL is associated with higher risk of frailty is inconclusive. [14][15][16] We have recently generated cohort-wide LTL measurements in UK Biobank (UKB).…”

Section: Introductionmentioning

confidence: 99%

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Association of leucocyte telomere length with frailty: a large–scale cross–sectional analysis in UK Biobank

Bountziouka

Wang

et al. 2021

Preprint

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BackgroundLeucocyte telomere length (LTL), a potential marker of biological age, has been associated with risk of many diseases. We investigated whether LTL is associated with risk of frailty, a multidimensional syndrome of decline that affects multiple systems and predisposes to adverse health outcomes.MethodsIn a cross–sectional analysis, we studied 441,781 UK Biobank participants (aged 40–70 years), with complete data on LTL and frailty indicators. We defined frailty as the presence of at least three of five indicators: weaker grip strength, slower walking pace, weight loss in the past year, lower physical activity, and exhaustion in the past two weeks. We evaluated association of LTL with frailty using adjusted (chronological age, sex, deprivation, smoking, alcohol intake, body mass index, multimorbidity) multinomial and ordinal regression models. We used Mendelian randomisation (MR), using 131 genetic variants associated with LTL, to assess if the association of LTL with frailty was causal.FindingsFrail participants (4·6%) were older (median age difference (95% CI): 3 (2·5; 3·5) years), more likely to be female (61%), and had shorter LTL (−0·13SD vs 0·03SD) than non–frail. In adjusted analyses, both age and LTL were associated with frailty (OR=1·03 (95%CI: 1·02–1·04) per year of older chronological age; 1·10 (1·08; 1·11) per SD shorter LTL). Within each age group (40–49, 50–59, 60–69 years) the prevalence of frailty was about 33% higher in participants with shorter (−2SD) versus longer telomeres (+2SD). MR analysis showed an association of LTL with frailty that was directionally consistent with the observational association, but not statistically significant.InterpretationInter–individual variation in LTL is associated with the risk of frailty independently of chronological age and other risk factors. Our findings provide evidence for an additional biological determinant of frailty.FundingThe UK Medical Research Council, the Biotechnology and Biological Sciences Research Council and the British Heart Foundation (MRC grant: MR/M012816/1) funded our measurements of LTL in UK Biobank. The funders had no role in study design; the collection, analysis, and interpretation of data; the writing of the report; and the decision to submit the paper for publication.Research in contextEvidence before this studyTelomere length has been proposed as a biomarker of biological age. Shorter leucocyte telomere length (LTL) is associated with higher incidence of several age–associated diseases, spanning multiple body systems, and with lower life expectancy. However, the association of shorter LTL with frailty, a multidimensional syndrome of decline across multiple systems, is inconclusive. We searched PubMed using the terms “telomere length AND frailty” in the title, abstract, or text with no language restrictions. This search identified 50 papers published before 30 November, 2020. Of these, three systematic reviews and/ or meta–analyses of modest size (five to nine studies, with total n<10,000) and 11 original research articles reported on associations between telomere length and frailty. These small–scale studies, primarily in older individuals, do not support an independent association between shorter LTL and higher risk of frailty.Added value of this studyOur large–scale population–based study, involving over 441,000 participants, provides strong evidence that shorter LTL is associated with higher risk of both pre–frailty and frailty even after adjustment for chronological age and other established determinants of frailty, namely, age, sex, alcohol intake, smoking, obesity, deprivation and multimorbidity. Within each age group (40–49, 50–59, 60–69 years) the prevalence of frailty was about 33% higher in participants with shorter (−2SD) versus longer telomeres (+2SD). Part of the association of shorter LTL with higher risk of frailty may be due to the association in aggregate of LTL with diseases. Findings using genetic variants associated with LTL as instruments were directionally consistent with the observational association, but not statistically significant.Implications of all the available evidenceShorter LTL is associated with frailty independent of chronological age and several other risk factors. The observation that risk of frailty associated with shorter LTL is proportionately similar across the age range of 40–70 years suggests that shorter LTL acts through a mechanism beyond just accelerating the impact of chronological ageing on risk of frailty.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Association of leucocyte telomere length with frailty: a large–scale cross–sectional analysis in UK Biobank

Bountziouka

Wang

et al. 2021

Preprint

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“…Transforming cells with relatively long telomeres, limited telomerase, and deleted checkpoints survive critical barriers until the telomerase upregulation. That is explained as an antecedent for the association between increased constitutive telomere length and cancer risk; the evolution of tumors is predicated on the serial accumulation of driver mutations through rapid cell divisions, and the variation in telomere length can affect the proliferative potential of premalignant cells 48,64,162,[175][176][177][178][179] .…”

Section: Tert Promoter Mutations and Telomere Lengthmentioning

confidence: 99%

Occurrence, functionality, and abundance of theTERTpromoter mutations

Rachakonda

Hoheisel

Kumar

2021

Preprint

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Telomere shortening at chromosomal ends due to the constraints of the DNA replication process acts as a tumor suppressor by restricting the replicative potential in primary cells. Cancers evade that limitation primarily through rejuvenation of telomerase via different mechanisms. Mutations within the promoter of the telomerase reverse transcriptase (TERT) gene define a definite method for the ribonucleic enzyme regeneration predominantly in cancers that arise from tissues with low rates of self-renewal. The promoter mutations cause a moderate surge in TERT transcription and telomerase rejuvenation to the levels sufficient to delay replicative senescence but not prevent bulk telomere shortening and genomic instability. Since the discovery, a staggering number of studies and publications have resolved the discrete aspects, effects, and clinical relevance of the TERT promoter mutations. Those noncoding alterations link the TERT transcription with oncogenic pathways, associate with markers of poor outcome, and define patients with reduced survivals in several cancers. In this review, we discuss the occurrence and impact of the promoter mutations and highlight the mechanism of TERT activation. We further deliberate on the foundational question of the abundance of the TERT promoter mutations and a general dearth of functional mutations within noncoding sequences as evident from pan-cancer analysis of the whole-genomes. We posit that the favorable genomic constellation within the TERT promoter may be less than a common occurrence in other noncoding functional elements and the evolutionary constraints limit the functional fraction within the human genome, hence the lack of abundant mutations outside the coding sequences.

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Telomere Length and Development of Systemic Lupus Erythematosus: A Mendelian Randomization Study

Wang

et al. 2022

Arthritis & Rheumatology

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Objective. Previous observational studies demonstrated that a subset of patients with systemic lupus erythematosus (SLE) have markedly short telomere length in leukocytes. This study was undertaken to test whether leukocyte telomere length is causally associated with risk of SLE.Methods. A 2-sample Mendelian randomization (MR) analysis was conducted to estimate causality of telomere length on SLE in European populations. A replication 2-sample MR study using Asian genetic data was also conducted. A reverse MR analysis was then performed to test the effects of SLE on telomere length. The autoantibodies targeting telomere-associated protein (telomeric repeat-binding factor 1 [TERF1] autoantibodies) were detected in patients with SLE, healthy controls, and patients with rheumatoid arthritis.Results. The results of the inverse variance-weighted method (odds ratio [OR] 2.96 [95% confidence interval (95% CI) 1.58-5.55], P < 0.001) showed strong evidence for a causal relationship between longer telomere length and risk of SLE in people with European ancestry. The outcomes of MR-Egger regression analysis ], P = 0.033) and MR pleiotropy residual sum and outlier analysis (OR 3.62 [95% CI 2.03-6.46], P = 0.002) also showed that longer telomere length was significantly associated with increased risk of SLE in a European population. Sensitivity analyses using different methods and summary data sets showed that the results were still broadly consistent. A replication MR study using Asian genetic data yielded similar findings. However, the reverse MR analysis showed that genetically predicted SLE was not causally associated with telomere length. In addition, we found that TERF1 autoantibodies were present in 2 of 40 SLE patients (5.0%).Conclusion. In contrast with previous observational studies, MR analyses show that longer telomere length is significantly associated with increased risk of SLE.Available data have suggested that telomere length is associated with inflammation and immunity (1), which indicated that there might be potential linkage between telomere length and risk of SLE. To date, considerable observational studies have compared telomere length in SLE patients with that of healthy controls. In the majority of these studies (2-4), telomere length was found to become shorter in SLE patients compared to healthy controls. A previous meta-analysis tried to combine these

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Polygenic basis and biomedical consequences of telomere length variation

Cited by 36 publications

References 66 publications

Association of leucocyte telomere length with frailty: a large–scale cross–sectional analysis in UK Biobank

Association of leucocyte telomere length with frailty: a large–scale cross–sectional analysis in UK Biobank

Occurrence, functionality, and abundance of theTERTpromoter mutations

Telomere Length and Development of Systemic Lupus Erythematosus: A Mendelian Randomization Study

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