A major population resource of 474,074 participants in UK Biobank to investigate determinants and biomedical consequences of leukocyte telomere length

Codd, Veryan; Denniff, Matthew; Swinfield, Chloe; Warner, Sophie C; Papakonstantinou, Manolo; Sheth, Shilpi; Nanus, Dominika E; Budgeon, Charley; Musicha, Crispin; Bountziouka,; Wang, Q; Bramley, R.; Allara, Elias; Kaptoge, Stephen; Stoma, Svetlana; Jiang, Tao; Butterworth, Adam S.; Wood, Angela; Angelantonio, Emanuele Di; Thompson, John R.; Danesh, John; Nelson, Christopher P.; Nj, Samani

doi:10.1101/2021.03.18.21253457

Cited by 27 publications

(54 citation statements)

References 44 publications

(44 reference statements)

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“…Participants: Participants in UKB have been characterised in detail using questionnaires, physical measurements, urinary and plasma biomarker measurements, genomic assays and longitudinal linkage with multiple health record systems, including Hospital Episode Statistics (HES) and Office for National Statistics (ONS) mortality data [16]. We have described the associations of inter-individual variation in LTL with multiple biomedical traits and risk of several diseases in UKB [15]. Since the onset of the COVID-19 pandemic, UKB has also linked participants with results from clinically indicated SARS-CoV-2 testing and COVID-19 outcomes.…”

Section: Methodsmentioning

confidence: 99%

“…TL À commonly measured in leucocytes (LTL) À shows a consistent negative association with age in cross sectional population cohorts and has previously been proposed as a marker of biological age for an individual. However, age only accounts for a small proportion of the substantial inter-individual variation in LTL [6] that exists at all ages, including birth [7]. More recently, TL has also been proposed as a marker of replicative capacity and repair ability [8], both of which, within the haematopoietic system, could potentially impair an individual's response to SARS-CoV-2 infection, above any effect of age [9,10].…”

Section: Introductionmentioning

confidence: 99%

“…Here, we examine whether LTL measured several years prior to SARS-CoV-2 infection is associated with adverse COVID-19 outcomes, leveraging our recent completion of LTL measurements in 474,074 participants aged 40À69 at time of recruitment into UK Biobank (UKB) [6] between 2006 and 2010 [14,15].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Shorter leukocyte telomere length is associated with adverse COVID-19 outcomes: A cohort study in UK Biobank

Wang¹,

Codd²,

Raisi‐Estabragh³

et al. 2021

EBioMedicine

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Shorter leukocyte telomere length is associated with adverse COVID-19 outcomes: A cohort study in UK Biobank

Wang¹,

Codd²,

Raisi‐Estabragh³

et al. 2021

EBioMedicine

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“…We also report observed associations of the average ("usual") LTL values, adjusted for the regression dilution ratio (RDR) of 0•68 (0•64-0•72) for loge-LTL that was derived using 1351 serial measurements of LTL taken at mean interval of 5.5 years (range: 2-10 years). 17 Secondary analysis involved multinomial regression and binary logistic regression to assess associations (RRR and odds ratios (OR)) with the number of frailty indicators and the individual frailty indicators respectively.…”

Section: Discussionmentioning

confidence: 99%

“…[14][15][16] We have recently generated cohort-wide LTL measurements in UK Biobank (UKB). 17 Using this large-scale resource we investigated whether LTL is associated with frailty independently of chronological age and other established risk factors.…”

Section: Introductionmentioning

confidence: 99%

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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Association of Longer Leukocyte Telomere Length With Cardiac Size, Function, and Heart Failure

et al. 2023

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ImportanceLonger leukocyte telomere length (LTL) is associated with a lower risk of adverse cardiovascular outcomes. The extent to which variation in LTL is associated with intermediary cardiovascular phenotypes is unclear.ObjectiveTo evaluate the associations between LTL and a diverse set of cardiovascular imaging phenotypesDesign, Setting, and ParticipantsThis is a population-based cross-sectional study of UK Biobank participants recruited from 2006 to 2010. LTL was measured using a quantitative polymerase chain reaction method. Cardiovascular measurements were derived from cardiovascular magnetic resonance using machine learning. The median (IQR) duration of follow-up was 12.0 (11.3-12.7) years. The associations of LTL with imaging measurements and incident heart failure (HF) were evaluated by multivariable regression models. Genetic associations between LTL and significantly associated traits were investigated by mendelian randomization. Data were analyzed from January to May 2023.ExposureLTL.Main Outcomes and MeasuresCardiovascular imaging traits and HF.ResultsOf 40 459 included participants, 19 529 (48.3%) were men, and the mean (SD) age was 55.1 (7.6) years. Longer LTL was independently associated with a pattern of positive cardiac remodeling (higher left ventricular mass, larger global ventricular size and volume, and higher ventricular and atrial stroke volumes) and a lower risk of incident HF (LTL fourth quartile vs first quartile: hazard ratio, 0.86; 95% CI, 0.81-0.91; P = 1.8 × 10−6). Mendelian randomization analysis suggested a potential causal association between LTL and left ventricular mass, global ventricular volume, and left ventricular stroke volume.Conclusions and RelevanceIn this cross-sectional study, longer LTL was associated with a larger heart with better cardiac function in middle age, which could potentially explain the observed lower risk of incident HF.

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A major population resource of 474,074 participants in UK Biobank to investigate determinants and biomedical consequences of leukocyte telomere length

Cited by 27 publications

References 44 publications

Shorter leukocyte telomere length is associated with adverse COVID-19 outcomes: A cohort study in UK Biobank

Shorter leukocyte telomere length is associated with adverse COVID-19 outcomes: A cohort study in UK Biobank

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

Association of Longer Leukocyte Telomere Length With Cardiac Size, Function, and Heart Failure

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