Polygenic basis and biomedical consequences of telomere length variation

Codd, Veryan; 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:10.1038/s41588-021-00944-6

Cited by 231 publications

(276 citation statements)

References 75 publications

Supporting

Mentioning

258

Contrasting

Order By: Relevance

“…Notably, expression of TERC was found to be significantly higher in monocytes of MS patients relative to healthy subjects [133]. Recently, a prepublished study reported >100 novel genomic loci to be associated with LTL based on data from 472,174 individuals [33]. This study also showed a positive association with MS risk by Mendelian randomization analysis (OR = 1.35 per SD genetically-determined longer LTL) [33].…”

Section: Genetic Variantsmentioning

confidence: 63%

“…Shorter telomeres in MS patients were also found to be associated with greater disability and brain atrophy as well as disease progression independent of chronological age, as we have discussed in a previous review [32]. Recent data from the UK Biobank indicated that longer telomeres are related to a higher risk of developing MS later in life (adjusted hazard ratio (HR) per standard deviation (SD) longer LTL = 1.27) [33]. This somewhat contradictory finding may suggest that shortened TLs in MS patients result from a higher rate of telomere attrition and/or as a consequence of pathophysiological processes.…”

Section: Telomere Biologymentioning

confidence: 76%

“…Recently, a prepublished study reported >100 novel genomic loci to be associated with LTL based on data from 472,174 individuals [33]. This study also showed a positive association with MS risk by Mendelian randomization analysis (OR = 1.35 per SD genetically-determined longer LTL) [33]. Last but not least, SNPs in the gene coding for CYP19A1, a neuroprotective enzyme that converts testosterone to estradiol [134], were associated with shorter LTL and lower estradiol levels in serum [108] but not with MS.…”

Section: Genetic Variantsmentioning

confidence: 99%

See 2 more Smart Citations

Genetic, Environmental and Lifestyle Determinants of Accelerated Telomere Attrition as Contributors to Risk and Severity of Multiple Sclerosis

et al. 2021

View full text Add to dashboard Cite

Telomeres are protective structures at the ends of linear chromosomes. Shortened telomere lengths (TL) are an indicator of premature biological aging and have been associated with a wide spectrum of disorders, including multiple sclerosis (MS). MS is a chronic inflammatory, demyelinating and neurodegenerative disease of the central nervous system. The exact cause of MS is still unclear. Here, we provide an overview of genetic, environmental and lifestyle factors that have been described to influence TL and to contribute to susceptibility to MS and possibly disease severity. We show that several early-life factors are linked to both reduced TL and higher risk of MS, e.g., adolescent obesity, lack of physical activity, smoking and vitamin D deficiency. This suggests that the mechanisms underlying the disease are connected to cellular aging and senescence promoted by increased inflammation and oxidative stress. Additional prospective research is needed to clearly define the extent to which lifestyle changes can slow down disease progression and prevent accelerated telomere loss in individual patients. It is also important to further elucidate the interactions between shared determinants of TL and MS. In future, cell type-specific studies and advanced TL measurement methods could help to better understand how telomeres may be causally involved in disease processes and to uncover novel opportunities for improved biomarkers and therapeutic interventions in MS.

show abstract

Section: Genetic Variantsmentioning

confidence: 63%

Section: Telomere Biologymentioning

confidence: 76%

Section: Genetic Variantsmentioning

confidence: 99%

See 1 more Smart Citation

Genetic, Environmental and Lifestyle Determinants of Accelerated Telomere Attrition as Contributors to Risk and Severity of Multiple Sclerosis

et al. 2021

View full text Add to dashboard Cite

show abstract

“…In general, most studies have reported shorter rLTL among subjects with type 1 or type 2 diabetes compared with subjects without diabetes ( 7 ). In the largest study of LTL to date involving 472,174 participants from UK Biobank, Codd et al ( 18 ) found LTL was significantly associated with glucose and type 2 diabetes in the observational data set, but the MR analysis did not support a causal relationship between LTL and diabetes. As far as we are aware, no study has so far, in Europeans or other populations, examined the relationship between LTL and diabetes progression.…”

Section: Discussionmentioning

confidence: 98%

Shortened Leukocyte Telomere Length Is Associated With Glycemic Progression in Type 2 Diabetes: A Prospective and Mendelian Randomization Analysis

et al. 2022

View full text Add to dashboard Cite

OBJECTIVE Several studies support associations between relative leukocyte telomere length (rLTL), a biomarker of biological aging and type 2 diabetes. This study investigates the relationship between rLTL and the risk of glycemic progression in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS In this cohort study, consecutive Chinese patients with type 2 diabetes (N = 5,506) from the Hong Kong Diabetes Register with stored baseline DNA and available follow-up data were studied. rLTL was measured using quantitative PCR. Glycemic progression was defined as the new need for exogenous insulin. RESULTS The mean (SD) age of the 5,349 subjects was 57.0 (13.3) years, and mean (SD) follow-up was 8.8 (5.4) years. Baseline rLTL was significantly shorter in the 1,803 subjects who progressed to insulin requirement compared with the remaining subjects (4.43 ± 1.16 vs. 4.69 ± 1.20). Shorter rLTL was associated with a higher risk of glycemic progression (hazard ratio [95% CI] for each unit decrease [to ∼0.2 kilobases]: 1.10 [1.06–1.14]), which remained significant after adjusting for confounders. Baseline rLTL was independently associated with glycemic exposure during follow-up (β = −0.05 [−0.06 to −0.04]). Each 1-kilobase decrease in absolute LTL was on average associated with a 1.69-fold higher risk of diabetes progression (95% CI 1.35–2.11). Two-sample Mendelian randomization analysis showed per 1-unit genetically decreased rLTL was associated with a 1.38-fold higher risk of diabetes progression (95% CI 1.12–1.70). CONCLUSIONS Shorter rLTL was significantly associated with an increased risk of glycemic progression in individuals with type 2 diabetes, independent of established risk factors. Telomere length may be a useful biomarker for glycemic progression in people with type 2 diabetes.

show abstract

“…On the cellular level, telomere attrition can ultimately lead to cell cycle arrest and cell senescence. Thus, short telomeres were suggested to cause aging-related pathologies, and long telomeres are associated with longevity, as well as increased risk of various cancers [11,12]. While telomeres in the sperm were shown to elongate with age, this is not the case in the oocytes [13].…”

Section: Of 11mentioning

confidence: 99%

Leukocyte Telomere Length Correlates with Extended Female Fertility

Michaeli

Smoom

Serruya

et al. 2022

Cells

View full text Add to dashboard Cite

Current social trends of delayed reproduction to the fourth and fifth decade of life call for a better understanding of reproductive aging. Demographic studies correlated late reproduction with general health and longevity. Telomeres, the protective ends of eukaryotic chromosomes, were implicated in various aging-associated pathologies and longevity. To examine whether telomeres are also associated with reproductive aging, we measured by Southern analysis the terminal restriction fragments (TRF) in leukocytes of women delivering a healthy infant following a spontaneous pregnancy at 43–48 years of age. We compared them to age-matched previously fertile women who failed to conceive above age 41. The average TRF length in the extended fertility group (9350 bp) was significantly longer than in the normal fertility group (8850 bp; p-value = 0.03). Strikingly, excluding women with nine or more children increased the difference between the groups to over 1000 bp (9920 and 8880 bp; p-value = 0.0009). Nevertheless, we observed no apparent effects of pregnancy, delivery, or parity on telomere length. We propose that longer leukocyte telomere length reflects higher oocyte quality, which can compensate for other limiting physiological and behavioral factors and enable successful reproduction. Leukocyte telomere length should be further explored as a novel biomarker of oocyte quality for assessing reproductive potential and integrating family planning with demanding women’s careers.

show abstract

Polygenic basis and biomedical consequences of telomere length variation

Cited by 231 publications

References 75 publications

Genetic, Environmental and Lifestyle Determinants of Accelerated Telomere Attrition as Contributors to Risk and Severity of Multiple Sclerosis

Genetic, Environmental and Lifestyle Determinants of Accelerated Telomere Attrition as Contributors to Risk and Severity of Multiple Sclerosis

Shortened Leukocyte Telomere Length Is Associated With Glycemic Progression in Type 2 Diabetes: A Prospective and Mendelian Randomization Analysis

Leukocyte Telomere Length Correlates with Extended Female Fertility

Contact Info

Product

Resources

About