Telomere length measurement in UK Biobank: advancing understanding of biological ageing and age-related diseases

英国生物银行的端粒长度测量：增进对生物衰老和年龄相关疾病的理解

• 批准号: MR/M012816/1
• 负责人: Nilesh Samani
• 金额: $ 263.28万
• 依托单位: University of Leicester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM012816%2F1
• 关键词: Telomere; length; measurement; UK; Biobank

Why do some individuals develop age-associated diseases such as coronary artery disease (CAD) early while others go through their entire life without being affected? The answer to this question is profoundly important for both understanding these diseases as well as healthy ageing. Because of their age-association, we have proposed that these diseases, at least to some extent, are manifestations of accelerated biological (as distinct from chronological) ageing. In this project, we will investigate this hypothesis by measuring a marker of biological ageing called telomere length (TL). Telomeres are structures that cap our chromosomes at each end. People are born with telomeres of different lengths and as cells divide a small amount of telomere is lost each time. Furthermore, the amount lost is known to be increased by some of the same factors that influence the risk of some age-related diseases. Importantly, cells "sense" their TL and become senescent and subsequently die when TL reaches a critically short value. Thus, TL acts as a biological clock that determines cell behaviour and lifespan. Translating this to a whole person, those born with shorter telomeres or whose telomeres attrition faster may "biologically" age more quickly than others. In turn, this could explain why some people develop specific age-associated diseases at an earlier age while others can remain healthy to an advanced age despite similar life exposures.In support of our hypothesis, in previous work we and others have shown an association between shorter mean TL in DNA from blood cells (leucocytes) (LTL) and risk of several chronic diseases, including CAD. Other studies have shown correlations between LTL and diet, life-style characteristics and disease risk factors such as obesity and smoking. However, many of the findings require further definitive evidence especially of a prospective nature i.e. whether variation in LTL predicts future occurrence of age-related disease. UK Biobank provides an ideal cohort to undertake such research. It comprises 500,000 participants, aged 45-69 years at enrolment, recruited UK-wide. A vast amount of information has been collected on each participant including data on diet, lifestyle, behaviour and risk factors and on existing diseases. By linkage to a variety of health-related records, information is also being collected on new diseases as they occur. Each participant is having their DNA typed using a genome-wide array.Using a method that we have optimised to achieve high throughput, we propose to measure LTL of all 500,000 UK Biobank participants. Standardised measurement of LTL in all participants in one go will enable a wide-range of hypotheses to be explored and provide a long-term enhancement of UK Biobank whose value will only increase with time as more disease outcomes accrue. Furthermore, we will be taking advantage of a one-off opportunity that has presented itself from an ongoing genotyping project in UK Biobank. By using the residual DNA samples left over from this project to measure LTL, we will avoid the substantial costs of further DNA extraction, quantification and arraying that would otherwise be required. Using the data we will:(i) Identify personal, environmental and life-style factors that correlate with LTL, which may be determinants of LTL. (ii) Characterise associations of LTL with cardiovascular traits/risk factors as well as with selected cardiovascular disease outcomes that occur after enrolment into the study.(iii) Test whether LTL is likely to be a causative factor in cardiovascular diseases using genetic methods, which, if positive, would support the biological ageing hypothesis and potentially open up new strategies for prevention and treatment. (iv) Make the data widely available to enable other researchers to test the association of LTL with other age-associated diseases, such as dementia and cancers, and with the likelihood of healthy ageing and longevity.

为什么一些人很早就患上了与年龄相关的疾病，如冠状动脉疾病(CAD)，而另一些人一生都没有受到影响？这个问题的答案对于理解这些疾病以及健康老龄化都是极其重要的。由于它们与年龄相关，我们提出，这些疾病，至少在某种程度上，是生物(不同于时间)老化的加速表现。在这个项目中，我们将通过测量一种名为端粒长度(TL)的生物衰老标志来研究这一假说。端粒是两端覆盖着染色体的结构。人类天生就有不同长度的端粒，当细胞分裂时，每次都会丢失少量的端粒。此外，一些影响某些年龄相关疾病风险的相同因素也会增加损失的数量。重要的是，细胞“感觉”到它们的TL，然后变得衰老，然后在TL达到临界短值时死亡。因此，TL充当决定细胞行为和寿命的生物钟。将这一点推算到一个完整的人身上，那些出生时端粒较短或端粒磨损较快的人，在生物学上可能比其他人衰老得更快。反过来，这可以解释为什么一些人在较早的年龄患上特定的年龄相关疾病，而另一些人在类似的生活暴露下可以保持健康到高龄。为了支持我们的假设，我们和其他人在之前的工作中证明了血细胞(白细胞)DNA中较短的平均TL(LTL)与包括CAD在内的几种慢性病的风险之间的关联。其他研究表明，LTL与饮食、生活方式特征以及肥胖和吸烟等疾病风险因素之间存在相关性。然而，许多发现需要进一步的确凿证据，特别是前瞻性的证据，即LTL的变异是否预示着未来与年龄相关的疾病的发生。英国生物库提供了进行此类研究的理想群体。它由50万名参与者组成，注册时年龄在45岁至69岁之间，在英国范围内招募。收集了每个参与者的大量信息，包括饮食、生活方式、行为和风险因素以及现有疾病的数据。通过与各种与健康有关的记录建立联系，还可以在新疾病发生时收集有关它们的信息。每个参与者都使用全基因组阵列对他们的DNA进行了分型。使用一种我们优化的方法来实现高通量，我们建议测量所有500,000名英国生物库参与者的LTL。一次性对所有参与者的LTL进行标准化测量将使一系列假设得以探索，并提供英国生物库的长期增强，其价值只会随着更多疾病结果的增加而增加。此外，我们将利用英国生物库正在进行的基因分型项目带来的一次性机会。通过使用这个项目遗留下来的DNA样本来测量LTL，我们将避免进一步提取、量化和排列DNA的大量成本，否则将需要。利用这些数据，我们将：(I)确定与LTL相关的个人、环境和生活方式因素，这可能是LTL的决定因素。(Ii)描述LTL与心血管特征/风险因素以及纳入研究后发生的选定心血管疾病结果的关系。(Iii)使用遗传学方法测试LTL是否可能是心血管疾病的致病因素，如果呈阳性，将支持生物衰老假说，并可能开辟新的预防和治疗策略。(Iv)广泛提供数据，使其他研究人员能够测试LTL与其他与年龄相关的疾病，如痴呆症和癌症，以及与健康老龄化和长寿的可能性之间的联系。

项目成果

The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease

人类血细胞性状变异的等位基因景观及其与常见复杂疾病的联系

• DOI: 10.17863/cam.7108
• 发表时间: 2016
• 作者: Astle W

Association of shorter leucocyte telomere length with risk of frailty.

• DOI: 10.1002/jcsm.12971
• 发表时间: 2022-06
• 期刊: Journal of cachexia, sarcopenia and muscle

Inherited myeloproliferative neoplasm risk affects haematopoietic stem cells.

• DOI: 10.1038/s41586-020-2786-7
• 发表时间: 2020-10
• 期刊: Nature
• 影响因子: 64.8
• 作者: Bao EL;Nandakumar SK;Liao X;Bick AG;Karjalainen J;Tabaka M;Gan OI;Havulinna AS;Kiiskinen TTJ;Lareau CA;de Lapuente Portilla AL;Li B;Emdin C;Codd V;Nelson CP;Walker CJ;Churchhouse C;de la Chapelle A;Klein DE;Nilsson B;Wilson PWF;Cho K;Pyarajan S;Gaziano JM;Samani NJ;FinnGen;23andMe Research Team;Regev A;Palotie A;Neale BM;Dick JE;Natarajan P;O'Donnell CJ;Daly MJ;Milyavsky M;Kathiresan S;Sankaran VG
• 通讯作者: Sankaran VG

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

• DOI: 10.1001/jamacardio.2023.2167
• 发表时间: 2023-09-01
• 期刊: JAMA cardiology
• 影响因子: 24

Modifiable traits, healthy behaviours, and leukocyte telomere length: a population-based study in UK Biobank.

• DOI: 10.1016/s2666-7568(22)00072-1
• 发表时间: 2022-05
• 期刊: LANCET HEALTHY LONGEVITY
• 影响因子: 13.1
• 作者: Bountziouka, Vasiliki;Musicha, Crispin;Allara, Elias;Kaptoge, Stephen;Wang, Qingning;Angelantonio, Emanuele Di;Butterworth, Adam S;Thompson, John R;Danesh, John N;Wood, Angela M;Nelson, Christopher P;Codd, Veryan;Samani, Nilesh J
• 通讯作者: Samani, Nilesh J