Elsevier

The Lancet

Volume 369, Issue 9556, 13–19 January 2007, Pages 107-114
The Lancet

Articles
Telomere length, risk of coronary heart disease, and statin treatment in the West of Scotland Primary Prevention Study: a nested case-control study

https://doi.org/10.1016/S0140-6736(07)60071-3Get rights and content

Summary

Background

Inter-individual differences in biological ageing could affect susceptibility to coronary heart disease. Our aim was to determine whether mean leucocyte telomere length is a predictor of the development of coronary heart disease.

Methods

We compared telomere lengths at recruitment in 484 individuals in the West of Scotland Primary Prevention Study (WOSCOPS) who went on to develop coronary heart disease events with those from 1058 matched controls who remained event free. We also investigated whether there was any association between telomere length and observed clinical benefit of statin treatment in WOSCOPS.

Findings

Mean telomere length decreased with age by 9% per decade (95% CI 3·6–14·1; p=0·001) in controls; much the same trend was seen in cases (−5·9% per decade, −3·1 to 14·1; p=0·1902). Individuals in the middle and the lowest tertiles of telomere length were more at risk of developing a coronary heart disease event than were individuals in the highest tertile (odds ratio [OR] for coronary heart disease: 1·51, 95% CI 1·15–1·98; p=0·0029 in the middle tertile; 1·44, 1·10–1·90, p=0·0090 in the lowest). In placebo-treated patients, the risk of coronary heart disease was almost double in those in the lower two tertiles of telomere length compared with those in the highest tertile (1·93, 1·33–2·80, p=0·0005 in the middle tertile; 1·94, 1·33–2·84, p=0·0006 in the lowest). By contrast, in patients treated with pravastatin, the increased risk with shorter telomeres was substantially attenuated (1·12, 0·75–1·69, p=0·5755 in the middle tertile; 1·02, 0·68–1·52, p=0·9380 in the lowest).

Interpretation

Mean leucocyte telomere length is a predictor of future coronary heart disease events in middle-aged, high-risk men and could identify individuals who would benefit most from statin treatment. Our findings lend support to the hypothesis that differences in biological ageing might contribute to the risk—and variability in age of onset—of coronary heart disease.

Introduction

Although epidemiological studies have identified several cardiovascular risk factors that potentially explain most of the risk of coronary heart disease in a population,1 at an individual level there is wide variation in both the occurrence of coronary heart disease and age of manifestation, even in individuals with much the same risk factor profiles. The reasons for this wide inter-individual variation in susceptibility are poorly understood. Coronary heart disease is an age-associated disease. Histologically, cellular senescence is a major feature of atherosclerotic plaques,2, 3 and in-vitro induction of senescence in coronary endothelial cells causes the expression of molecules implicated in atherogenesis.4 Therefore, the hypothesis has emerged that, at least to some extent, inter-individual variation in risk of coronary heart disease might result from variation in the rate of biological ageing.5, 6, 7

Telomeres are the extreme ends of chromosomal DNA, made up of a large number of tandem repeats of the sequence TTAGGG. Although the full extent of their functions is not fully understood, they are involved in the maintenance of cellular stability.8 Because DNA polymerase cannot fully complete the replication of the 3′ end of linear DNA, telomeres progressively shorten with repeated cell division.9 Olovnikov10 was the first to suggest that this shortening is a potential mechanism for a biological clock that determines cellular behaviour, and this concept has since been lent support by experiments.11, 12 In many cell types, senescence and subsequent cell death often occurs when the mean telomere length reaches a critical value.13 Therefore, mean telomere length provides a marker for biological age, at least at the cellular level, with shorter telomeres indicating increased biological age.

We have shown that mean telomere length in leucocytes is shorter in patients with severe triple vessel coronary artery disease than it is in individuals with angiographically normal coronary arteries,5 and also in patients who have had a premature myocardial infarction before age 50 years than in age and sex matched people without such a history.6 We have also shown that the association of shorter telomeres with coronary heart disease is independent of classic and novel risk factors for coronary heart disease, including markers of inflammation. A limitation of these cross-sectional studies is that they cannot exclude the possibility that the shorter telomere lengths might simply be a consequence of the development of coronary heart disease, rather than being a primary abnormality. Here, by use of the DNA bank established as part of the West of Scotland Primary Prevention Study (WOSCOPS)14 and a recently described PCR-based assay for measuring telomere length,15 we investigated the prospective association of leucocyte telomere length with development of coronary heart disease. Because WOSCOPS randomly assigned some patients to receive statin treatment,14 we also investigated whether there was any relation between mean telomere length and the observed benefit of statin treatment.

Section snippets

Patients

In WOSCOPS, 6595 statin-naive men aged 45–64 years (mean 55·2 years) who had a total cholesterol concentration of 6·5–7·8 mmol/L at recruitment, an LDL-cholesterol concentration over 4·5 mmol/L on a National Cholesterol Education Programme (NCEP) diet on one occasion before randomisation, and no history of a myocardial infarction were randomly assigned to receive pravastatin (40 mg daily) or placebo.14 The study complied with the Declaration of Helsinki, was approved by the local ethics

Results

Table 1 shows the characteristics of cases and controls at the time of recruitment to WOSCOPS, together with the OR for coronary heart disease risk associated with changes in—or presence of—various risk factors. Cases had higher body-mass index, triglyceride and LDL-cholesterol concentrations, and lower HDL-cholesterol concentrations than did controls. Systolic blood pressure was, on average, 3·9 mm Hg higher in cases than in controls; likewise, diastolic blood pressure was 1·9 mm Hg higher in

Discussion

By use of a nested case-control approach from observations made in a prospective randomised primary prevention trial of a statin, we have shown that individuals with shorter leucocyte telomere length at the time of recruitment had a significantly higher risk of developing subsequent coronary heart disease. Interestingly, this increased risk with shorter baseline telomeres was attenuated in individuals receiving treatment with a statin. The risk of coronary heart disease associated with shorter

References (34)

  • KF Burrig

    The endothelium of advanced arteriosclerotic plaques in humans

    Arterioscler Thromb

    (1991)
  • T Minamino et al.

    Endothelial cell senescence in human atherosclerosis. Role of telomere in endothelial dysfunction

    Circulation

    (2002)
  • NJ Samani et al.

    Telomere shortening in atherosclerosis

    Lancet

    (2002)
  • S Brouilette et al.

    White cell telomere length and risk of myocardial infarction

    Arterioscler Thromb Vasc Biol

    (2003)
  • SR Chan et al.

    Telomeres and telomerase

    Philos Trans R Soc Lond B Biol Sci

    (2004)
  • CB Harley et al.

    Telomeres shorten during ageing of human fibroblasts

    Nature

    (1990)
  • H Vaziri et al.

    Telomere length predicts replicative capacity of human fibroblasts

    Proc Natl Acad Sci USA

    (1992)
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