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