Research Article: Telomere length and mortality in the Ludwigshafen Risk and Cardiovascular Health study

Date Published: June 19, 2018

Publisher: Public Library of Science

Author(s): Irene Pusceddu, Marcus Kleber, Graciela Delgado, Wolfgang Herrmann, Winfried März, Markus Herrmann, Tanja Zeller.

http://doi.org/10.1371/journal.pone.0198373

Abstract

Short telomeres have been associated with adverse lifestyle factors, cardiovascular risk factors and age-related diseases, including cardiovascular disease (CVD), myocardial infarction, atherosclerosis, hypertension, diabetes, and also with mortality. However, previous studies report conflicting results.

The aim of the present study has been to investigate the involvement of telomere length in all-cause and CVD mortality in subjects hospitalized for diagnostic coronary angiography of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study.

Relative telomere length (RTL) was measured with a Q-PCR based method in 3,316 participants of the LURIC study. Age-corrected RTL was calculated as the ratio between RTL and age. Median follow-up was 9.9 years. Cox regression and Kaplan-Maier analyses were performed to evaluate the role of RTL for all-cause and cardiovascular mortality.

RTL correlated negatively with age (r = -0.09; p<0.001). In surviving patients the correlation between age and RTL was statistically significant (r = -0.088; p<0.001), but not in patients who died during follow-up (r = -0.043; p = 0.20). Patients in quartiles 2–4 of RTL had a lower hazard ratio for all-cause mortality (HR:0.822; 95%CI 0.712–0.915; p = 0.008) and CVD-mortality (HR:0.836; 95%CI 0.722–0.969; p = 0.017) when compared to those in the 1st quartile. Adjustment for major cardiovascular risk factors did not change this result, however additional adjustment for age attenuated this effect. Patients in the 4th quartile of age-corrected RTL compared to those in the 1st quartile had a lower hazard ratio for all-cause mortality, even with adjustment for major cardiovascular risk factors. The present study supports the hypothesis that short telomere length increases the risk of all-cause and CVD mortality. Age appears to be an important co-variate that explains a substantial fraction of this effect. It remains unclear whether short telomeres contribute directly to the increase in mortality or if they are simply a surrogate marker for other adverse processes of aging.

Partial Text

Aging is a major risk factor for the development of many common diseases, including cardiovascular disease (CVD), myocardial infarction (MI), stroke, hypertension, type 2 diabetes mellitus (T2DM), cancer, and chronic kidney disease (CKD) [1]. The prevalence of these diseases significantly increases with age, and they are major causes of frailty and death [1]. Telomeres are protective end caps of chromosomes, supporting genomic integrity and stability, key aspects of aging [1]. They are nucleoprotein structures composed by a non-coding, repetitive DNA sequence (TTAGGG) and associated proteins that form the shelterin complex [1]. Due to the inability of the DNA polymerase to fully replicate the 3’ end of chromosomes, telomeres progressively shorten with every cell division [1]. The consequence of this phenomenon is that a somatic cell can undergo a defined number of doublings before telomeres become critically short, lose their protective properties and send cells into senescence, or cause cell death [1]. Therefore, mean telomere length has been used as a biomarker of biological age [1]. Short telomeres have been associated with older age, adverse lifestyle factors, such as stress, smoking and obesity and reduced physical activity [1]. In addition, telomere length has been studied as a potential biomarker of age-related diseases, such as CVD [1,2–4], MI [1,2], atherosclerosis [1], hypertension [1,5], T2DM [1], and mortality [6–8]. In population-based prospective studies it has repeatedly been shown that individuals with short telomeres have an increased risk for cardiovascular events, stroke, MI and all-cause mortality [2,3,9,10]. Despite the increase in all-cause mortality, in the general elderly population short telomeres are not necessarily associated with a higher risk of cardiovascular death [6,9]. In studies that found a significant increase in cardiovascular mortality the effect was rather small [11] or limited to distinct sub-groups, such as African-American [10].

This large-scale prospective study demonstrates that RTL is a predictor of all causes mortality and CVD mortality. Subjects with a RTL below the median of the cohort showed a reduced survival compared to those with RTL above the median. In addition, pre-existing diabetes mellitus or CAD were associated with shorter telomeres when compared to subjects without these conditions. However, traditional cardiovascular risk factors, in particular age, explain a substantial fraction of the association between RTL and mortality.

In conclusion, the present study supports the hypothesis that short telomere length increases the risk of all-cause and CVD mortality. However, a significant fraction of this association is explained by established cardiovascular risk factors, in particular chronologic age. It remains unclear whether short telomeres directly contribute to the increase in mortality or if they are simply a surrogate marker for other adverse processes of aging.

 

Source:

http://doi.org/10.1371/journal.pone.0198373

 

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