Telomere length as a risk marker for cardiovascular disease: the next big thing?

Keywords::

• cardiovascular disease
• risk factor
• telomere

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in the USA and other Western countries, and is expected to become an increasingly important cause of morbidity and mortality globally in both developed and developing countries over the next few decades [1,2,101]. Conventional risk factors, such as smoking, blood pressure and lipid values, are the mainstays of CVD and coronary heart disease (CHD) risk prediction. Even though some authors argue that conventional risk factors are sufficient to explain the vast bulk of new cases of CHD, improving risk prediction is still a widely shared goal [3,4]. Novel biomarkers, such as C-reactive protein, B-type natriuretic peptide, homocysteine and D-dimer, have shown independent relationships with CVD risk but they have added little additional explanatory value to standard risk factors [5,6].

A common limitation to current risk markers is their transient nature, which can miss the cumulative impact of oxidative stress, dyslipidemia and inflammation. Even the Framingham Risk Score is based on current measures of factors that can change over time, such as lipids, smoking status and blood pressure [7]. The majority of novel risk biomarkers are also transient in nature and thus do not reflect cumulative damage. Such transiency limits risk prediction since single measures of cardiovascular risk factors may not accurately reflect an individual’s previous exposure to risk factors or oxidative stress. This cumulative effect may be particularly damaging [8]. For example, people who stop smoking cigarettes can bring their risk of CVD back to that of people who have never smoked but this process may require at least 10 years [9,10]. A current assessment of an individual’s smoking status, lipid profile or even a biomarker of oxidative stress may miss years of damage and provide a much rosier and inaccurate estimate of the individual’s risk for future CVD events. Data indicate that knowing the history of an individual’s risk factors can be added to current state assessments in order to improve the prediction of future CVD risk [7].

The recent increase in genome-wide associations with common diseases has spurred an interest in the potential utility of genetic markers as predictors of CVD. The expectations that genetic markers will be the future for prediction and lead to personalized medicine are very high [11,12].The studies attempting to use a SNP or even multiple SNPs have yielded mixed results, ranging from little or no additional value to moderate additional predictive value above that provided by standard risk factors for CVD [13–16]. In particular, substantial interest in CVD risk markers has focused on SNPs on the chromosome 9p21 locus [4,17].

Most common forms of CVD are believed to be multifactorial and to result from many genes, each with a relatively small effect working alone or in combination with modifier genes and/or environmental factors [18,19]. A limitation of genetic markers, even clumps of SNPs, in risk prediction is that they may be restricted in their value based on gene–environment interactions. Environmental or nongenetic variables appear to play crucial roles in the genetic impact on CVD [20]. The importance of gene–environment interactions is that only when individuals with a high-risk genetic profile have the exposure will the effect be substantial enough to develop premature disease. Absence of exposure to major CVD risk factors is strongly protective against developing the clinical sequelae of CVD [3]. Genes controlling the atherosclerotic phenotypes may be of limited value in risk prediction because for them to have an impact they require exposure to previously identified CVD risk factors or even currently unidentified variables.

Telomere length has been related to atherosclerosis and CVD, and may ultimately be one of the best indicators of CVD risk [21–24]. Telomere length has emerged as a marker that appears to represent biological aging [25]. Telomeres consist of TTAGGG tandem repeats and telomere binding proteins cap the ends of chromosomes and protect them from degradation. Telomeres become progressively shorter with each replication of somatic cells. Telomere attrition ultimately leads to a loss of replicative capacity.

Telomeres hold several unique advantages as a marker of CVD risk that overcomes the limitations of both currently used biomarkers and genotyping. First, telomere length functions as a marker for risk of disease development because it represents both an inherited predisposition to cell senescence as well as a cumulative lifelong burden of oxidative stress. Several studies have shown that telomere length is familial [26–28]. Oxidative stress is associated with telomere shortening [29,30]. Thus, telomere length can generally represent gene–environment interactions across multiple genes and multiple exposures that may cause oxidative stress (e.g., smoking, insulin resistance, psychosocial stress). Second, telomere length and associated shortening is a cumulative process. As the biomarkers currently used to indicate oxidative stress or even other biomarkers, such as D-dimer, are basically reflections of the status at the time of sample collection, telomere length has the potential to provide a better appraisal of the individual’s past exposure history and, therefore, their future risk of disease development. Furthermore, a recent study of the telomere trajectory in individuals with coronary artery disease demonstrated that telomere length can shorten or lengthen over time, suggesting telomere length may not only be able to reflect oxidative damage by shortening, but may also reflect improved risk status by lengthening [31]. Third, as mentioned earlier, telomere length represents both an inherited component and lifelong exposure to oxidative stress, but it is not limited to one gene or locus, nor exposure to one risk factor. Many indicators of genetic susceptibility are focused on one gene, which may be too limited to appropriately represent CVD risk across the population. Similarly, even multivariable risk factor scores, such as the Framingham Risk Score or the Reynolds Risk Score, include only a small number of variables. Telomere length has the advantage of representing an inherited predisposition across multiple genes and oxidative stress burden across multiple types of variables.

It is currently unclear how well telomere length will ultimately perform as a risk marker for CVD and the research is still ongoing. Recent studies suggest that a variety of factors can attenuate the risk conferred by shortened telomeres. For instance, healthy behaviors, such as exercise and fruit and vegetable consumption, as well as the use of statins and social support decrease the risk associated with shorter telomeres [22,32,33]. Further studies will be needed to understand the mechanisms behind these relationships. Moreover, without a current viable measure for easy use in a clinical setting, telomere length may never achieve widespread consideration as a useful indicator. However, there are distinct advantages that may make it the next ‘big thing’ for CVD risk assessment.

Financial & competing interests disclosure

Arch G Mainous 3rd is Professor and Vanessa A Diaz is Assistant Professor in the Department of Family Medicine at the Medical University of South Carolina (SC, USA). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.