European Journal of Vascular & Endovascular Surgery
Volume 39, Issue 5 , Pages 559-564, May 2010

Short Leukocyte Telomere Length is Associated with Abdominal Aortic Aneurysm (AAA)

Vascular Surgery Group, Department of Cardiovascular Sciences, Robert Kilpatrick Building, Leicester Royal Infirmary, University of Leicester, Leicester LE2 7LX, United Kingdom

Received 5 November 2009; accepted 18 January 2010. published online 22 February 2010.

Article Outline

Abstract 

Objective

Telomeres are specialised DNA structures present at the ends of linear chromosomes, which shorten with each successive cell division and the length of which represents cellular biological age. The aim of this study was to determine the relationship between abdominal aortic aneurysm (AAA) and white cell telomere length.

Methods

Peripheral blood samples were collected from 190 patients with AAA and 183 controls. Genomic DNA was extracted from white cells and telomere lengths determined using a chemiluminescence technique.

Results

The mean white cell telomere length was significantly lower in AAA patients compared to controls (median age 66 years in both groups), with a mean difference of 189 base pairs (bp) (95% confidence interval 77bp to 301bp, P=0.005). This relationship between case–control status and mean telomere restriction fragment (TRF) length did not change after adding other risk factors into a multiple regression model. The risk of having AAA doubled in patients with a mean TRF length in the lowest quartile compared to patients with a mean TRF length in the highest quartile (odds ratio 2.30, 95% Confidence Interval 1.28–4.13, P=0.005).

Conclusion

Our data show that patients with AAA have shorter leukocyte telomere length compared to controls. This suggests that vascular biological aging may have a role in the pathogenesis of AAA.

Keywords: Telomere, Abdominal aorta, Aneurysm, Vascular, Leukocyte

 

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Introduction 

Telomeres are specialised DNA (deoxyribonucleic acid) structures present at the ends of linear chromosomes. They are made up of a string of TTAGGG repeats and protect the chromosome ends from enzymatic degradation, reconstruction, fusion and loss.1 With each cell division, inevitable loss of telomeric DNA occurs due to an ‘end replication problem’, where a few bases at the 3′ end of each template are not copied during DNA replication. Germ cells and some somatic cells produce an enzyme called telomerase that can add TTAGGG repeats and prevent telomere attrition. The difference between initial telomere length and telomere length at any given time thereafter predicts the biological age of the cell, hence telomeres can be considered as a mitotic clock.2 Human telomere length is genetically determined3, 4, 5, 6 and is influenced by environmental factors such as oxidative stress7 and smoking.8 Within an individual there is a high similarity in telomere length between various tissues9, 10, 11 and leukocyte telomere length is commonly used as a surrogate marker for overall telomere length.

Vascular tissue is constantly exposed to mechanical and haemodynamic insults and a healthy endothelial layer is essential to withstand this repetitive stress. Damaged and dysfunctional endothelial cells are constantly replaced by surrounding endothelial cells and endothelial progenitor cells. Arteries exposed to high haemodynamic disturbances show increased endothelial cell turnover and consequent telomere shortening.12 Iliac artery endothelial cells have shorter telomere lengths than endothelial cells from iliac veins and the internal thoracic artery.13 The intima and media of the distal abdominal aorta demonstrates increased telomere attrition compared to the proximal abdominal aorta.14

In addition to local vascular telomere attrition, the telomere length of circulating white cells is also decreased in patients with cardiovascular diseases. Patients with coronary atherosclerosis,15 premature myocardial infarction,16 congestive cardiac failure17 and aortic stenosis18 have shorter leukocyte telomere lengths compared to healthy controls. Wilson10 found significant reduction in telomere content of abdominal aortic aneurysm (AAA) wall samples compared to normal aorta. The aim of this study was to determine the association between white cell telomere length and abdominal aortic aneurysm.

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Methods 

Subjects and tissue samples 

One hundred and ninety patients with infrarenal AAA from the Leicester vascular unit were recruited together with 183 age-matched controls. All consecutive patients attending the out-patient clinics with aortic diameters greater than 30mm were invited to participate in the study. The only exclusion criterion was an inability or refusal to consent to participate in the study. Subjects were considered to have AAA when the maximum external diameter of the infrarenal abdominal aorta was equal to or more than 30mm, measured using ultrasound scan or CT scan. All controls were screened by either ultrasound or CT scan to exclude the presence of AAA and the same exclusion criteria applied as per the AAA group. Control participants were recruited from the regional AAA screening programme and the same out-patient clinics as the participants with AAA. The presence or absence of risk factors including smoking (current, ex-smoker or non smoker), hypertension and diabetes (type I or type II) were self-reported by the subjects. Positive family history was defined as having a minimum of one first degree relative with AAA. Fifteen to twenty millilitres of blood was collected from the antecubital vein and separated into plasma and white cells (buffy coat). The buffy coat was snap frozen and stored at −80°C for future batch analysis. The study was approved by the local NHS Research Ethics Committee.

Telomere length assay 

DNA was extracted from the buffy coat using a Puregene DNA extraction kit (Flowgen Bioscience Ltd, United Kingdom). The mean terminal restriction fragment (TRF) length, a marker of telomere length, was measured by a chemiluminesence technique using teloTAGGG telomere length assay kits (Roche-Applied Science, Germany). In brief, 25μl of each DNA sample (75ng/μl) was digested with 10U of Rsa I (Invitrogen Ltd, UK) and 10U of Hinf I (Invitrogen Ltd, UK) at 37°C for two and half hours. The DNA fragments were separated by electrophoresis on 0.6% agarose gels (20×20cm) at 150V for 1h and 50V for 18h. The DNA was then depurinated with 0.25% HCl for 20min, denatured with 0.5mol/L NaOH/1.5mol/L NaCl for 30min and neutralized with 0.5mol/L Tris/1.5mol/L NaCl, pH 8 for 30min. The DNA was transferred overnight on to a positively charged nylon membrane (Amersham Hybon N+, GE Healthcare, UK) using a southern blot technique and fixed with ultraviolet light. The membrane was then hybridized with a telomere repeat specific digoxigen (DIG) labelled probe overnight at 42°C. The membrane was washed three times with 2× SSC (saline sodium citrate)/0.1% SDS (sodium dodecyl sulphate) followed by 0.2× SSC/0.1% SDS. The membrane was then incubated with a DIG specific antibody covalently coupled to alkaline phosphatase. The immobilised telomere probe was then visualised using CDP star, a highly chemiluminescent substrate for alkaline phosphate. Exposing the membrane to an autoradiograph film (Amersham Hyperfilm ECL, GE Healthcare, UK) revealed the telomere smears. The mean terminal restriction fragment of each sample was calculated using the formula mean TRF=, where ODi is the optical density at a given position on the gel and Li is the molecular weight at that position. An internal control with a known mean TRF length (DNA extracted from HUVEC cells) was used to study the inter-gel and intra-gel variation in mean TRF length (data not shown). The mean TRF length of samples from cases and controls were adjusted to the standardised internal control to account for the inter-gel and intra-gel variation (Fig. 1).

  • View full-size image.
  • Figure 1 

    An autoradiogram showing the telomere smears of leukocyte DNA from cases and controls. Each sample is labelled by case–control status, gender and age. At the both ends molecular weight markers were run to calculate the mean TRF length. In this gel a mixture of 20 cases and controls were run on the left hand side and one internal control on the right hand side.

Statistical analysis 

All statistical analysis was performed using SPSS version 16.0 (SPSS Inc. Chicago). Demographic characteristics of cases and controls were compared using chi square test for categorical variables and an independent samples ‘t’ test for continuous variables. The difference in mean TRF length between cases and controls was analysed using an independent samples ‘t’ test. The difference in mean TRF length in subjects with different risk factors was analysed using bivariate correlation for continuous variables and independent samples ‘t’ test for categorical variable. The independent effect of age, sex and other risk factors on the mean TRF length was analysed using a linear regression model controlling for case control status. Those demographic variables found to be associated with AAA on univariate analysis were entered into a binary logistic regression model using a forward entry method together with mean leukocyte TRF length to determine whether any association seen between AAA and telomere length was independent of other covariates. Only covariates found to be significantly associated with AAA were retained in the final model.

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Results 

One hundred and ninety patients with infrarenal AAA (median age 66 years, range 56–91 years) were recruited together with 183 age-matched controls (median age 66 years, range 57–87 years). The mean aneurysm size was 5.15cm (range 3–10cm). The demographic characteristics of patients with AAA and controls are shown in Table 1.

Table 1. Demographics of cases and controls.
CasesControlsP
(n=190)(n=183)
Mean age (SD)69.47 (6.66)68.98 (6.2)0.46
Male gender176 (93%)171(93%)0.75
Current or ex-smokers (%)179 (94%)131 (72%)<0.0001
Hypertension (%)105 (55%)87(47%)0.15
Diabetes (type I/type II)23 (12%)29 (16%)0.27
Positive history of MI (%)60 (32%)39 (21%)0.02
Positive family history of AAAa19 (10%)12 (7%)0.14
Aneurysm size in centimetres (cm)5.15 (1.57)NA–

Data are shown as percentages for categorical variables and means (standard deviation) for continuous variables.

Abbreviations: SD – standard deviation, NA – not applicable, MI – Myocardial Infarction, AAA – Abdominal Aortic Aneurysm, cm – centimetre.

aFamily history was not reported in 18 patients.

The mean TRF length in the AAA group (5.550, standard deviation (SD)=0.605kbp), was significantly lower than that observed in the control group (5.739, SD=0.485kbp). There was a mean difference of 189bp between AAA and controls (95% Confidence Interval 77bp to 301bp, P=0.001). There was no significant change in the mean TRF length with age in both AAA and controls (6bp increase per year, SD=4; P=0.16). There was also no significant correlation between aneurysm size and mean TRF length (P=0.35). There was no significant difference in the mean TRF length between male and female subjects.

The difference in mean TRF length between subjects based on risk factors such as gender, smoking, hypertension, diabetes, history of MI and family history of AAA is shown in Table 2. Sex as an independent risk factor did not have any significant effect on the mean TRF length (P=0.99). Positive family history of AAA was the only risk factor which was significantly associated with the mean TRF length (P=0.04). Subjects with a positive family history of AAA had a significantly shorter mean TRF length (5.491, SD=0.485) compared to subjects without a family history of AAA (5.684, SD=0.502), (mean difference 192bp, Confidence interval 7bp to 378bp, P=0.02). Entering all these risk factors into a multiple regression model did not affect the relationship between AAA–control status and mean TRF length (P=0.01). The impact of each risk factor on the mean TRF length was estimated individually using a linear regression model after controlling for AAA–control status (Table 3).

Table 2. Mean (standard deviation) telomere restriction fragment length and the difference in telomere lengths between subjects based on risk factors (Students t-test).
Risk FactorMean TRF length (kbp) in subjectsMean difference95% Confidence intervalP
AbsentPresent
Male gender5.64 (0.85)5.64 (0.53)0.00−0.22 to 0.220.99
Positive smoking history (ever/current)5.68 (0.62)5.63 (0.54)0.05−0.10 to 0.200.51
Hypertension5.67 (0.54)5.61 (0.57)0.06−0.05 to 0.180.26
Diabetes mellitus (type I/type II)5.66 (0.57)5.55 (0.45)0.11−0.05 to 0.280.18
History of MI5.67 (0.54)5.55 (0.60)0.12−0.01 to 0.250.06
Family history of AAA5.68 (0.50)5.49 (0.49)0.190.01 to 0.380.04
Table 3. Effects of risk factors on mean TRF length (Standard Deviation) after adjusting for case–control status (P-values taken from linear regression model).
VariableEffect on mean TRF length (bp)P
Age (change per year)6 (4)0.16
Male gender−7 (112)0.94
Smoking28 (80)0.72
Hypertension−50 (57)0.37
Diabetes (type I or type II)−126 (82)0.12
Myocardial infarction−99 (65)0.12
Family history of AAA−174 (94)0.06
Aneurysm Size (cases only)−29 (31)0.35

Negative values indicate that the telomere length was shorter in subjects with this risk factor.

The effect of telomere length as a risk factor for AAA is shown in Table 4. With each kilo base pair decrease in mean TRF length the odds ratio for AAA was 1.99 (95% Confidence interval, 1.31–3.00, P=0.001). Compared with those in the highest quartile for mean TRF length, people in the lowest, second and third quartiles had an odds ratio of 2.30 (95% Confidence interval, 1.28–4.13, P=0.005), 1.42 (95% Confidence interval, 0.80–2.52, P=0.22), 1.07 (95% Confidence interval, 0.60–1.91, P=0.80) respectively.

Table 4. Results of binary logistic regression modelling. Only variables found to be significantly associated with AAA were retained in the model. Risk factors shown are for the presence of AAA.
BetaStandard errorPOdds ratio95% Confidence interval
Smoking2.000.37<0.00017.393.57–15.27
Telomere length0.680.210.0011.991.31–3.00
Constant−4.201.20<0.00010.02–

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Discussion 

In this study we have shown that patients with AAA have significantly shorter mean white cell TRF length compared to controls. This difference in telomere length between AAA and controls was not affected by other confounding factors such as smoking, hypertension and diabetes. In our study the risk of having AAA doubled in patients with mean leukocyte TRF length in the lowest quartile compared to patients with mean TRF length in the highest quartile.

Relatively large numbers of subjects were recruited in this study and all the subjects were well matched for age and gender. AAA is a well-defined phenotype and hence we did not find difficulty in identifying patients with AAA. We have used the International Society of Cardiovascular Surgery (ISCS)/Society for Vascular Surgery (SVS) definition19 to identify patients with AAA. The age of our subjects ranged from 56 years to 91 years as the incidence of AAA in adults is rare below 50 years of age and the prevalence increases steadily thereafter.20 We have measured telomere length using terminal restriction fragment assay (southern blot technique) rather than the recently developed assays like polymerase chain reaction or quantitative hybridization.21 Although the terminal restriction fragment assay is time consuming and laborious it measures the telomere length directly rather than measuring the telomere content.

Previous studies have shown that human leukocytes undergo age dependent telomere attrition.16, 22, 23, 24 In spite of the wide range in the age group of subjects in this study we did not find any significant decrease in mean TRF length with age in either group. In contrast we found an increase in telomere length by 6bp per year, although this did not have statistical significance. Similarly, Martin-Ruiz25 did not find significant changes in mean leukocyte telomere length with aging in subjects older than 85 years and Mukherjee26 did not find any correlation between subjects' age and leukocyte telomere length in coronary patients of Indian origin.

The exact effect of gender on telomere length and its attrition rate is not clear. Some studies5, 27, 28, 29 found that females have longer telomeres than males whereas others16, 17, 30, 31 did not find a difference. Age dependent telomere attrition was found to be higher in males compared to females and the difference disappeared in postmenopausal women.32 The possible role of estrogens on telomerase and their anti-oxidant effect could contribute to the slower telomere attrition rate in pre-menopausal women.33 In our study female subjects were all post-menopausal. Other risk factors such as hypertension, diabetes and a positive history of MI, although having a negative trend did not have a statistically significant association with mean TRF length.

The association of shortened telomeres with AAA is biologically plausible. Telomere shortening is classically thought to be due to increased cellular turnover – which occurs at an increased rate in the distal aorta compared to other tissues14 and telomere length can thus be seen to be directly related to cellular aging. However, in addition oxidative stress can directly cause telomere shortening34 and whilst there is some evidence for the role of pathways that modulate oxidative stress in the pathogenesis of AAA in both animal and human studies.35, 36, 37 Several descriptive transcriptomic studies38, 39, 40 have not consistently demonstrated a role for oxidative stress in AAA. In fact, the most consistent finding across these studies is a role for immune function in the pathogenesis of AAA – which has not been examined in relation to telomere length in AAA but associations between decreasing immune function and shortened telomere lengths have been observed in human populations.41, 42

Several limitations of our study need to be considered. Telomere length varies between different chromosomes and cells types.43 Mean TRF length is a crude way of measuring cellular telomere attrition. Critical shortening in the telomere length can occur in one chromosome without affecting the mean TRF length. Studies aimed at identifying individual chromosomal telomere length variations will help in understanding the effect of such changes on cellular function and disease. Such studies may provide an insight into the common association of cardiovascular diseases with shorter telomere length and identify culprit chromosomes. Haematological malignancies have been shown to be associated with leucocyte telomere length.44, 45 Whilst we did not screen our patients for the presence of haematological malignancy no patients reported having any such disease and this missing data is therefore unlikely to have significantly altered the results from this study. In a similar fashion every single co-morbidity suffered by each participant was not recorded. Previous myocardial infarction was used as a surrogate measure of coronary artery disease but no further assessment of systemic atherosclerosis was made (for example ankle-brachial pressure-index or history of cerebrovascular disease). We believe that the addition of multiple further covariates to our model would in all likelihood have resulted in a high chance of a type I error and, in a study of a relatively small size such as this, the minimal covariate dataset used is appropriate.

We have not examined the correlation between leukocyte telomere length and aortic wall biopsy telomere length. Although Wilson10 found a correlation, the sample size was small (20 AAA and 12 controls) and the results need to be confirmed in larger studies. In this case–control study, we cannot completely exclude the possibility that an unmeasured factor accounts for the observed relationship. A prospective longitudinal study will help in identifying the true changes in mean TRF length with age and its role in the pathogenesis of AAA. Such a prospective study will also help in identifying the possible prognostic value of leucocyte telomere length on the rate of aneurysm expansion, rupture and overall mortality.

No evaluation of telomere lengths in patients with ruptured AAA was made in this study. This data may add further information to confirm or refute the association seen in this data on intact AAA. It would be expected that patients with ruptured AAA would have even shorter telomere lengths than those with intact AAA if telomere length was associated not only with AAA but progression of AAA. Patients with ruptured AAA may exhibit an acute inflammatory response with a higher proportion of circulating leucocytes being activated rendering their DNA at risk of degradation. This would potentially affect the telomere assay in circulating leucocytes and in these patients a better choice of tissue to compare may be aortic wall specimens. No data exists in the literature examining this hypothesis.

In summary, we report a significant association between shorter leukocyte telomere length and the risk of AAA. The mean leukocyte TRF length of patients with AAA is significantly shorter compared to controls. This suggests that vascular biological aging may have a role in the pathogenesis of AAA.

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Conflict of Interest 

The authors have declared no conflict of interest.

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Funding 

None.

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References 

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PII: S1078-5884(10)00049-3

doi:10.1016/j.ejvs.2010.01.013

European Journal of Vascular & Endovascular Surgery
Volume 39, Issue 5 , Pages 559-564, May 2010

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