Journal of Vascular Surgery
Volume 46, Issue 4 , Pages 687-693, October 2007

The interleukin-10-1082 ‘A’ allele and abdominal aortic aneurysms

  • Matthew J. Bown, MD, MRCS

      Affiliations

    • Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
    • Corresponding Author InformationReprint requests: Matthew J. Bown, MD, MRCS, Vascular Surgery Research Group, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester, LE2 7LX, UK.
    • ,
  • Geraint M. Lloyd, MB, ChB, MRCS

      Affiliations

    • Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
    • ,
  • Rebecca M. Sandford, MB, ChB, MRCS

      Affiliations

    • Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
    • ,
  • John R. Thompson, BSc, PhD

      Affiliations

    • Department of Health Sciences, University of Leicester, Leicester, UK.
    • ,
  • Nicholas J.M. London, MD, FRCS, FRCP

      Affiliations

    • Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
    • ,
  • Nilesh J. Samani, MD, FRCP

      Affiliations

    • Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
    • ,
  • Robert D. Sayers, MD, FRCS

      Affiliations

    • Department of Cardiovascular Sciences, University of Leicester, Leicester, UK

Article Outline

Background

Abdominal aortic aneurysms (AAA) are caused by inflammatory processes in the wall of the aorta resulting in degradation of structural proteins. This inflammatory process is mediated, in part, by cytokines, and interleukin-10 (IL-10) is a predominately anti-inflammatory cytokine. A single nucleotide polymorphism in the promoter region of the IL-10 gene that affects transcription has been associated with AAA in a small study. The aim of this study was to determine whether this polymorphism is associated with AAA and also examine its effect on the growth of small AAA.

Methods and Results

A case control study was performed. A total of 389 patients with AAA and 404 healthy controls were recruited. IL-10-1082 polymorphisms were determined by polymerase chain reaction-based methods. In the case of patients with small AAA (<5.5 cm), serial size measurements were recorded to determine mean growth rate. There was a statistically significant difference both in allele and genotype frequencies between the case and control groups with the IL-10-1082 ‘A’ allele being more common in the AAA group (P = .006). In the AAA group, genotype frequencies were as follows: GG 84, GA 201, and AA 104. In the control group, the genotype frequencies were GG 118, GA 205, and AA 81. The odds ratio for the ‘A’ allele as a risk factor for AAA was 1.50 (95% confidence interval 1.09 to 2.07). Regression modeling revealed that the IL-10-1082 genotype was, however, not independently associated with AAA if age, tobacco use, hypertension, and history of coronary or peripheral artery disease was taken into account. There was a trend towards lower plasma IL-10 level in IL-10 AA carriers, but the IL-10 ‘A’ allele did not have any discernible effect on the growth of small AAA.

Conclusions

This study demonstrates that the IL-10-1082 ‘A’ allele is associated with AAA, although this association is likely to be secondary to an association between IL-10-1082 genotype and other markers of cardiovascular disease rather than AAA per se.

 

Abdominal aortic aneurysms are characterized by the destruction of medial elastin,1 increased collagen turnover,2 apoptotic loss of smooth muscle cells,3 and infiltration of chronic inflammatory cells.4 The structural integrity of the aortic wall depends primarily on collagen and elastin, and the degenerative changes seen in AAAs are accompanied by increased production of several members of the matrix metalloproteinase (MMP) family. The activity of MMPs is partly controlled by specific tissue inhibitors of MMPs (TIMPs),5 and an imbalance of MMPs and TIMPs is thought to result in uncontrolled destruction of elastin and collagen leading to aneurysm formation.6

Tissue macrophages are the principal source of MMPs in the aneurysm wall and form part of the chronic inflammatory infiltrate.7 The production of MMPs is regulated by cytokines, and both pro- and anti-inflammatory cytokines have been identified in the aneurysm wall. In particular, one small study found increased levels of interleukin (IL)-10 in the aortic wall of patients with AAAs compared with aortic occlusive disease.8 In a similar study, Shteinberg9 found that patients with AAA had significantly higher levels of the pro-inflammatory cytokines TNF-α and IL-1β than those with occlusive aortic disease. These inflammatory processes may also mediate the growth of small aneurysms.

Many cytokine genes contain polymorphic sites but only a small number of these polymorphisms have been shown to affect cytokine gene transcription in vitro. The IL-10 gene contains a single nucleotide polymorphism (SNP) at position -1082 in relation to the start codon. The bases present at these sites are either guanine (G) or adenine (A). The presence of an ‘A’ allele at -1082 results in a 25% reduction in IL-10 production by lymphocytes.10 The IL-10-1082 ‘A’ allele has been shown to be associated with several chronic inflammatory diseases such as systemic lupus erythematosis,11 rheumatoid arthritis,12 and juvenile rheumatoid arthritis.13 Given the role of chronic inflammation in the pathogenesis of AAA it is feasible that the IL-10 polymorphism may have a role in the development and growth of AAAs. We have previously identified in a pilot study that the IL-10-1082 ‘A’ allele is more common in patients with AAA compared with unscreened, age-matched controls.14 The aim of this study was to investigate the role of the IL-10-1082 genotype in a definitive, appropriately powered and screened replication group, and, in addition, examine the effect of this polymorphism on the growth of small AAA.

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Methods 

A case-control study was performed. Cases with AAA were recruited from the regional AAA screening program, the vascular outpatient clinics and the vascular admissions unit of a university teaching hospital. Controls were recruited from the same AAA screening program, and the general surgical unit of the same hospital. All cases and controls were screened for AAA by either ultrasonography or computed tomography. AAA was defined as abdominal aortic diameter >3 cm. Both male and female subjects were included in the study. No participants recruited in our previous study14 were included in this study group. Demographic and phenotypic data (age, gender, smoking history, family history of AAA, hypertension, ischemic heart disease, previous myocardial infarction, previous coronary artery bypass grafting, previous cerebro-vascular disease, peripheral vascular disease, diabetes mellitus, chronic airways disease, or previous cancer) were recorded for each participant.

Blood samples were taken from each participant, centrifuged, and the white cell layer stored at −80°C prior to DNA extraction using a commercially available kit utilizing the salting out method (Puregene, Gentra Systems Inc., Minneapolis, Minn). The IL-10-1082 genotype was determined by induced heteroduplex genotyping (IHG) as described previously.14, 15 Briefly, polymerase chain reaction (PCR) mixes (25 μl) contained 2.5 μl of either DNA (100 ng/μl) or heteroduplex generator (0.5 ng/μl), 8 μM each deoxy-nucleotide tri-phosphate (dNTP), 5 μM of each forward and reverse primers, 0.25 units Taq polymerase, 1 × 2.5 μl Taq polymerase buffer (Sigma Aldrich, Poole, UK) and 2.5 mM magnesium chloride (MgCl2) in heteroduplex generator reaction or 1.5 mM MgCl2 in each reaction using patient DNA. PCR parameters, optimised for a Perkin Elmer 480 Thermal Cycler (Perkin Elmer, Waltham, Mass.), were an initial denaturation at 95°C for 5 minutes, followed by 30 cycles of denaturation at 95°C for 1 minute, annealing at 57°C for 1 minute, and extension at 72°C for 1 minute, with a final extension at 72°C for 5 minutes.

Following the initial PCR step, equal volumes (12 μl) of genomic DNA and heteroduplex generator amplicons were mixed, heated to 95°C for 5 minutes, and then allowed to cool to 45°C over 25 minutes to allow DNA heteroduplex formation. Heteroduplexes were stained with ethidium bromide solution (Sigma, UK) and resolved on 15% TBE polyacrylamide minigels (27.5:1 acrylamide:bis, Bio-Rad, Hercules, Calif) run for 3 hours at a constant 100 V. Gels were visualised using ultraviolet light.

In a subgroup where samples could be transported back to the laboratory according to the experimental protocol (on ice and within one hour of sampling) and where the subjects were at rest in an outpatient setting (ie, nonperi- or postoperative cases/controls), plasma IL-10 levels were determined by ELISA (Biosource, Paisley, UK) (Intra-assay coefficient of variation 10.1%, inter-assay coefficient of variation 10.3%). All of these study participants were those attending outpatient clinics, and all of those with AAA were preoperative cases. To determine AAA growth rates and to determine whether IL-10-1082 genotype had any effect on AAA growth, cases identified with small AAA (3-5.5 cm) or those unsuitable for surgery were followed up by serial ultrasonography at the following intervals depending on the aneurysm diameter: 12 months if <4 cm, 6 months if 4 cm to 5 cm, and 3 months if >5 cm. In addition, historical data detailing previous AAA size was recorded for each patient with an AAA where this had been assessed.

Separate power calculations were performed using the results from our previous study14 to ensure 80% power to detect differences in both IL-10-1082 allele and genotype frequency between the case and control groups (alpha = 0.001). These calculations determined that 290 cases and 290 controls would be required to detect the same difference in allele frequency as previously observed and 314 in each group for the purposes of detecting differences in genotype frequency.16

Tests for deviance from Hardy-Weinberg equilibrium and comparisons between genotype frequency in the case and control groups was determined using binary logistic regression. Binary logistic regression was also used to construct separate models for IL-10 allele and genotype as a risk for AAA adjusted for age and other recorded patient demographics. Covariates were included in the model if they had a statistically significant effect (alpha = 0.05). IL-10 concentrations were compared between groups using one-way ANOVA and Student t-test. Mean AAA growth rates were compared by Student t-test and ANOVA. All statistical tests were carried out using SPSS v12.0 (SPSS Inc., Chicago, Ill).

Ethical approval for the study was obtained from the Leicestershire Research Ethics Committee, and each participant consented to their inclusion in the study.

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Results 

In total, 793 participants were included in the study. The AAA group consisted of 389 individuals with median age of 71 years (range 52 years to 94 years) and median aortic diameter of 5.3 cm (range 3.0 cm to 12 cm). One hundred eight (27.7%) of the patients in the AAA group had previously undergone AAA repair; 404 control patients with a median age of 65 years (range 52 years to 94 years) and median aortic diameter of 1.8 cm (range 1.4 cm to 2.4 cm) were recruited. Demographic data for both groups are shown in Table I. Hypertension, smoking, ischemic heart disease, and chronic obstructive pulmonary disease were more common in the AAA group who were also older than the control group.

Table I. Numbers and percentages of cases and controls with associated previously diagnosed pathology
Control (n = 404)AAA (n = 389)
NPercentagenPercentage
Female92%349%
Male39598%35591%
Age group (years):
50-5920%113%
60-6933884%15641%
70-794411%16843%
80+205%5413%
Current smoker5714%9725%
Prior smoker26666%36393%
Family history113%174%
Hypertension17944%28273%
IHD6316%12131%
MI4511%9324%
CABG184%4913%
CVA338%6116%
PVD236%9123%
Diabetes379%318%
Cancer296%277%
COPD328%4712%

IHD, Ischemic heart disease; MI, myocardial infarction; CABG, coronary artery bypass graft; CVA, stroke; PVD, peripheral vascular disease; COPD, chronic obstructive pulmonary disease.

IL-10-1082 allele/genotype frequencies 

Both AAA and control groups were in Hardy-Weinberg equilibrium. Genotype and allele frequencies are shown in Table II. There was a statistically significant difference both in allele and genotype frequencies between the case and control groups with the IL-10-082 ‘A’ allele being more common in the AAA group (P = .014). The odds ratio for the IL-10-1082 ‘A’ allele as a risk for AAA was 1.50 (95% confidence interval 1.09 to 2.07). Each additional ‘A’ allele had an increasing effect on the odds of AAA. The ‘GA’ genotype was associated with an odds ratio of 1.38 (95% confidence interval 0.98 to 1.94, P = .07), and the odds ratio for the ‘AA’ genotype was 1.76 (95% confidence interval 1.21 to 2.70, P = .004).

Table II. Genotype and allele frequencies in the AAA and control groups
Control (n = 404)AAA (n = 389)P value⁎
nPercentageNPercentage
GG11829%8421%P = .016
GA20551%20152%
AA8120%10427%
G allele44155%36947%P = .014
A allele36745%40953%

⁎Binary logistic regression.

To adjust for the effect of the differing demographics and ages between the case and control groups a binary logistic regression model was developed, initially inputting all variables into the model and subsequently rejecting those that failed to reach statistical significance (ischemic heart disease, previous cerebrovascular accident, diabetes, cancer, chronic obstructive pulmonary disease, and history of myocardial infarction). The results are shown in Table III. This model demonstrated that the effect of IL-10 genotype became nonsignificant after adjusting for the demographic differences between the case and control groups.

Table III. Results of binary logistic regression modeling to adjust for the effect of covariates
POdds ratio95% CI
IL-10 AA (vs GG).1341.4480.836to1.916
IL-10 GA (vs GG).2661.2650.892to2.350
Male gender.0033.6161.535to8.517
Age.0001.1311.097to1.166
Current smoker.0041.8891.230to2.900
Prior smoker.0007.4584.316to12.886
Family history.0024.3401.736to10.849
Hypertension.0002.2051.547to3.143
Previous CABG.0003.1391.669to5.903
PVD.0012.4931.452to4.280
Model statistics: Beta = −11.369 (SE 1.16, P < .001)

CABG, Coronary artery bypass graft; PVD, peripheral vascular disease.

Non-significant covariates excluded from model: ischemic heart disease, previous cerebrovascular accident, diabetes, cancer, chronic obstructive pulmonary disease, and history of myocardial infarction.

Plasma IL-10 concentration and genotype 

One hundred nineteen controls and 131 cases had plasma IL-10 levels assayed. There was no significant difference in IL-10 levels between these two groups. Those with AAA had a mean IL-10 level of 0.802 pg/ml (95% confidence interval 0.615 pg/ml to 1.045 pg/ml), and those in the control group 0.904 pg/ml (95% confidence interval 0.737 pg/ml to 1.111 pg/ml) (P = .485, Student t-test) (Statistical analysis was performed on log-transformed data but results are presented as untransformed values). There was no significant correlation between AAA size and IL-10 levels in the case group (P = .34, Pearson correlation). There was no difference in IL-10 levels across the three IL-10 genotypes (P = .684, one way ANOVA) with IL-10 levels as follows: ‘GG’ genotype 0.938 pg/ml (95% confidence interval 0.703 pg/ml to 1.253 pg/ml, n = 67), ‘GA’ genotype 0.853 pg/ml (95% confidence interval 0.651 pg/ml to 1.118 pg/ml, n = 113), ‘AA’ genotype 0.767 pg/ml (95% confidence interval 0.554 pg/ml to 1.061 pg/ml, n = 70). The presence of one or more ‘A’ alleles had no effect on plasma IL-10 levels (P = .483, Student t-test) (GG genotype 0.938 pg/ml (95% confidence interval 0.703 pg/ml to 1.253 pg/ml, n = 67), GA or AA genotype 0.819 pg/ml (95% confidence interval 0.667 pg/ml to 0.993 pg/ml, n = 183).

Growth of small AAA 

Of the 389 participants with AAA, 178 had two or more serial measurements of aortic diameter, thereby allowing expansion rate to be calculated (966 total observations, median 5, total follow up 591.8 person-years). Mean growth rate was 0.267 cm/year (standard deviation 0.280 cm/y, range 0.00 cm/y to 2.40 cm/y). There was no statistically significant difference in mean growth rate between the three different IL-10-1082 genotypes, however, there was a trend toward increasing growth rate with increasing numbers of ‘A’ alleles present. The presence of either a G allele or ‘A’ allele at the IL-10-1082 locus also had no effect on mean growth rate (Table IV).

Table IV. Mean growth rates observed in patients with AAA grouped according to IL-10-1082 genotype and allele possession
nMean growth rate (cm/y)Standard deviationP
Genotype
GG370.2240.235.468(ANOVA)
GA990.2700.231
AA420.3010.398
G allele
Present1360.2570.232.375Student t-test
Absent420.3010.398
A allele
Present1410.2790.290.283Student t-test
Absent370.2240.235

ANOVA, Analysis of variance.

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Discussion 

This study demonstrates that the IL-10-1082 ‘A’ allele is associated with AAA, although in terms of risk, traditional markers of aneurysmal disease (age, tobacco use) have a much greater influence on the development of AAA than this SNP. After controlling for age and other common demographic factors, IL-10 genotype was no longer significantly associated with AAA. Neither IL-10-1082 genotype nor the ‘A’ allele can be considered as a genetic marker for AAA. Indeed, in the AAA group, 21% did not possess an ‘A’ allele at all, and in the control group, a similar proportion of individuals were homozygous for the ‘A’ allele. It is more likely, therefore, that IL-10 genotype is associated with one of the other risk factors for AAA identified in this study rather than directly with AAA (hypertension or coronary artery disease for example).

The IL-10-1082 allele appeared to be associated with AAA in a codominant manner, with each additional ‘A’ allele at this SNP associated with increasing risk of AAA. This finding is in keeping with our previously reported association of this SNP with AAA in a separate case-control study group. There was no evidence that this SNP affected circulating IL-10 levels and whilst there was a trend towards accelerated growth of small AAA with each additional ‘A’ allele at this locus, this finding was not statistically significant.

The IL-10-1082 ‘A’ allele has been shown to be associated with other diseases such as systemic lupus erythematosis,11 rheumatoid arthritis,12 juvenile rheumatoid arthritis,13 renal cell carcinoma,17 prostate cancer,18 breast cancer,19 and malignant melanoma.20 Studies have been performed to determine any association between urological malignancy and AAA and whilst several case reports exist describing coexisting AAA and renal cell carcinoma21, 22 studies designed to determine whether these associations are true have determined that these are chance findings alone rather than a true association.23 None of the other diseases above have been demonstrated to have any association with AAA and, indeed, given the gender associations of both breast cancer and AAA, these two diseases in particular would seem to be unlikely to be related.

To our knowledge, this is the largest single genetic association study of AAA to date, almost double the size of any previous study24 and one of the few studies that has demonstrated significant findings in a replication group, albeit not after multivariate analysis. The failure of the multivariate analysis to demonstrate the same associations seen in the preliminary study analysis and our previous study is disappointing. The most obvious conclusion is that there is no association between the IL-10-1082 SNP and AAA, but discrepancies between the demographic constitution of the case and control groups, especially in terms of age, may have contributed to this failure. The most obvious nonenvironmental (fixed) difference between the two groups was age. We believe that this is unlikely to have significantly contributed to the lack of findings. Every control participant in this study had undergone ultrasonographic confirmation that no AAA was present and similarly all in the case group had confirmed AAA at the time they were recruited into the study. The main reason for the difference in ages was the large number of male controls aged 65 years (n = 231) and 66 years (n = 89) recruited from the regional AAA screening program. This resulted in the skewed age distribution of the controls. Data from AAA screening programs demonstrates that very few of those without AAA at this age go on to develop AAA in the future.25 It is, therefore, unlikely that a significant number of these controls would go on to develop AAA and “cross over” into the case group, and since genotype is constant over time, the allele and genotype frequencies of this group would remain consistent assuming that this study population is a random sample of the whole population. Indeed, if the regression model is constructed without including age as a covariate, not surprisingly, IL-10 genotype becomes more significant with the odds ratios for AAA of 1.53 (95% confidence interval 0.97 to 2.42 (P = .07)) for those with an AA genotype and an odds ratio of 1.32 (95% confidence interval 0.89 to 1.94 (P = 0.17)) for those with an GA genotype.

The necessity to control for demographic factors in the multivariate analysis obviously also contributes to the finding that IL-10 genotype was not associated with AAA after multivariate analysis. One solution to this problem would have been to match cases and controls precisely for all demographic factors; however, this would have led to two main problems. First, recruitment into the study would have taken several years and resulted in a noncontemporaneous dataset. Second, this could have resulted in “over-matching”, a phenomenon that occurs when case and control groups are matched for variables that are related to the disease in question.26 In this case, those variables (other than the fixed variables age and gender) that were significant in the logistic regression model were smoking history, family history of AAA, previous coronary artery bypass graft, and peripheral vascular disease. All of these could be seen to be associated with AAA, and it is likely that they were significant in the regression model for that very reason. This principally informs us that these factors are more significantly associated with AAA than IL-10 genotype.

A further limitation of this study is the inclusion of patients with both small AAA (less than 5 cm) and large AAA (greater than 5 cm) together in the same analysis. It is recognized that there are differences in the vascular biology of the AAA wall between small and large AAA.27 It may be that further association studies comparing controls, patients with small AAA, and patients with large AAA would be able to determine the role of IL-10 at different stages of AAA development, however, each separate group would need to be of a sample size similar to the whole sample size of this study.

There is clear evidence that genetics contribute to the pathogenesis of AAA. Patients with first degree relatives with AAA are at increased risk of AAA themselves.28, 29, 30 Previous studies examining potential candidate genes for AAA have shown that a deletion/insertion in the angiotensin converting enzyme (ACE) gene that is associated with elevated plasma ACE levels has been shown to be more common in patients with AAA than in control groups.31, 32 Other genetic polymorphisms that have been shown to be associated with AAA are an estrogen receptor beta (ER) single nucleotide polymorphism (SNP),33 a haem oxygenase I (HOI) promoter dinucleotide repeat,34 a methylene tetrahydrofolate reductase (MTHFR) SNP,35 a platelet activating factor acetyl-hydrolase (PAFAH) SNP,36 a common chemokine receptor-5 (CCR-5) insertion/deletion,37 a matrix metallo-proteinase-9 (MMP-9) SNP,38 and two tissue inhibitor of metallo-proteinase-1 (TIMP-1) SNPs.24 In addition, some genetic polymorphisms have been shown to be associated with growth of small AAA but not necessarily the presence of AAA per se.39

In the majority of the studies above the findings are biologically plausible. An ACE promoter deletion associated with high plasma ACE levels is commoner in patients with AAA and since high ACE leads to high angiotensin II, and this is over-expressed in the wall of AAA, the authors suggest that this may be a causal link.31, 32 Patients with AAA have been shown to have a higher frequency of long HOI promoter dinucleotide repeats, which impairs the ability of cells to upregulate the production of HOI in response to stimuli. This reduction in HOI which is an antioxidant and anti-inflammatory was postulated by the authors to be related to the inflammatory degradation of the aortic wall in AAA.34 Elevated plasma homocysteine levels have been shown to be associated with vascular diseases such as AAA and a SNP in the MTHFR gene which results in reduced MTHFR activity, thus, leading to high levels of plasma homocysteine is more common in patients with AAA.35

However, none of the above studies, including this one have demonstrated a single genetic locus that could be used as a marker for AAA. This suggests that there may be multiple genetic factors that lead to an individual being genetically predisposed to the development of AAA. The pattern of inheritance of AAA is not precisely known and various different models have been suggested. In a study of 41 patients with AAA from 16 families, Tilson40 found that there were two probable modes of inheritance, a common X-linked model and a rarer autosomal dominant model, but stated that a multifactorial mode of inheritance was possible. Majumder41 studied 91 patients with AAA and using segregation analysis found that a nongenetic model was not possible and that autosomal recessive inheritance was the most likely. Powell,42 Verloes,43 and van Keulen44 suggested multifactorial, autosomal dominant, and autosomal dominant with incomplete penetrance were the likely modes of inheritance. The largest study to date, which includes the authors of three of the previous studies42, 43, 44 as coauthors and appears to include their subjects, is that by Kuivaniemi.45 In this study, a total of 233 families with 653 documented AAA were examined and multiple differering inheritance patterns were observed: autosomal dominant (25%), autosomal recessive (72%), and autosomal dominant with incomplete penetrance (3%). The authors suggest that this demonstrates a multifactorial genetic mode of inheritance for AAA.

The hypothesis that low IL-10 producer genotype is associated with AAA is biologically plausible. IL-10 is also a potent anti-inflammatory agent. It is feasible that low IL-10 levels lead to disregulation of the proinflammatory cascades in the wall of the aorta and, thus, AAA formation. Whilst candidate gene approaches such as in this study and those discussed may go some way to explaining the genetic pathogenesis of AAA it is likely that the potential for this approach is limited in diseases with multifactorial genetic pathogeneses. Currently, a number of studies of complex genetic diseases utlilizing whole genome association approaches are underway, and if these initial experiments demonstrate this to be a robust approach, then given the heritability of AAA, which is similar to if not greater than some other complex traits, it would be appropriate to move to this approach in appropriately powered cohorts.

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Author contributions 


Conception and design: MB, GL, RDS

Analysis and interpretation: MB, GL, JT, RDS

Data collection: GL, RMS

Writing the article: MB, GL, RMS, NL, NS, RDS

Critical revision of the article: JT, NL, NS, RDS

Final approval of the article: MB, GL, RMS, JT, NL, NS, RDS

Statistical analysis: MB, JT

Obtained funding: NL, NS, RDS

Overall responsibility: MB, RDS

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 Competition of interest: none.CME article

PII: S0741-5214(07)00996-2

doi:10.1016/j.jvs.2007.06.025

Journal of Vascular Surgery
Volume 46, Issue 4 , Pages 687-693, October 2007

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