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(Circulation. 2001;103:2260.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Interleukin-6 (IL-6) and the Prognosis of Abdominal Aortic Aneurysms
From the Department of Vascular Surgery, Imperial College at Charing Cross Hospital (K.G.J., L.C.B., M.S., R.M.G., J.T.P.), and the Department of Cardiovascular Genetics, Rayne Institute (D.J.B., S.E.H.), London, UK.
Correspondence to Professor J.T. Powell, University Hospitals of Coventry and Warwickshire, Clifford Bridge Road, Walsgrave, Coventry CV2 2DX, UK. E-mail janet.powell{at}wh-tr.wmids.nhs.uk
 |
Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background—Abdominal aortic aneurysm is a multifactorial disorder in which inflammation is an important pathophysiological feature. In explant culture, aneurysm biopsies secrete large amounts of interleukin-6 (IL-6), and among aneurysm patients, the circulating concentration of IL-6 appears to be increased.
Methods and Results—We
investigated, in 19 patients, whether aneurysm wall was an
important source of circulating IL-6. We also tested the hypotheses, in
466 patients with a small aneurysm, that (1) high
concentrations of circulating IL-6 signaled rapid aneurysm
growth and (2) the -174 G
C polymorphism in the
IL-6 promoter predicted
survival. For 19 patients with large or inflammatory aneurysms,
the concentration of IL-6 was higher in the iliac arteries than the
brachial arteries (median difference 26.5 pg/mL, this difference
increasing with aneurysm diameter,
P=0.01). In 466 patients with
small aneurysms, the frequency of the -174 C allele
(0.40) was similar to that in a normal healthy population. Patients of
GG genotype had lower plasma concentrations of IL-6 than
patients of GC and CC genotypes (medians 1.9, 4.8, and 15.6
pg/mL, respectively, Kruskal-Wallis
P=0.047).
Cardiovascular and all-cause mortalities were lower for
patients of GG genotype than for patients of GC and CC
genotype: hazard ratios 0.32 (95% CI 0.12 to 0.93),
P=0.036, and 0.51 (95% CI 0.25
to 1.00), P=0.05, respectively.
There was no association between plasma IL-6 or
IL-6 genotype and
aneurysm growth.
Conclusions—Aortic
aneurysms appear to be an important source of circulating IL-6,
the concentration being influenced by genotype. For patients
with small aneurysms, the -174 GC
IL-6 genotype predicts
future cardiovascular
mortality.
Key Words: aneurysm • survival • interleukins • genetics
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Abdominal aortic aneurysm (AAA) is a common cardiovascular disease of increasing incidence.1 2 Patients with small AAAs (<5.5 cm in diameter) are at increased risk of cardiovascular death, but prophylactic surgical repair is not recommended.3 Inflammation appears to be an important component of the pathological process causing aneurysm expansion.4 5 Indeed, when biopsies of the aneurysm wall are placed in tissue culture, large amounts of cytokines, including interleukin (IL)-1 and IL-6 are secreted.6
Elevated circulating concentrations of cytokines have been found in several conditions in which inflammation is an important aspect of the pathology. Patients with AAA appear to have significantly higher serum concentrations of IL-1 and IL-6 than either coronary heart disease patients or control subjects.7 Furthermore, there has been a suggestion that serum IL-6 concentrations are increased among patients with early aortic dilatation.8 Circulating cytokines also are being assessed as markers of coronary heart disease,9 and in healthy men, an elevated concentration of circulating IL-6 is associated with an increased future risk of myocardial infarction.10 In the first part of the present study, we investigated the possibility that the aneurysm itself was a significant source of circulating IL-6, to explain the increased circulating levels observed in AAA patients.
IL-6 has a pivotal role in stimulating the acute-phase
response, which elevates the circulating concentrations of several
plasma proteins, including fibrinogen and C-reactive protein (CRP). The
circulating concentrations of IL-6 are likely to be influenced by
several environmental and genetic factors, including a polymorphic
site (-174 GC) in the IL-6
gene promoter.11 The
familial predisposition to AAA is well
established.12 Therefore, we
investigated the extent to which either plasma IL-6 or
IL-6 genotype predicted
aneurysm growth rate. In AAA patients, most deaths are
attributed to a cardiovascular
cause.3 Therefore, after the
recent evidence concerning IL-6 as a cardiovascular
risk factor, we also wished to investigate whether either plasma IL-6
or IL-6 genotype
predicted the survival of AAA patients.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Patients
The patients studied for aneurysm growth and survival were randomized to ultrasound surveillance as part of the UK Small Aneurysm Trial.3 Briefly, patients 60 to 76 years old with asymptomatic AAAs 4.0 to 5.5 cm in diameter were randomized to either early elective surgery or a period of ultrasound surveillance. Patients in the surveillance arm (n=527) had their aortic diameter measured either every 6 months (AAA 4.0 to 4.9 cm) or every 3 months (AAA 5.0 to 5.5 cm). When aneurysm diameter exceeded 5.5 cm, aneurysm growth rate exceeded 1 cm/y, or the aneurysm became tender, surgery was recommended. All patients were "flagged" with the Office of National Statistics (ONS) to obtain information for deaths and cause of death. Baseline resting ECGs were coded by 2 independent observers.3 A baseline peripheral venous blood sample was taken to provide cells for the extraction of DNA and plasma for the measurement of cholesterol, cotinine (by radioimmunoassay), fibrinogen, and CRP (both by immunonephelometry) and for storage at -70°C. Stored plasma was used for the measurement of IL-6. Aneurysm growth rates were calculated from linear regression analysis only in patients with
3 diameter measurements. In addition,
simultaneous blood samples from brachial and iliac arteries
were obtained from 19 other patients (17 men, 2 women; mean age 74±7
years) undergoing elective surgical resection of large or inflammatory
AAAs (diameter range 4.1 to 12.0 cm). For these 19 patients, the
posterior aortic wall thickness was measured on the CT scan by an
independent observer.
Measurement of IL-6 by ELISA
The polyclonal and monoclonal antibody pair for the
IL-6 ELISA, together with the recombinant IL-6 standard, were obtained
from R&D, and the assay was amplified with Ampak (Dako): range 3 to 300
pg/mL, coefficient of variation 10%.
IL-6
Genotyping
DNA was prepared from peripheral blood
cells and stored in 96-well arrays at -20°C. The DNA was amplified
by polymerase chain reaction as previously
described.11 After
polymerase chain reaction, genotypes were resolved by use of
the restriction endonuclease
NIaIII. The digestion
product size was determined by electrophoresis on an 8% microtiter
array diagonal gel electrophoresis
(MADGE).13 The -174 G and
-174 C alleles were characterized by 190-bp and 143-bp bands,
respectively (the 47-bp cleavage product was not
visualized).
Data Analysis
All analyses were performed with STATA
software. The distribution of both plasma IL-6 and CRP were
highly skewed, and square root (which uses 0 values) and logarithmic
transformations, respectively, were used for normalization. For IL-6,
the Shapiro-Francia test for normality showed W=0.47. All other
continuous variables (age, initial aneurysm diameter,
aneurysm growth rates, and plasma fibrinogen) were normally
distributed. The effect of IL-6 and
IL-6 genotype on
survival was considered in 2 time periods: (1) the surveillance period
and (2) the long-term survival until September 2000. For the former
analysis, patients were censored at the end of the trial (June
30, 1998) or time of aneurysm rupture and/or
surgery.
Univariate estimates of survival were calculated by the Kaplan-Meier method. Cox proportional-hazards models were used to estimate adjusted hazard ratios for the effect of IL-6 genotype on survival.
|
Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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IL-6 Concentration in Brachial and Iliac Artery Plasma
Plasma IL-6 concentration was measured in samples taken simultaneously in the brachial and iliac arteries from 19 patients. These patients were classified into 2 groups according to the aneurysm wall thickness measured on preoperative CT scan. In 16 patients the aneurysm was thin-walled, 0.2 to 0.5 cm, and in 3 patients the aneurysm was thick-walled, 1 to 2 cm. In 17 of 19 patients the concentration of plasma IL-6 was higher in the iliac arteries than the brachial arteries, median difference 26.5 pg/mL, P<0.001 (Wilcoxon matched pairs rank test). For the 16 patients with thin-walled aneurysm, there was a significant association between the IL-6 difference and aneurysm diameter, r=0.67, P=0.01 (Kendall’s tau), Figure 1
. The 3 patients with wall thickness of 1 cm had
the highest IL-6 difference (iliac-brachial artery). These 3 patients
were the only ones with inflammatory aneurysm (dense fibrotic
outer layer and adherent periaortic tissues). These findings were
confirmed by histology: all 3 patients had a thick, fibrotic adventitia
with an extensive infiltrate of inflammatory cells; from the remaining
16 patients, only 7 biopsies had been sent for histology, but none
displayed such an intense inflammatory infiltrate. For the 3 patients
with thick-walled inflammatory aneurysms, there appeared to be
a linear relationship between the IL-6 difference and AAA diameter
(Figure 1).
|
, data for 1 to 2 cm.
Plasma IL-6 Concentration and
Aneurysm Growth Rate
Stored baseline plasma was available for only 231 of
527 patients of the surveillance arm of the UK Small Aneurysm
Trial. The median plasma IL-6 concentration was 4.9 pg/mL (range 0 to
604 pg/mL). The plasma IL-6 concentrations increased with age
(regression analysis, adjusted for sex,
r=0.16,
P=0.049) but not with
self-reported smoking habit (ANOVA
P=0.9). In 25 patients whose
AAA became tender, median IL-6 concentration was 5.5 pg/mL
(interquartile range [IQR] 0 to 27 pg/mL) compared with 4.8 pg/mL
(IQR 0 to 25 pg/mL) in the remainder, Mann-Whitney test
P=0.99. There was no
association between plasma IL-6 concentration and aneurysm
growth rates
(Figure 2). The survival of patients with above-median plasma
IL-6 concentrations was similar to that of patients with below-median
concentrations, P=0.86 (data
not shown).
|
IL-6
Genotype and IL-6 Plasma Concentration
The IL-6 -174
GC genotype information was available for 466 of 527
patients. The frequency of the C allele was 0.40, similar to that
in a normal healthy
population11 with the
genotype distribution in Hardy-Weinberg equilibrium.
Table 1 shows the genotype distribution,
together with the median IL-6, fibrinogen, and CRP measures. Mean age,
sex, smoking status, and initial aneurysm diameter did not
differ between the genotypes. Patients of genotype CC
had the highest median plasma IL-6 concentration, patients of
genotype GC an intermediate plasma IL-6 concentration, and
patients of genotype GG the lowest median plasma IL-6
concentration, Kruskal-Wallis
P=0.047
(Table 1). After normalization of data by square-root
transformation, the association between the presence of the C
allele and higher plasma IL-6 concentration appeared more
significant, ANOVA P=0.003
(Table 1). This association was robust to adjustment for
age, sex, smoking status, and initial aneurysm diameter. Plasma
CRP and fibrinogen concentrations were not significantly different
between patients of different genotype
(Table 1), and this did not change after adjustment for age,
sex, and smoking status. The mean aneurysm growth rates did not
vary by genotype
(Table 1).
|
IL-6
Genotype and Cardiovascular Mortality in the
Surveillance Period
In the surveillance period, the median follow-up was 33
months, and there were 47 deaths (13 from acute myocardial infarction,
7 from stroke, 10 other cardiovascular causes, 9 from
cancer, 7 from other causes, and 1 unknown). The median time to surgery
was 35 months.3 There was a
significant association between
IL-6 genotype and
cardiovascular mortality, with patients of CC
genotype being at highest risk of
cardiovascular mortality in the surveillance period and
patients of GG genotype at lowest risk
(Table 2). The unadjusted hazard ratio was 0.32 (95% CI
0.12 to 0.95), P=0.036, and
after adjustment for age, sex, aneurysm diameter, and smoking,
the hazard ratio was 0.32 (95% CI 0.13 to 0.94),
P=0.032. For all-cause
mortality, the unadjusted hazard ratio was 0.51 (95% CI 0.25 to 1.00),
P=0.05, and after adjustment
for age, sex, aneurysm diameter, and smoking, the hazard ratio
was 0.52 (95% CI 0.24 to 1.01),
P=0.05. The Kaplan-Meier curves
for cardiovascular mortality according to
IL-6 genotype are shown
in
Figure 3.
|
|
ECG Findings, Angina, Ankle Pressures, and
IL-6 Genotype
To test whether the association between
IL-6 genotype and
cardiovascular mortality was indirect, we investigated
the association between IL-6
genotype and baseline resting ECG findings, angina as
determined by the Rose
questionnaire,14 and
ankle/brachial systolic pressure index (ABPI, mean of right and
left leg). We also performed subgroup survival analysis in
those without a history of angina or myocardial infarction (n=403). The
distribution of genotypes according to ECG status is shown in
Table 3. The frequency of the -174 C allele was 0.42
for patients with no ECG evidence of ischemia, 0.39 for
patients with possible ischemia, and 0.49 for patients with
probable ischemia, 
2
P=0.2. Among those with no
evidence of ischemia, cardiovascular mortality
was lowest for the GG genotype, hazard ratio 0.52 (95% CI 0.2
to 1.04), P=0.09. The frequency
of the -174 C allele for patients with and without a history of
angina was 0.45 and 0.42, respectively, 2
P=0.3. In patients without
history of angina or myocardial infarction, those of GG
genotype were at lowest risk of cardiovascular
mortality, hazard ratio 0.54 (95% CI 0.32 to 0.91),
P=0.02. The frequency of the
-174 C allele was 0.40 for patients with a baseline ABPI of 0.9
(n=307), compared with 0.45 for patients with ABPI <0.9 (n=154),
2
P=0.1.
|
IL-6
Genotype and Long-Term Survival
In total, there were 194 deaths in the period to
September 2000; the median time to death or censoring was 72 months
(IQR 55 to 87 months). The median time to aneurysm repair was
37 months. There was a nonsignificant trend for patients of CC
genotype to have the highest all-cause and
cardiovascular mortality
(Figure 4). Although the Kaplan-Meier curves remain separated
at 84 months, the separation is most marked in the first 3 to 4 years.
After 72 months, the survival was 71%, 66%, and 62% in patients of
GG, GC, and GG genotype, respectively, unadjusted hazard ratio
0.86 (95% CI 0.70 to 1.05),
P=0.15. Adjustment for age,
sex, smoking, and aneurysm diameter did not alter the hazard
ratio.
|
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Two novel findings of this study are that (1) the aneurysm wall appears to be an important source of circulating IL-6 and (2) the -174 G
C polymorphism of the IL-6 gene
predicted the survival of patients with small AAA kept under ultrasound
surveillance. This polymorphism also was associated with plasma
IL-6 concentrations in the AAA patients. Patients of genotype
CC had the highest plasma IL-6 concentrations and worst
survival.
Previously increased venous IL-6 concentrations have been
associated with early aortic dilatation and established aortic
aneurysms.7 8
Juvonen et al7 reported that
IL-6 concentration was similar for patients with small and large AAAs,
independent of the presence of thrombus, and that plasma
interferon-
, but not IL-6, predicted aneurysm growth. The
inference from both previous
studies7 8 was that
circulating IL-6 had an important role in aneurysm formation.
We observed that IL-6 concentration was higher in iliac artery plasma
than brachial artery plasma. By studying patients with a wide range of
aneurysm diameters (4 to 12 cm), we have shown that the
iliac-brachial difference increased with AAA diameter and was higher in
thick-walled inflammatory aneurysms
(Figure 1
). These data are a strong indication, but do not
prove, that the aneurysm is a significant source of circulating
IL-6. IL-6 from an AAA could reach the portal circulation via the
inferior mesenteric artery and vein. Hence, the IL-6
concentration in the portal circulation might be much higher than in
the peripheral venous circulation. If so, IL-6 secreted
from the AAA could stimulate the hepatic acute-phase response more
directly than peripheral sources of IL-6. Furthermore, in a
much larger study than
previously,7 we also failed
to observe an association between plasma IL-6 concentration and
aneurysm growth. Therefore, in contrast to previous
studies,7 8 we
suggest that the effect of IL-6 secretion from the aneurysm on
distant targets is more important than its effect on aneurysm
formation.
Patients with AAA have established
cardiovascular disease, and 
67% of these patients
will die of a cardiovascular
cause.3 The survival of these
patients is lower than the age- and sex-matched population both before
and after aneurysm
surgery.2 15
Therefore, if the AAA is an important source of plasma IL-6 and plasma
IL-6 predicts future myocardial
infarction,10 we might have
expected to observe an association between plasma IL-6 and
cardiovascular mortality. No such association was
observed for the 231 patients in whom IL-6 concentration was measured
in peripheral venous plasma. This was perhaps too small a
population in which to observe association, particularly when the
biological activity of IL-6 is not determined by immunoassay and IL-6
concentration is affected by diurnal variation, low-grade infection,
environmental and genetic factors, and the concentration of circulating
soluble IL-6 receptor.16 For
these latter reasons, IL-6
genotype may provide a more robust marker of
cardiovascular risk.
The association between IL-6 genotype and mortality, particularly cardiovascular mortality, was strongest during the surveillance period before aneurysm repair. The group of patients with the CC genotype, associated with the highest plasma IL-6 concentrations, had the highest mortality risk. These data from a group of fit patients were gathered prospectively and were of high quality, with no patients lost to follow-up. The association between IL-6 genotype and survival remained after adjustment for factors known to influence patient survival, eg, age and aneurysm diameter. A potential weakness of our study is the possibility that the mortality risk associated with IL-6 genotype resulted from an association of genotype with preexisting coronary artery disease. There was no evidence of a confounding association, however, between IL-6 genotype and ischemic changes on baseline ECG, history of angina, or ABPI, a marker of generalized atherosclerosis.17
During the course of the UK Small Aneurysm Trial,
>60% of the surveillance patients eventually underwent
aneurysm repair, with median time to surgery 2.9
years.3 Many of the remaining
surveillance patients may have undergone aneurysm exclusion
after the trial closed, but these later events are not recorded,
and follow-up information relates to mortality only. The overall
survival curve
(Figure 4) clearly shows the early survival disadvantage for
patients of CC genotype. Although the survival curves remain
separated, in the longer term this disadvantage becomes
nonsignificant.
Our results showed a clear association of plasma IL-6 concentration and mortality in the surveillance period with IL-6 genotype. Intriguingly, the association between the -174 C allele and higher levels of plasma IL-6 is opposite to that previously reported in healthy subjects.11 It also is in contrast to in vitro data in HeLa cells, which showed that compared with the -174 G construct, the -174 C construct showed lower basal and stimulated (lipopolysaccharide or IL-1) expression of reporter gene.11 Several explanations for this apparent discrepancy can be proposed. The relative activity of -174 alleles may be reversed in physiologically relevant cells, such as endothelial cells and macrophages, that secrete IL-6 and express IL-6 receptors. Some recent data focusing on the importance of haplotype support this hypothesis and show that -174 C constructs support higher reporter gene expression in endothelial and macrophage cell lines.18 In addition, the important determinant of plasma IL-6 concentration may not be simply the peak value of expression after an inflammatory stimulus but rather the time taken for activity to return to basal levels after stimulation. Thus, for AAA patients, the constant chronic stimulation appears to result in higher IL-6 expression from the -174 C allele than the -174 G allele. Furthermore, the overall control of IL-6 expression is extremely complex, partly because of the autocrine effects of IL-6 and its interaction with soluble IL-6 receptors.16 18 19 Therefore, in subjects with extensive atherosclerosis (most AAA patients), the association between IL-6 genotype and plasma IL-6 may be the converse of that observed in a healthy, younger population. Perhaps surprisingly, we did not detect any association between IL-6 genotype and fibrinogen or CRP. The strong effect of smoking on plasma fibrinogen and CRP, coupled with the poor reporting of smoking status,20 may explain why there was no association between these analytes and IL-6. Moreover, recent evidence indicates that in smaller samples, association of risk with fibrinogen may depend on the particular assay used.21
The secretion of IL-6 from an abdominal aortic aneurysm is likely to have important systemic effects. Exclusion of the aneurysm from the circulation is likely to diminish these effects and explain why, in AAA patients, the association between IL-6 genotype and survival is strongest in the surveillance period.
|
Acknowledgments |
|---|
The UK Small Aneurysm Trial was funded by the Medical Research Council and the British Heart Foundation; the latter also supported the experimental work reported here. We thank all the participants of the UK Small Aneurysm Trial for allowing us to study their patients.
Received October 31, 2000; revision received February 8, 2001; accepted February 8, 2001.
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 H. S. Al-Barjas, R. Ariens, P. Grant, and J. A. Scott Raised Plasma Fibrinogen Concentration in Patients With Abdominal Aortic Aneurysm Angiology, October 1, 2006; 57(5): 607 - 614. [Abstract] [PDF]
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 C. Huth, I. M. Heid, C. Vollmert, C. Gieger, H. Grallert, J. K. Wolford, B. Langer, B. Thorand, N. Klopp, Y. H. Hamid, et al. IL6 Gene Promoter Polymorphisms and Type 2 Diabetes: Joint Analysis of Individual Participants' Data From 21 Studies. Diabetes, October 1, 2006; 55(10): 2915 - 2921. [Abstract] [Full Text] [PDF]
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 L Morgan, J Cooper, H Montgomery, N Kitchen, and S E Humphries The interleukin-6 gene -174G>C and -572G>C promoter polymorphisms are related to cerebral aneurysms J. Neurol. Neurosurg. Psychiatry, August 1, 2006; 77(8): 915 - 917. [Abstract] [Full Text] [PDF]
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 Y. Liu, Y. Berthier-Schaad, M. D. Fallin, N. E. Fink, R. P. Tracy, M. J. Klag, M. W. Smith, and J. Coresh IL-6 Haplotypes, Inflammation, and Risk for Cardiovascular Disease in a Multiethnic Dialysis Cohort J. Am. Soc. Nephrol., March 1, 2006; 17(3): 863 - 870. [Abstract] [Full Text] [PDF]
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 M Libra, S S Signorelli, Y Bevelacqua, P M Navolanic, V Bevelacqua, J Polesel, R Talamini, F Stivala, M C Mazzarino, and G Malaponte Analysis of G(-174)C IL-6 polymorphism and plasma concentrations of inflammatory markers in patients with type 2 diabetes and peripheral arterial disease J. Clin. Pathol., February 1, 2006; 59(2): 211 - 215. [Abstract] [Full Text] [PDF]
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M. P.S. Sie, F. A. Sayed-Tabatabaei, H.-H. S. Oei, A. G. Uitterlinden, H. A.P. Pols, A. Hofman, C. M. van Duijn, and J. C.M. Witteman Interleukin 6 -174 G/C Promoter Polymorphism and Risk of Coronary Heart Disease: Results from the Rotterdam Study and a Meta-Analysis Arterioscler Thromb Vasc Biol, January 1, 2006; 26(1): 212 - 217. [Abstract] [Full Text] [PDF]
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 B. J. Nicklas, J. Mychaleckyj, S. Kritchevsky, S. Palla, L. A. Lange, E. M. Lange, S. P. Messier, D. Bowden, and M. Pahor Physical Function and Its Response to Exercise: Associations With Cytokine Gene Variation in Older Adults With Knee Osteoarthritis J. Gerontol. A Biol. Sci. Med. Sci., October 1, 2005; 60(10): 1292 - 1298. [Abstract] [Full Text] [PDF]
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 M. Cardellini, L. Perego, M. D'Adamo, M. A. Marini, C. Procopio, M. L. Hribal, F. Andreozzi, S. Frontoni, M. Giacomelli, M. Paganelli, et al. C-174G Polymorphism in the Promoter of the Interleukin-6 Gene Is Associated With Insulin Resistance Diabetes Care, August 1, 2005; 28(8): 2007 - 2012. [Abstract] [Full Text] [PDF]
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 M. Bhanoori, K. A. Babu, M. Deenadayal, S. Kennedy, and S. Shivaji The Interleukin-6 -174G/C Promoter Polymorphism Is Not Associated With Endometriosis in South Indian Women Reproductive Sciences, July 1, 2005; 12(5): 365 - 369. [Abstract] [PDF]
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 A. D. Shaw, A. A. Vaporciyan, X. Wu, T. M. King, M. R. Spitz, J. B. Putnam, and B. F. Dickey Inflammatory Gene Polymorphisms Influence Risk of Postoperative Morbidity After Lung Resection Ann. Thorac. Surg., May 1, 2005; 79(5): 1704 - 1710. [Abstract] [Full Text] [PDF]
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M. Weger, I. Steinbrugger, A. Haas, W. Marz, Y. El-Shabrawi, W. Weger, O. Schmut, and W. Renner Role of the Interleukin-6 -174 G>C Gene Polymorphism in Retinal Artery Occlusion Stroke, February 1, 2005; 36(2): 249 - 252. [Abstract] [Full Text] [PDF]
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 D. R. Harding, S. Dhamrait, A. Whitelaw, S. E. Humphries, N. Marlow, and H. E. Montgomery Does Interleukin-6 Genotype Influence Cerebral Injury or Developmental Progress After Preterm Birth? Pediatrics, October 1, 2004; 114(4): 941 - 947. [Abstract] [Full Text] [PDF]
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L. Pawlikowska, M. N. Tran, A. S. Achrol, C. E. McCulloch, C. Ha, D. L. Lind, T. Hashimoto, J. Zaroff, M. T. Lawton, D. A. Marchuk, et al. Polymorphisms in Genes Involved in Inflammatory and Angiogenic Pathways and the Risk of Hemorrhagic Presentation of Brain Arteriovenous Malformations Stroke, October 1, 2004; 35(10): 2294 - 2300. [Abstract] [Full Text] [PDF]
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P. Norman, C. A. Spencer, M. M. Lawrence-Brown, and K. Jamrozik C-Reactive Protein Levels and the Expansion of Screen-Detected Abdominal Aortic Aneurysms in Men Circulation, August 17, 2004; 110(7): 862 - 866. [Abstract] [Full Text] [PDF]
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 M. Mohlig, H. Boeing, J. Spranger, M. Osterhoff, A. Kroke, E. Fisher, M. M. Bergmann, M. Ristow, K. Hoffmann, and A. F. H. Pfeiffer Body Mass Index and C-174G Interleukin-6 Promoter Polymorphism Interact in Predicting Type 2 Diabetes J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1885 - 1890. [Abstract] [Full Text] [PDF]
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G. Engstrom, G. Borner, B. Lindblad, L. Janzon, and F. Lindgarde Incidence of Fatal or Repaired Abdominal Aortic Aneurysm in Relation to Inflammation-Sensitive Plasma Proteins Arterioscler Thromb Vasc Biol, February 1, 2004; 24(2): 337 - 341. [Abstract] [Full Text]
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 G. Endler, C. Marsik, C. Joukhadar, R. Marculescu, F. Mayr, C. Mannhalter, O. F. Wagner, and B. Jilma The Interleukin-6 G(-174)C Promoter Polymorphism Does Not Determine Plasma Interleukin-6 Concentrations in Experimental Endotoxemia in Humans Clin. Chem., January 1, 2004; 50(1): 195 - 200. [Abstract] [Full Text] [PDF]
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D. Harding, S. Dhamrait, A. Millar, S. Humphries, N. Marlow, A. Whitelaw, and H. Montgomery Is Interleukin-6 -174 Genotype Associated With the Development of Septicemia in Preterm Infants? Pediatrics, October 1, 2003; 112(4): 800 - 803. [Abstract] [Full Text] [PDF]
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 C. M.L. Chapman, J. P. Beilby, S. E. Humphries, L. J. Palmer, P. L. Thompson, and J. Hung Association of an allelic variant of interleukin-6 with subclinical carotid atherosclerosis in an Australian community population Eur. Heart J., August 2, 2003; 24(16): 1494 - 1499. [Abstract] [Full Text] [PDF]
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 S. Landi, V. Moreno, L. Gioia-Patricola, E. Guino, M. Navarro, J. de Oca, G. Capella, and F. Canzian Association of Common Polymorphisms in Inflammatory Genes Interleukin (IL)6, IL8, Tumor Necrosis Factor {alpha}, NFKB1, and Peroxisome Proliferator-activated Receptor {gamma} with Colorectal Cancer , Cancer Res., July 1, 2003; 63(13): 3560 - 3566. [Abstract] [Full Text] [PDF]
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 J. T. Powell and R. M. Greenhalgh Small Abdominal Aortic Aneurysms N. Engl. J. Med., May 8, 2003; 348(19): 1895 - 1901. [Full Text] [PDF]
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R. Pola, A. Flex, E. Gaetani, R. Flore, M. Serricchio, and P. Pola Synergistic Effect of -174 G/C Polymorphism of the Interleukin-6 Gene Promoter and 469 E/K Polymorphism of the Intercellular Adhesion Molecule-1 Gene in Italian Patients With History of Ischemic Stroke Stroke, April 1, 2003; 34(4): 881 - 885. [Abstract] [Full Text] [PDF]
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P. Jerrard-Dunne, M. Sitzer, P. Risley, D. A. Steckel, A. Buehler, S. von Kegler, and H. S. Markus Interleukin-6 Promoter Polymorphism Modulates the Effects of Heavy Alcohol Consumption on Early Carotid Artery Atherosclerosis: The Carotid Atherosclerosis Progression Study (CAPS) Stroke, February 1, 2003; 34(2): 402 - 407. [Abstract] [Full Text] [PDF]
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N. S. Jenny, R. P. Tracy, M. S. Ogg, L. A. Luong, L. H. Kuller, A. M. Arnold, A. R. Sharrett, and S. E. Humphries In the Elderly, Interleukin-6 Plasma Levels and the -174G>C Polymorphism Are Associated With the Development of Cardiovascular Disease Arterioscler Thromb Vasc Biol, December 1, 2002; 22(12): 2066 - 2071. [Abstract] [Full Text] [PDF]
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The United Kingdom Small Aneurysm Trial Participan Long-Term Outcomes of Immediate Repair Compared with Surveillance of Small Abdominal Aortic Aneurysms N. Engl. J. Med., May 9, 2002; 346(19): 1445 - 1452. [Abstract] [Full Text] [PDF]
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F. Basso, G. D.O. Lowe, A. Rumley, A. D. McMahon, and S. E. Humphries Interleukin-6 -174G>C Polymorphism and Risk of Coronary Heart Disease in West of Scotland Coronary Prevention Study (WOSCOPS) Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 599 - 604. [Abstract] [Full Text] [PDF]
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 M. A Vickers, F. R Green, C. Terry, B. M Mayosi, C. Julier, M. Lathrop, P. J Ratcliffe, H. C Watkins, and B. Keavney Genotype at a promoter polymorphism of the interleukin-6 gene is associated with baseline levels of plasma C-reactive protein Cardiovasc Res, March 1, 2002; 53(4): 1029 - 1034. [Abstract] [Full Text] [PDF]
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 J. Pfeilschifter, R. Koditz, M. Pfohl, and H. Schatz Changes in Proinflammatory Cytokine Activity after Menopause Endocr. Rev., February 1, 2002; 23(1): 90 - 119. [Abstract] [Full Text] [PDF]
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S.E. Humphries, L.A. Luong, M.S. Ogg, E. Hawe, and G.J. Miller The interleukin-6 -174 G/C promoter polymorphism is associated with risk of coronary heart disease and systolic blood pressure in healthy men Eur. Heart J., December 2, 2001; 22(24): 2243 - 2252. [Abstract] [PDF]
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D.J. Brull, H.E. Montgomery, J. Sanders, S. Dhamrait, L. Luong, A. Rumley, G.D.O. Lowe, and S.E. Humphries Interleukin-6 Gene -174G>C and -572G>C Promoter Polymorphisms Are Strong Predictors of Plasma Interleukin-6 Levels After Coronary Artery Bypass Surgery Arterioscler Thromb Vasc Biol, September 1, 2001; 21(9): 1458 - 1463. [Abstract] [Full Text] [PDF]
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A. J. Marian On Genetics, Inflammation, and Abdominal Aortic Aneurysm : Can Single Nucleotide Polymorphisms Predict the Outcome? Circulation, May 8, 2001; 103(18): 2222 - 2224. [Full Text] [PDF]
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F. Basso, G. D.O. Lowe, A. Rumley, A. D. McMahon, and S. E. Humphries Interleukin-6 -174G>C Polymorphism and Risk of Coronary Heart Disease in West of Scotland Coronary Prevention Study (WOSCOPS) Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 599 - 604. [Abstract] [Full Text] [PDF]
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