Amy R. Tso, Jos G.

Merino and Steven Warach

174G/C Polymorphism and Ischemic Stroke: A Systematic Review Interleukin-6
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doi: 10.1161/STROKEAHA.107.492231
2007;38:3070-3075; originally published online October 4, 2007; Stroke.
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Interleukin-6 174G/C Polymorphism and Ischemic Stroke
A Systematic Review
Amy R. Tso, BA; Jose G. Merino, MD, MPhil; Steven Warach, MD, PhD
Background and PurposeInterleukin-6 (IL-6) is associated with atherosclerotic disease and is also a key mediator in the
inflammatory response to cerebral ischemia. Although the IL-6 174G/C promoter polymorphism has been associated
with carotid artery atherosclerosis and coronary heart disease, its relation to ischemic stroke is unclear. This review
summarizes the current literature and discusses methodological considerations for future studies.
MethodsElectronic searches were conducted in the PubMed MEDLINE, Scopus, and ISI Web of Science databases. Two
investigators independently reviewed all abstracts to identify studies examining the association between the IL-6
174G/C polymorphism and ischemic cerebrovascular events.
ResultsTwelve relevant publications were identified. Three reported on a subset of patients from a later publication,
leaving 9 independent studies. Two studies found an association between ischemic stroke and the G allele or GG
genotype, whereas 4 found an association with the C allele or CC genotype. One study found the CC genotype to be
significantly less frequent in retinal artery occlusion patients. Two studies found no association between the 174G/C
polymorphism and stroke.
ConclusionsStudies investigating stroke and the 174G/C polymorphism report conflicting results, which may reflect
the complex physiology of IL-6 and true differences between stroke subtypes and populations. However, interpretation
of published results is hindered by methodological limitations, and greater rigor and consistency in future studies will
help unravel the relationship between the 174G/C polymorphism and stroke. (Stroke. 2007;38:3070-3075.)
Key Words: acute stroke

genetics

inflammation
S
troke is a leading cause of morbidity and mortality in the
United States, and 85% of cases are ischemic in origin.
Cerebral ischemia and inflammation are closely interrelated:
ischemia is a robust stimulus for potentially damaging in-
flammation, and infection and its associated inflammation is
a known risk factor for ischemic stroke.
15
Inflammation also
contributes to ischemic events through the promotion of
atherosclerosis.
6
Functional polymorphisms of inflammatory
genes may thereby influence the incidence and outcome of
ischemic stroke.
Interleukin-6 (IL-6) is a pleiotropic cytokine associated
with atherosclerosis
711
and cardiovascular disease
1215
that
may also be a key mediator in the inflammatory response to
cerebral ischemia.
16
IL-6 levels rise in both serum and
cerebrospinal fluid after ischemic stroke,
1720
and elevated
IL-6 levels have been associated with greater stroke severity,
early neurological worsening, larger final infarct volume, and
worse clinical outcome at 3, 6, and 12 months.
18,2126
How-
ever, whether IL-6 plays a pathogenic role in tissue damage
after ischemia or is merely a marker of the magnitude of the
ischemic insult remains unclear.
In 1998, Fishman et al
27
described a G to C polymorphism
at the 174 position of the IL-6 promoter in patients with
juvenile chronic arthritis. Using transfection experiments in
human cells, they demonstrated that the C allele was associ-
ated with lower expression than the G allele in both unstimu-
lated and stimulated cells. Furthermore, in their sample of
healthy controls, IL-6 levels were nearly twice as high in
subjects with the GG genotype as in those with the CC
genotype. However, subsequent studies have reported con-
flicting results, with higher IL-6 levels associated with the
GG genotype in some patient populations
28,29
but with the CC
genotype in others.
30,31
Several studies have examined the IL-6 174G/C poly-
morphism in relation to various ischemic and atheroscle-
rotic cardiovascular diseases. Associations have been re-
ported between the GG genotype and asymptomatic carotid
artery atherosclerosis,
32,33
risk of coronary heart disease,
34
peripheral arterial occlusive disease,
35
multiinfarct demen-
tia,
36
and longer hospital and intensive care unit stays after
coronary artery bypass graft surgery. However, other
studies have found associations between the CC genotype
and asymptomatic carotid artery atherosclerosis
30,37
and
increased mortality among abdominal aortic aneurysm
patients.
31
Reasons for these contradictory findings are
unclear.
Received April 25, 2007; accepted April 27, 2007.
From the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Md, USA.
Correspondence to Steven Warach, MD, PhD, Section on Stroke Diagnostics and Therapeutics, National Institute of Neurological Disorders and Stroke,
National Institutes of Health, 10 Center Dr, Rm B1D733, MSC 1063, Bethesda, MD 20892. E-mail warachs@ninds.nih.gov
2007 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.107.492231
3070
Progress Reviews
by guest on November 26, 2013 http://stroke.ahajournals.org/ Downloaded from
It is well-established that inflammation and ischemic
stroke are interrelated, with many studies suggesting IL-6
may play a central role in the inflammatory response to
cerebral ischemia.
1626
However, although the role of IL-6 in
ischemic stroke has been extensively studied, the influence of
IL-6 genetic polymorphisms on stroke is not well understood.
The purpose of this review is to summarize the studies that
have examined the IL-6 174G/C polymorphism in relation
to ischemic stroke and to discuss the implications of these
results for future research.
Methods
Search Strategy
The PubMed MEDLINE, Scopus, and ISI Web of Science databases
were searched for publications through September 2006 using the
following terms: interleukin-6, polymorphism, and (cerebrovascular
or stroke or ischemi* or cardiovascular or brain or cerebral). For the
MEDLINE database, an additional search was conducted using the
relevant MeSH search terms (interleukin-6, genetic polymorphisms,
and cerebrovascular disorders). Two investigators (A.R.T., J.G.M.)
reviewed all abstracts and reached a consensus on which studies to
include for review. The bibliographies of these selected articles were
then examined for pertinent references.
Study Selection
Studies meeting the following criteria were included: (1) study
investigated the association between the interleukin-6 174G/C
polymorphism with any ischemic cerebrovascular event, and (2)
study published in English.
Data Extraction
The following information was extracted from the selected studies:
authors, publication year, study design, number of cases/controls/
patients, method of patient/control selection, sample ethnicity, mean
age of each group, primary outcome, and statistical measures of
association between the IL-6 174G/C single-nucleotide polymor-
phism (by allele or genotype) and the primary outcome(s).
Results
The PubMed MEDLINE, Scopus, and Web of Science
databases returned 128, 137, and 168 abstracts, respec-
tively. From the combined search, a total of 13 studies
were identified that examined ischemic stroke in relation
to the IL-6 174G/C polymorphism specifically.
21,3849
We excluded 1 article published in Chinese; this case-
control study found the GG genotype to be significantly
more frequent in transient ischemic attack patients and to
be predictive of subsequent ischemic stroke within 3
months.
49
Three of the remaining 12 articles reported on a
subset of patients from a later publication (confirmed by
the listed corresponding authors),
41,46,47
leaving 9 unique
patient populations (Table). No additional references were
found from the bibliographies of the selected articles. No
reviews on the topic were identified.
Except for one prospective, longitudinal study in cardiac
surgery patients,
42
all qualifying articles used a case-control
design. The ethnicity of all patient populations was white,
with the majority from Europe. All studies investigated the
association between the IL-6 174G/C polymorphism and the
occurrence of ischemic cerebrovascular events (including
retinal artery occlusion
48
), with some examining stroke sub-
types in addition.
41
Two studies found the G allele or the GG genotype to be
significantly more frequent in patients with ischemic
stroke.
38,40
One study found the CC genotype to be signifi-
cantly less frequent in patients with retinal artery occlusion.
48
Four studies found the C allele or the CC genotype to be
associated with ischemic stroke
42,43,45
or with lacunar
stroke.
39
Genetic associations were sometimes found only in
subpopulations, such as nonsmokers
43
or patients without
hypertension,
38
or in interaction with fever
45
or another
inflammatory polymorphism.
42
The remaining 2 studies
found no difference in allele, genotype, or haplotype frequen-
cies between cases and controls.
21,44
All studies are summa-
rized in the Table.
Discussion
Although the evidence suggests that IL-6 plays a central role
in stroke pathophysiology, the genetic studies identified in
this review report conflicting associations between the
174G/C polymorphism and ischemic stroke. These discrep-
ant results may reflect the complexity of IL-6 physiology and
genuine differences between stroke subtypes and the popula-
tions studied or limitations in experimental design.
Associations with IL-6 promoter polymorphisms are inher-
ently difficult to interpret because IL-6 has both pro- and
antiinflammatory effects and complex transcriptional regula-
tion. IL-6 is often considered to be proinflammatory because
it mediates fever and the production of acute phase reactants
after infection or injury. IL-6 contributes to postischemic
inflammation via the release of adhesins and matrix metallo-
proteinases, leading to leukocyte adhesion and migration
through the blood-brain barrier.
16
However, IL-6 also has
antiinflammatory effects including the production of IL-1ra
and TNFp55, antagonists to the potently proinflammatory
cytokines IL-1 and tumor necrosis factor (TNF)-.
50
Further-
more, different cell lines may have different transcriptional
regulation of IL-6.
51
Thus, the effect of the 174G/C poly-
morphism on IL-6 expression and the effect of IL-6 itself may
vary by situation or cell type.
Given this, it is biologically plausible that IL-6 expression
and its effects differ among stroke subtypes and populations
because of dissimilarities in vascular biology and pathophys-
iology. For example, IL-6 may contribute differently to
lipohyalinosis and fibrinoid necrosis than it does to thrombo-
sis and embolization. Also, the role of IL-6 may vary at
different stages of the disease process. Although chronically
high IL-6 levels likely contribute to thromboembolic stroke
through the promotion of atherosclerosis, high levels of IL-6
acutely after stroke could be protective through its negative
feedback on IL-1 and TNF-, cytokines that initiate the
postischemic inflammatory cascade. Lastly, Chamorro and
colleagues
39
postulated that the association of lacunar stroke
with the CC genotype instead of the GG genotype may
represent differential distribution of IL-6 receptors in cortical
versus deep brain structures. A deeper understanding of the
role of IL-6 in various cerebral ischemic processes may be the
key to explaining the contradictory associations reported.
Interpretation of the discrepant results is also hindered by
methodological limitations. Like all association studies, the
ones presented in this review lack the ability to distinguish
Tso et al IL-6 174G/C Polymorphism and Stroke 3071
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between correlation and causation. Additionally, in case-
control studies, appropriate selection of the control popula-
tion is essential. Although 8 of the 9 investigations used a
case-control design, only 2 intentionally matched control
subjects by age and sex, known risk factors for stroke.
21,40
Because the effect of the 174G/C polymorphism on IL-6
expression may be modulated by both age
52
and sex,
53
the use
of appropriately matched controls is particularly important
for IL-6 genetic studies.
In all studies except one,
38
patients underwent CT or MR
neuroimaging. However, in 2 of these studies,
39,45
patients
lacking imaging evidence of infarction were included in cases
of lacunar stroke or transient ischemic attack. An eligibility
criterion of imaging-confirmed ischemia (and therefore the
Table. Summary of Published Studies on the Incidence of Ischemic Stroke and the IL-6 174G/C Polymorphism
Reference Year Population
No. of
Cases/Controls Age* Race Test Result
P Value/
95% CI
Flex et al
40
2004 Consecutive patients with
history of ischemic stroke
237 cases 76.2 (9.4) W
2
GG genotype more frequent in
cases vs controls
0.00001
Age- and sex-matched from
same department
223 controls 76.1 (6.8) W
2
G allele more common in cases
vs controls
0.00001
Logistic
regression
For history of stroke, adjusted
OR8.1 for GG vs CC
4.016.4
Logistic
regression
For history of stroke, adjusted
OR4.5 for GC vs CC
2.48.3
Logistic
regression
NS for GG vs GC NS
Balding
et al
38
2004 Consecutive patients with
ischemic stroke
105 cases 69.0
(range 3599)
W
2
No difference in genotype
frequencies between cases and
controls
NS
Healthy blood donors 389 controls 37.1
(range 1865)
W
2
No difference in genotype
frequencies between stroke
subgroups
NS

2
G allele more frequent in stroke
patients without HTN vs stroke
patients with HTN
0.0009

2
G allele more frequent in stroke
patients without HTN vs controls
0.0027
Weger
et al
48
2005 Patients with RAO 182 cases 69.1 (11.3) W
2
CC genotype (vs GG/GC) less
frequent in RAO cases vs
controls
0.006
Ophthalmology patients
without RAO
307 controls 70.9 (11.4) W Logistic
regression
For RAO, adjusted
OR0.5 for CC vs GG/GC
0.30.9
Jenny
et al
43
2002 Patients from Cardiovascular
Health Study cohort (65 y)
with MRI-detected infarcts
248 cases 72.8 (5.3) W Logistic
regression
For stroke, adjusted OR1.5 for
presence of C allele vs absence
when comparing cases to
controls
1.052.14
Patients without
MRI-detected infarcts
randomly selected from
cohort
491 controls 72.3 (5.4) W Logistic
regression
For stroke, adjusted OR3.8 for
presence of C allele vs absence
in male nonsmokers only when
comparing cases with subclinical
disease-free controls
1.112.7
Patients from cohort without
MRI-detected infarcts and
without baseline subclinical
cardiovascular disease
249 controls
free of
subclinical
cardiovascular
disease
69.9 (3.9) W
Chamorro
et al
39
2005 Consecutive patients with
ischemic stroke
273 cases 67 (10) W Logistic
regression
No association of CC (vs GC/GG)
in all stroke pts vs controls after
adjustment
NS
Controls identified through
random digit dialing from
same geographic area
105 controls 64 (10) W
2
CC genotype more frequent in
lacunar vs nonlacunar stroke
0.03
Logistic
regression
For CC genotype, adjusted
OR3.22 for lacunar stroke vs
controls
9.11.1
Grocott
et al
42
2005 1635 cardiac surgery
patients
28 (1.7%)
patients with
ischemic stroke
within 1 week
of surgery
68 (10) W
2
No single SNP associated with
perioperative stroke
NS
1607 patients
without stroke
after surgery
63 (12) W Logistic
regression
For perioperative stroke, OR3.3
for SNP pair of CRP 3 UTR
1846C/T and IL-6 174G/C
(presence of at least 1 minor
allele at each locus vs absence)
1.48.1
(Continued)
3072 Stroke November 2007
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exclusion of transient ischemic attack patients) is warranted
in future studies to ensure certainty of the diagnosis.
In addition, only Acalovschi et al
21
examined IL-6 pro-
moter haplotypes. The 174 G to C polymorphism may
create a nuclear repressor binding site,
27
but IL-6 expression
is regulated through the interaction of several transcription
factors binding at distinct sites in the promoter region. Thus,
the effect of the 174G/C polymorphism on IL-6 expression
may depend on the surrounding genetic variations, and
associations with a single polymorphism could be due to
linkage disequilibrium with other genetic variants. For future
investigations, haplotype analysis of the 597G/A,
572G/C, 373A(n)T(n), and 174G/C polymorphisms may
be more appropriate than examination of a single nucleotide
polymorphism.
The study by Acalovschi et al was also the only one to
correlate serum IL-6 with genotype. It reported lower IL-6
levels after adjustment for infarct volume in patients with
haplotype F, the only haplotype present with a C allele
53
at
the 174 position. However, because the influence of the
174G/C polymorphism on IL-6 expression appears to vary
among diseases, with higher IL-6 levels reported with both
the GG and CC genotypes,
2731
associations between this
polymorphism and stroke are best interpreted within the
context of which genotype correlated with higher serum IL-6
levels in that study.
Final methodological considerations include timing of
sample collection and statistical analysis. Genetic samples
should be collected at the time of hospital admission to avoid
survival bias. Statistical analyses should adjust for traditional
vascular risk factors such as hypertension, hyperlipidemia,
smoking, and diabetes. Although most studies used logistic
regression to adjust for some confounding factors, greater
methodological consistency among future studies will facili-
tate the comparison of results.
In conclusion, although 2 studies found no association
between the IL-6 174G/C polymorphism and stroke, 1
examined the incidence of pediatric stroke using an inappro-
priate comparison of adult controls
44
and the other may have
been insufficiently powered because of small sample size.
21
The remaining studies found an association between ischemic
stroke and the 174G/C polymorphism, but with different
genotypes or alleles, only in specific subpopulations or stroke
subtypes, or only in interacting with other inflammatory
polymorphisms. Although these discrepant findings may
reflect methodological limitations, they likely represent the
complexity of IL-6 physiology and genuine differences in
stroke pathophysiology and populations. Elucidating the rea-
sons behind these contradictory results could lead to a
detailed understanding about IL-6 expression and its role in
stroke, and this opportunity is precisely why genetic studies
are valuable. Additional prospective studies with imaging
confirmation of ischemic disease, appropriately selected con-
trols, haplotype analysis, serum IL-6 measurements, and
statistical adjustment for known vascular risk factors will
allow further insight into the relationships between inflam-
mation, IL-6, and stroke.
Sources of Funding
This research was supported by the Division of Intramural Research
of the National Institute of Neurological Disorders and Stroke,
National Institutes of Health. Part of this research was made possible
through the Clinical Research Training Program (A.R.T.), a public-
private partnership supported jointly by the NIH and a grant to the
Foundation for the NIH from Pfizer Pharmaceuticals Group.
Table. Continued
Reference Year Population
No. of
Cases/Controls Age* Race Test Result
P Value/
95% CI
Lalouschek
et al
45
2006 Consecutive patients from
Vienna Stroke Registry (age
60) with ischemic stroke or
transient ischemic attack
404 cases median 53 (IQR
4957)
W Logistic
regression
No difference in genotype
frequencies between patients
and controls, even after
exclusion of transient ischemic
attack patients
NS
Controls free of clinically
manifest vascular disease
415 controls median 49 (IQR
4356)
W Logistic
regression
For stroke, adjusted OR4.4 for
patients with fever and GC
genotype vs no fever and GG
genotype
1.118.2
Logistic
regression
For stroke, adjusted OR5.6 for
patients with fever and CC
genotype vs no fever and GG
genotype
0.934.5
Acalovschi
et al
21
2003 Patients with ischemic stroke 34 cases 64.9 (SEM1.4) W Mann
Whitney
No difference in haplotype
frequency distribution between
cases vs controls
NS
Age- and sex-matched from
Ophthalmology Department
21 controls 64.9 (SEM1.5)
Karahan
et al
44
2005 Pediatric arterial stroke
patients
86 cases median 5.5 (range
014)
W
2
No difference in genotype or
allele frequencies between cases
and controls
NS
Healthy adults 83 controls none reported W
W indicates white; IQR, interquartile range; RAO, retinal artery occlusion; OR, odds ratio; SNP, single-nucleotide polymorphism; CRP, C-reactive protein; HTN,
hypertension; pts, patients; NS, not significant.
*Unless otherwise noted, values represent mean age (SD).
P value given for
2
test and 95% CI given for odds ratio.
Genotype analyses were limited to whites because of the relatively small number of black participants in the Cardiovascular Health Study cohort.
Prospective, longitudinal study in patients undergoing coronary artery bypass grafting, valve, or combined coronary artery bypass grafting/valve surgery using
cardiopulmonary bypass. Study patients were 80% white.
Tso et al IL-6 174G/C Polymorphism and Stroke 3073
by guest on November 26, 2013 http://stroke.ahajournals.org/ Downloaded from
Disclosures
None.
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