Published online before print October 4, 2007, doi: 10.1161/STROKEAHA.107.492231
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(Stroke. 2007;38:3070.)
© 2007 American Heart Association, Inc.
Progress Reviews |
Interleukin-6 –174G/C Polymorphism and Ischemic Stroke
A Systematic Review
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{at}ninds.nih.gov
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Abstract |
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Background and Purpose— Interleukin-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.
Methods— Electronic 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.
Results— Twelve 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.
Conclusions— Studies 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.
Key Words: acute stroke • genetics • inflammation
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Introduction |
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Stroke 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 inflammation, and infection and its associated inflammation is a known risk factor for ischemic stroke.1–5 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 atherosclerosis7–11 and cardiovascular disease12–15 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,17–20 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.18,21–26 However, 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 al27 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 associated with lower expression than the G allele in both unstimulated 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 conflicting results, with higher IL-6 levels associated with the GG genotype in some patient populations28,29 but with the CC genotype in others.30,31
Several studies have examined the IL-6 –174G/C polymorphism in relation to various ischemic and atherosclerotic cardiovascular diseases. Associations have been reported between the GG genotype and asymptomatic carotid artery atherosclerosis,32,33 risk of coronary heart disease,34 peripheral arterial occlusive disease,35 multiinfarct dementia,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 atherosclerosis30,37 and increased mortality among abdominal aortic aneurysm patients.31 Reasons for these contradictory findings are unclear.
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.16–26 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.
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Methods |
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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 polymorphism (by allele or genotype) and the primary outcome(s).
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Results |
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The PubMed MEDLINE, Scopus, and Web of Science databases returned 128, 137, and 168 abstracts, respectively. 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.21,38–49 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.
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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 occlusion48), with some examining stroke subtypes 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 significantly less frequent in patients with retinal artery occlusion.48 Four studies found the C allele or the CC genotype to be associated with ischemic stroke42,43,45 or with lacunar stroke.39 Genetic associations were sometimes found only in subpopulations, such as nonsmokers43 or patients without hypertension,38 or in interaction with fever45 or another inflammatory polymorphism.42 The remaining 2 studies found no difference in allele, genotype, or haplotype frequencies between cases and controls.21,44 All studies are summarized in the Table
.
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Discussion |
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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 discrepant results may reflect the complexity of IL-6 physiology and genuine differences between stroke subtypes and the populations studied or limitations in experimental design.
Associations with IL-6 promoter polymorphisms are inherently difficult to interpret because IL-6 has both pro- and antiinflammatory effects and complex transcriptional regulation. 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 metalloproteinases, 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 Furthermore, different cell lines may have different transcriptional regulation of IL-6.51 Thus, the effect of the –174G/C polymorphism 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 pathophysiology. For example, IL-6 may contribute differently to lipohyalinosis and fibrinoid necrosis than it does to thrombosis 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 colleagues39 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 between correlation and causation. Additionally, in case-control studies, appropriate selection of the control population 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 age52 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 exclusion of transient ischemic attack patients) is warranted in future studies to ensure certainty of the diagnosis.
In addition, only Acalovschi et al21 examined IL-6 promoter 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 allele53 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,27–31 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 facilitate 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 inappropriate comparison of adult controls44 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 reasons 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 controls, haplotype analysis, serum IL-6 measurements, and statistical adjustment for known vascular risk factors will allow further insight into the relationships between inflammation, IL-6, and stroke.
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Acknowledgments |
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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.
Disclosures
None.
Received April 25, 2007; accepted April 27, 2007.
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