Correlation between Interleukin-6 174G/C Polymorphism and Ischemic Stroke: A Meta-Analysis_Chinese Journal of Evidence-Based Medicine

Authors：

LI Binghu , ZHANG Lili , YIN Yanwei , PI Yan , YANG Qingwu , FANG Chuanqin , GAO Changyue , WANG Jingzhou ,  LI Jingcheng

Department of Neurology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China;

Corresponding author：

LI Jingcheng, Email: lijingcheng11@yahoo.com.cn

Keywords：

Ischemic stroke; Interleukin-6; 174 G/C; Gene polymorphism; Meta-analysis

DOI：

10.7507/1672-2531.20120091

Video：

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Objective 　To explore the correlation between interleukin-6 (IL-6) 174G/C polymorphism and ischemic stroke risks.
Methods 　Systematic searches of electronic databases as CBM, CNKI, PubMed, MEDLINE and EMbase were performed. Meta-analysis was conducted by using RevMan 5.1.2 and Stata 11.0 software. The pooled odds ratios (ORs) with 95% confidence intervals (95%CIs) were performed. Publication bias was tested by funnel plot, Egger’s regression test and Begg’s test. Sensitivity analysis was made by repeating the fixed effects model or random effects model Meta-analysis with each of the studies individually removed.
Results 　A total of 11 publications with 12 studies were identiﬁed. The results of meta-analyses showed no signiﬁcant difference was found in the correlation between IL-6 174G/C polymorphism and ischemic stroke risks (for G/C vs. G/G: OR=0.98, 95%CI 0.78 to 1.24; for C/C vs. G/G: OR=0.75, 95%CI 0.38 to 1.50; for dominant inheritance model: OR=0.93, 95%CI 0.68 to 1.28; for recessive inheritance model: OR=0.80, 95%CI 0.45 to 1.42). In the subgroup analyses on ethnicity, no signiﬁcant correlation was found. But in the subgroup analyses on source of control population, the hospital-based subgroup showed IL-6 174G/C polymorphism was the protective factor of ischemic stroke (for G/C vs. G/G: OR=0.56, 95%CI 0.40 to 0.79; for C/C vs. G/G: OR=0.17, 95%CI 0.11 to 0.27; for dominant inheritance model: OR=0.40, 95%CI 0.29 to 0.55; for recessive inheritance model: OR=0.24, 95%CI 0.16 to 0.37).
Conclusion 　Meta-analysis bly suggests that the correlation between IL-6 174 G/C polymorphism and ischemic stroke is not significantly different.

Citation： LI Binghu,ZHANG Lili,YIN Yanwei,PI Yan,YANG Qingwu,FANG Chuanqin,GAO Changyue,WANG Jingzhou,LI Jingcheng. Correlation between Interleukin-6 174G/C Polymorphism and Ischemic Stroke: A Meta-Analysis. Chinese Journal of Evidence-Based Medicine, 2012, 12(5): 563-569. doi: 10.7507/1672-2531.20120091 Copy

1.	Lloyd-Jones D, Adams RJ, Brown TM, et al. Executive summary: heart disease and stroke statistics-2010 update: a report from the American Heart Association. Circulation, 2010, 121(7): 948-954.
2.	Dichgans M. Genetics of ischaemic stroke. Lancet Neurol, 2007, 6(2): 149-161.
3.	Humphries SE, Morgan L. Genetic risk factors for stroke and carotid atherosclerosis: insights into pathophysiology from candidate gene approaches. Lancet Neurol, 2004, 3(4): 227-235.
4.	Castillo J, Rodriguez I. Biochemical changes and inflammatory response as markers for brain ischaemia: molecular markers of diagnostic utility and prognosis in human clinical practice. Cerebrovasc Dis, 2004, 17 (Suppl 1): 7-18.
5.	Pasarica D, Gheorghiu M, Topârceanu F, et al. Neurotrophin-3, TNF-α and IL-6 relations in serum and cerebrospinal fluid of ischemic stroke patients. Roum Arch Microbiol Immunol, 2005, 64(1-4): 27-33.
6.	Smith CJ, Emsley HC, Gavin CM, et al. Peak plasma interleukin-6 and other peripheral markers of inflammation in the first week of ischaemic stroke correlate with brain infarct volume, stroke severity and long-term outcome. BMC Neurol, 2004, 4: 2.
7.	Georges JL, Loukaci V, Poirier O, et al. Interleukin-6 gene polymorphisms and susceptibility to myocardial infarction: the ECTIM study. Etude Cas-TÊmoin de l’infarctus du Myocarde. J Mol Med, 2001, 79(5-6): 300-305.
8.	Strand M, Soderstrom I, Wiklund PG. Polymorphisms at the Osteoprotegerin and Interleukin-6 Genes in Relation to First-Ever Stroke. Cerebrovasc Dis, 2007, 24(5): 418-425.
9.	Marousi S, Antonacopoulou A, Karakantza M. Functional inﬂammatory genotypes: are they useful in the prediction of age of onset and long-term outcome of an ischaemic stroke? J Neurol, 2011, 258 (Suppl 1): S10.
10.	Ma S, Jiang LY, Dong ML, et al. Relation of polymorphism at -174 site of the interleukin-6 gene control region with the occurrence and development of disease in aged patients with cerebral infarction. Chinese Journal of Clinical Rehabilitation, 2004, 8(22): 4508-4509.
11.	Chakraborty B, Agarwal S, Vishnoi G. Interleukin-6 Promoter Polymorphism Predicts Stroke Severity and Outcome in Acute Ischemic Stroke Patients from North India. Stroke, 2011, 42(3): e266.
12.	Revilla M, Obach V, Cervera A, et al. A -174G/C polymorphism of the interleukin-6 gene in patients with lacunar infarction. Neurosci Lett, 2002, 324(1): 29-32.
13.	Pola R, Flex A, Gaetani E, et al. 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, 2003, 34(4): 881-885.
14.	Greisenegger S, Endler G, Haering D, et al. The (174) G/C polymorphism in the interleukin-6 gene is associated with the severity of acute cerebrovascular events. Thromb Res, 2003, 110(4): 181-186.
15.	Flex A, Gaetani E, Papaleo P, et al. Proinﬂammatory genetic proﬁles in subjects with history of ischemic stroke. Stroke, 2004, 35(10): 2270-2275.
16.	Balding J, LivingstoneWJ, Pittock SJ, et al. The IL-6 G-174C polymorphism may be associated with ischaemic stroke in patients without a history of hypertension. Ir J Med Sci, 2004, 173(4): 200-203.
17.	Chamorro A, Revilla M, Obach V, et al. The -174G/C polymorphism of the interleukin 6 gene is a hallmark of lacunar stroke and not other ischemic stroke phenotypes. Cerebrovasc Dis, 2005, 19(2): 91-95.
18.	Karahan ZC, Deda G, Sipahi T, et al. TNF-alpha -308G/A and IL-6 -174 G/C polymorphisms in the Turkish pediatric stroke patients. Thromb Res, 2005, 115(5): 393-398.
19.	Lalouschek W, Schillinger M, Hsieh K, et al. Polymorphisms of the inflammatory system and risk of ischemic cerebrovascular events. Clin Chem Lab Med, 2006, 44(8): 918-923.
20.	Banerjee I, Gupta V, Ahmed T, et al. Inflammatory system gene polymorphism and the risk of stroke: A case-control study in an Indian population. Brain Res Bull, 2008, 75(1): 158-165.
21.	Tong Y, Wang Z, Geng Y, et al. The association of functional polymorphisms of IL-6 gene promoter with ischemic stroke: analysis in two Chinese populations. Biochem Biophys Res Commun, 2010, 391(1): 481-485.
22.	刘东芳, 陈乃耀, 王大力, 等. 唐山地区汉族人群脑梗死患者IL-6基因-174G/C多态性研究. 现代预防医学, 2010, 37(18): 3419-3422.
23.	尤劲松, 黄培新, 刘茂才, 等. 脑梗死患者ICAM-1基因K469E及IL-6基因-174G/C多态性研究. 中国老年学杂志, 2007, 27(16): 1580-1582.
24.	张艳萍, 张蕴莉, 方伯言. 炎性因子IL-6、ICAM-1基因多态性与脑梗死的相关性. 医学综述, 2008；14(4): 539-541.
25.	张江, 王大力, 陈乃耀, 等. 唐山地区汉族人群脑梗死患者IL-6基因-174G/C多态性研究. 中风与神经疾病杂志, 2010, 27(9): 837-839.
26.	肖慧, 谷文萍, 梁静, 等. 白细胞介素-6基因多态性与动脉粥样硬化性脑梗死的关系. 中国神经精神疾病杂志, 2011, 37(1): 11-14.
27.	全国第四届脑血管病学术会议. 各类脑血管病的诊断要点. 中华神经科杂志, 1996, 29(6): 379-380.
28.	Wood PH. Appreciating the consequences of disease: the international classification of impairments, disabilities, and handicaps. WHO Chron, 1980, 34(10): 376-380.
29.	Wells GA, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa Health Research Institute. www.ohri.ca/programs/clinical_epidemiology/oxford.asp (accessed Oct 20, 2011).
30.	Clark WM, Rinker LG, Lessov NS, et al. Time course of IL-6 expression in experimental CNS ischemia. Neurol Res, 1999, 21(3): 287-292.

1. Lloyd-Jones D, Adams RJ, Brown TM, et al. Executive summary: heart disease and stroke statistics-2010 update: a report from the American Heart Association. Circulation, 2010, 121(7): 948-954.
2. Dichgans M. Genetics of ischaemic stroke. Lancet Neurol, 2007, 6(2): 149-161.
3. Humphries SE, Morgan L. Genetic risk factors for stroke and carotid atherosclerosis: insights into pathophysiology from candidate gene approaches. Lancet Neurol, 2004, 3(4): 227-235.
4. Castillo J, Rodriguez I. Biochemical changes and inflammatory response as markers for brain ischaemia: molecular markers of diagnostic utility and prognosis in human clinical practice. Cerebrovasc Dis, 2004, 17 (Suppl 1): 7-18.
5. Pasarica D, Gheorghiu M, Topârceanu F, et al. Neurotrophin-3, TNF-α and IL-6 relations in serum and cerebrospinal fluid of ischemic stroke patients. Roum Arch Microbiol Immunol, 2005, 64(1-4): 27-33.
6. Smith CJ, Emsley HC, Gavin CM, et al. Peak plasma interleukin-6 and other peripheral markers of inflammation in the first week of ischaemic stroke correlate with brain infarct volume, stroke severity and long-term outcome. BMC Neurol, 2004, 4: 2.
7. Georges JL, Loukaci V, Poirier O, et al. Interleukin-6 gene polymorphisms and susceptibility to myocardial infarction: the ECTIM study. Etude Cas-TÊmoin de l’infarctus du Myocarde. J Mol Med, 2001, 79(5-6): 300-305.
8. Strand M, Soderstrom I, Wiklund PG. Polymorphisms at the Osteoprotegerin and Interleukin-6 Genes in Relation to First-Ever Stroke. Cerebrovasc Dis, 2007, 24(5): 418-425.
9. Marousi S, Antonacopoulou A, Karakantza M. Functional inﬂammatory genotypes: are they useful in the prediction of age of onset and long-term outcome of an ischaemic stroke? J Neurol, 2011, 258 (Suppl 1): S10.
10. Ma S, Jiang LY, Dong ML, et al. Relation of polymorphism at -174 site of the interleukin-6 gene control region with the occurrence and development of disease in aged patients with cerebral infarction. Chinese Journal of Clinical Rehabilitation, 2004, 8(22): 4508-4509.
11. Chakraborty B, Agarwal S, Vishnoi G. Interleukin-6 Promoter Polymorphism Predicts Stroke Severity and Outcome in Acute Ischemic Stroke Patients from North India. Stroke, 2011, 42(3): e266.
12. Revilla M, Obach V, Cervera A, et al. A -174G/C polymorphism of the interleukin-6 gene in patients with lacunar infarction. Neurosci Lett, 2002, 324(1): 29-32.
13. Pola R, Flex A, Gaetani E, et al. 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, 2003, 34(4): 881-885.
14. Greisenegger S, Endler G, Haering D, et al. The (174) G/C polymorphism in the interleukin-6 gene is associated with the severity of acute cerebrovascular events. Thromb Res, 2003, 110(4): 181-186.
15. Flex A, Gaetani E, Papaleo P, et al. Proinﬂammatory genetic proﬁles in subjects with history of ischemic stroke. Stroke, 2004, 35(10): 2270-2275.
16. Balding J, LivingstoneWJ, Pittock SJ, et al. The IL-6 G-174C polymorphism may be associated with ischaemic stroke in patients without a history of hypertension. Ir J Med Sci, 2004, 173(4): 200-203.
17. Chamorro A, Revilla M, Obach V, et al. The -174G/C polymorphism of the interleukin 6 gene is a hallmark of lacunar stroke and not other ischemic stroke phenotypes. Cerebrovasc Dis, 2005, 19(2): 91-95.
18. Karahan ZC, Deda G, Sipahi T, et al. TNF-alpha -308G/A and IL-6 -174 G/C polymorphisms in the Turkish pediatric stroke patients. Thromb Res, 2005, 115(5): 393-398.
19. Lalouschek W, Schillinger M, Hsieh K, et al. Polymorphisms of the inflammatory system and risk of ischemic cerebrovascular events. Clin Chem Lab Med, 2006, 44(8): 918-923.
20. Banerjee I, Gupta V, Ahmed T, et al. Inflammatory system gene polymorphism and the risk of stroke: A case-control study in an Indian population. Brain Res Bull, 2008, 75(1): 158-165.
21. Tong Y, Wang Z, Geng Y, et al. The association of functional polymorphisms of IL-6 gene promoter with ischemic stroke: analysis in two Chinese populations. Biochem Biophys Res Commun, 2010, 391(1): 481-485.
22. 刘东芳, 陈乃耀, 王大力, 等. 唐山地区汉族人群脑梗死患者IL-6基因-174G/C多态性研究. 现代预防医学, 2010, 37(18): 3419-3422.
23. 尤劲松, 黄培新, 刘茂才, 等. 脑梗死患者ICAM-1基因K469E及IL-6基因-174G/C多态性研究. 中国老年学杂志, 2007, 27(16): 1580-1582.
24. 张艳萍, 张蕴莉, 方伯言. 炎性因子IL-6、ICAM-1基因多态性与脑梗死的相关性. 医学综述, 2008；14(4): 539-541.
25. 张江, 王大力, 陈乃耀, 等. 唐山地区汉族人群脑梗死患者IL-6基因-174G/C多态性研究. 中风与神经疾病杂志, 2010, 27(9): 837-839.
26. 肖慧, 谷文萍, 梁静, 等. 白细胞介素-6基因多态性与动脉粥样硬化性脑梗死的关系. 中国神经精神疾病杂志, 2011, 37(1): 11-14.
27. 全国第四届脑血管病学术会议. 各类脑血管病的诊断要点. 中华神经科杂志, 1996, 29(6): 379-380.
28. Wood PH. Appreciating the consequences of disease: the international classification of impairments, disabilities, and handicaps. WHO Chron, 1980, 34(10): 376-380.
29. Wells GA, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa Health Research Institute. www.ohri.ca/programs/clinical_epidemiology/oxford.asp (accessed Oct 20, 2011).
30. Clark WM, Rinker LG, Lessov NS, et al. Time course of IL-6 expression in experimental CNS ischemia. Neurol Res, 1999, 21(3): 287-292.

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Correlation between Interleukin-6 174G/C Polymorphism and Ischemic Stroke: A Meta-Analysis

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