Background: Polymorphisms of -174G/C and -572C/G in the Interleukin-6 (IL-6) promoter gene can affect both transcription and secretion of IL-6 and may be involved in the inflammatory mechanisms in early and delayed phases after intracerebral hemorrhage (ICH). The role of these polymorphisms remains unclear for the pathogenesis of ICH. Methods: PubMed, EMBASE, MEDLINE and Google Scholar searches were conducted from January 1, 1950 to February 29, 2016 and were supplemented with relevant articles identified in the references. The following search terms were used: (‘interleukin-6' or ‘IL-6') and (‘genetic polymorphism' or ‘single nucleotide polymorphisms' or ‘SNP') and (‘intracerebral hemorrhage' or ‘ICH') and (‘hemorrhagic stroke' or ‘HS'). Fixed or random effects models were used to estimate the pooled odds ratios and 95% confidence intervals. Begg's funnel plot was used to assess the potential for publication bias. Results: In our meta-analysis, three case-control studies involving 446 ICH cases and 2,322 controls were included. No significant association was observed for the IL-6 (-174G/C and -572C/G) gene polymorphisms with the risk of ICH under dominant, recessive and allelic models. Conclusion: Our meta-analysis suggests that IL-6 gene polymorphisms are not associated with the risk of ICH. However, caution must be taken while considering the results of our meta-analysis due to the presence of small sample size. Our results cannot be extrapolated to represent the effect of entire IL-6 genetic polymorphism on stroke patients worldwide. Therefore, further well-designed studies with large sample size are warranted to validate our findings and provide a profound conclusion.

Keywords:
Interleukin-6, Cytokine, Intracerebral hemorrhage, Single nucleotide polymorphisms
1.
Feigin VL, Forouzanfar MH, Krishnamurthi R, Mensah GA, Connor M, Bennett DA, Moran AE, Sacco RL, Anderson L, Truelsen T, O'Donnell M, Venketasubramanian N, Barker-Collo S, Lawes CMM, Wang W, Shinohara Y, Witt E, Ezzati M, Naghavi M, Murray C; and Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010) and the GBD Stroke Experts Group: Global and regional burden of stroke during 1990-2010: findings from the Global Burden of Disease Study 2010. Lancet 2014;383:245-254.
2.
Das SK, Banerjee TK: Stroke: Indian scenario. Circulation 2008;118:2719-2724.
3.
Bevan S, Markus HS: Genetics of common polygenic ischaemic stroke: current understanding and future challenges. Stroke Res Treat 2011;2011:179061.
4.
Seino Y, Ikeda U, Ikeda M, Yamamoto K, Misawa Y, Hasegawa T, Kano S, Shimada K: Interleukin 6 gene transcripts are expressed in human atherosclerotic lesions. Cytokine 1994;6:87-91.
5.
Castillo J, Rodríguez 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.
6.
Tso AR, Merino JG, Warach S: Interleukin-6 174G/C polymorphism and ischemic stroke: a systematic review. Stroke J Cereb Circ 2007;38:3070-3075.
7.
Ridker PM, Rifai N, Stampfer MJ, Hennekens CH: Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 2000;101:1767-1772.
8.
Sehgal PB, Zilberstein A, Ruggieri RM, May LT, Ferguson-Smith A, Slate DL, Revel M, Ruddle FH: Human chromosome 7 carries the beta 2 interferon gene. Proc Natl Acad Sci USA, 1986;83:5219-5222.
9.
Zilberstein A, Ruggieri R, Korn JH, Revel M: Structure and expression of cDNA and genes for human interferon-beta-2, a distinct species inducible by growth-stimulatory cytokines. EMBO J 1986;5:2529-2537.
10.
Suzuki S, Tanaka K, Suzuki N: Ambivalent aspects of interleukin-6 in cerebral ischemia: inflammatory versus neurotrophic aspects. J Cereb Blood Flow Metab 2009;29:464-479.
11.
Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin JS, Humphries S, Woo P: The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest 1998;102:1369-1376.
12.
März P, Cheng JG, Gadient RA, Patterson PH, Stoyan T, Otten U, Rose-John S: Sympathetic neurons can produce and respond to interleukin 6. Proc Natl Acad Sci USA 1998;95:3251-3256.
13.
Kumar P, Kumar A, Sagar R, Misra S, Farooq M, Suroliya V, Vivekanandhan S, Srivastava AK, Prasad K: Association between interleukin-6 (-174 G/C and -572 C/G) promoter gene polymorphisms and risk of intracerebral hemorrhage in North Indian population: a case control study. Acta Medica Int 2016;3:132-136.
14.
Banerjee I, Gupta V, Ahmed T, Faizaan M, Agarwal P, Ganesh S: Inflammatory system gene polymorphism and the risk of stroke: a case-control study in an Indian population. Brain Res Bull 2008;75:158-165.
15.
Yamada Y, Metoki N, Yoshida H, Satoh K, Ichihara S, Kato K, Kameyama T, Yokoi K, Matsuo H, Segawa T, Watanabe S, Nozawa Y: Genetic risk for ischemic and hemorrhagic stroke. Arterioscler Thromb Vasc Biol 2006;26:1920-1925.
16.
Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group: Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009;6:e1000097.
17.
Stang A: Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010;25:603-605.
18.
Higgins JPT, Thompson SG, Deeks JJ, Altman DG: Measuring inconsistency in meta-analyses. BMJ 2003;327:557-560.
19.
Brown JM, Grosso MA, Harken AH: Cytokines, sepsis and the surgeon. Surg Gynecol Obstet 1989;169:568-575.
20.
Fillman SG, Weickert TW, Lenroot RK, Catts SV, Bruggemann JM, Catts VS, Weickert CS: Elevated peripheral cytokines characterize a subgroup of people with schizophrenia displaying poor verbal fluency and reduced Broca's area volume. Mol Psychiatry 2015, Epub ahead of print.
21.
Cesari, M Penninx BWJH, Newman AB, Kritchevsky SB, Nicklas BJ, Sutton-Tyrrell K, Rubin SM, Ding J, Simonsick EM, Harris TB, Pahor M: Inflammatory markers and onset of cardiovascular events: results from the Health ABC study. Circulation 2003;108:2317-2322.
22.
Fassbender K, Rossol S, Kammer T, Daffertshofer M, Wirth S, Dollman M, Hennerici M: Proinflammatory cytokines in serum of patients with acute cerebral ischemia: kinetics of secretion and relation to the extent of brain damage and outcome of disease. J Neurol Sci 1994;122:135-139.
23.
Folsom AR, Chambless LE, Ballantyne CM, Coresh J, Heiss G, Wu KK, Boerwinkle E, Mosley TH, Sorlie P, Diao G, Sharrett AR: An assessment of incremental coronary risk prediction using C-reactive protein and other novel risk markers: the atherosclerosis risk in communities study. Arch Intern Med 2006;166:1368-1373.
24.
Miñambres E, Cemborain A, Sánchez-Velasco P, Gandarillas M, Díaz-Regañón G, Sánchez-González U, Leyva-Cobián F: Correlation between transcranial interleukin-6 gradient and outcome in patients with acute brain injury. Crit Care Med 2003;31:933-938.
25.
Pawlikowska L, Tran MN, Achrol AS, McCulloch CE, Ha C, Lind DL, Hashimoto T, Zaroff J, Lawton MT, Marchuk DA, Kwok P-Y, Young WL; UCSF BAVM Study Project: Polymorphisms in genes involved in inflammatory and angiogenic pathways and the risk of hemorrhagic presentation of brain arteriovenous malformations. Stroke J Cereb Circ 2004;35:2294-2300.
26.
Silva Y, Leira R, Tejada J, Lainez JM, Castillo J, Dávalos A; Stroke Project, Cerebrovascular Diseases Group of the Spanish Neurological Society: Molecular signatures of vascular injury are associated with early growth of intracerebral hemorrhage. Stroke J Cereb Circ 2005;36:86-91.
27.
Kumar P, Yadav AK, Kumar A, Sagar R, Pandit AK, Prasad K: Association between interleukin-6 (G174C and C572G) promoter gene polymorphisms and risk of ischaemic stroke: a meta-analysis. Ann Neurosci 2015;22:61-69.
© 2016 S. Karger AG, Basel
2016
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.