Gene Polymorphisms Increasing the Risk of Intracranial Aneurysms: Interleukin-6 -174G>C and -572G>C (Part II)
Keywords:
Allele Variations; Gene Polymorphisms; IL-6; Inflammatory Cytokines; Interleukin-6; Intracranial Aneurysm; Subarachnoid HemorrhageAbstract
Introduction
The interleukin-6 (IL-6), a proinflammatory cytokine, supports the adaptive immune response and regulates inflammatory processes. The -174 G>C and -572 G>C promoter polymorphisms of the IL-6 gene take part in the pathogenesis of intracranial aneurysms (IAs) and influence the clinical presentation of subarachnoid hemorrhage.
This meta-analysis purposes to evaluate whether and which IL-6 allelic variations are related to a risk of IAs formation.
Methods
A PRISMA-based literature search was performed on the PubMed/Medline and Web of Science databases. The keywords used were “interleukin-6,” “IL-6,” “polymorphism,” “interleukin-6 genotype,” combined with “intracranial aneurysms” and “subarachnoid hemorrhage.” Only human case-control studies, with a study (IAs) and a control group, written in English, and published in the last 15 years were selected. A meta-analysis was performed, estimating odds ratios and 95% confidence intervals in fixed- or random-effects models, as applicable. Statistical analysis was conducted with RevMan 5.0 software.
Results
9 studies were eligible. No associations were found between -174 G>C polymorphisms and IAs susceptibility. Notable results were reported by the analysis of -572G>C polymorphisms. -572GG/GC/CC genotypes were strongly related to IAs occurrence with a statistical significance of p=0.03, p=0.0009, and p=0.00001, respectively.
Conclusion
A higher incidence of -572G>C promoter polymorphisms were demonstrated in the IAs group, highlighting the pivotal role of inflammatory genes in the natural history of brain aneurysms.
Additional studies are required considering the racial heterogenicity and the need to widen the population sample.
References
Juvela S. Prevalence of and risk factors for intracranial aneurysms. Lancet Neurol. 2011;10(7):595-7.
Rinkel GJ, Djibuti M, Algra A, van Gijn J. Prevalence and risk of rupture of intracranial aneurysms: a systematic review. Stroke. 1998;29(1):251-6.
Vlak MH, Algra A, Brandenburg R, Rinkel GJ. Prevalence of unruptured intracranial aneurysms, with emphasis on sex, age, comorbidity, country, and time period: a systematic review and meta-analysis. Lancet Neurol. 2011;10(7):626-36.
Frösen J, Piippo A, Paetau A, Kangasniemi M, Niemelä M, Hernesniemi J, et al. Remodeling of saccular cerebral artery aneurysm wall is associated with rupture: histological analysis of 24 unruptured and 42 ruptured cases. Stroke. 2004;35(10):2287-93.
Pritchard C, Foulkes L, Lang DA, Neil-Dwyer G. Psychosocial outcomes for patients and carers after aneurysmal subarachnoid haemorrhage. Br J Neurosurg. 2001;15(6):456-63.
Johnston SC, Selvin S, Gress DR. The burden, trends, and demographics of mortality from subarachnoid hemorrhage. Neurology. 1998;50(5):1413-8.
Wiebers DO, Whisnant JP, Huston J, 3rd, Meissner I, Brown RD, Jr., Piepgras DG, et al. Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet. 2003;362(9378):103-10.
Serrone JC, Maekawa H, Tjahjadi M, Hernesniemi J. Aneurysmal subarachnoid hemorrhage: pathobiology, current treatment and future directions. Expert Rev Neurother. 2015;15(4):367-80.
Luzzi S, Gragnaniello C, Giotta Lucifero A, Del Maestro M, Galzio R. Surgical Management of Giant Intracranial Aneurysms: Overall Results of a Large Series. World Neurosurg. 2020;144:e119-e37.
Luzzi S, Gragnaniello C, Giotta Lucifero A, Del Maestro M, Galzio R. Microneurosurgical management of giant intracranial aneurysms: Datasets of a twenty-year experience. Data Brief. 2020;33:106537.
Luzzi S, Del Maestro M, Galzio R. Letter to the Editor. Preoperative embolization of brain arteriovenous malformations. J Neurosurg. 2019;132(6):2014-6.
Luzzi S, Del Maestro M, Elbabaa SK, Galzio R. Letter to the Editor Regarding "One and Done: Multimodal Treatment of Pediatric Cerebral Arteriovenous Malformations in a Single Anesthesia Event". World Neurosurg. 2020;134:660.
Cebral JR, Detmer F, Chung BJ, Choque-Velasquez J, Rezai B, Lehto H, et al. Local Hemodynamic Conditions Associated with Focal Changes in the Intracranial Aneurysm Wall. AJNR Am J Neuroradiol. 2019;40(3):510-6.
Tulamo R, Frösen J, Hernesniemi J, Niemelä M. Inflammatory changes in the aneurysm wall: a review. J Neurointerv Surg. 2010;2(2):120-30.
Giotta Lucifero A, Baldoncini M, Bruno N, Galzio R, Hernesniemi J, Luzzi S. Shedding the Light on the Natural History of Intracranial Aneurysms: An Updated Overview. Medicina (Kaunas). 2021;57(8).
Hasan D, Chalouhi N, Jabbour P, Hashimoto T. Macrophage imbalance (M1 vs. M2) and upregulation of mast cells in wall of ruptured human cerebral aneurysms: preliminary results. J Neuroinflammation. 2012;9:222.
Starke RM, Chalouhi N, Jabbour PM, Tjoumakaris SI, Gonzalez LF, Rosenwasser RH, et al. Critical role of TNF-α in cerebral aneurysm formation and progression to rupture. J Neuroinflammation. 2014;11:77.
Chalouhi N, Ali MS, Jabbour PM, Tjoumakaris SI, Gonzalez LF, Rosenwasser RH, et al. Biology of intracranial aneurysms: role of inflammation. J Cereb Blood Flow Metab. 2012;32(9):1659-76.
Niu PP, Wang X, Xu YM. Association of Interleukin-6 Signaling and C-Reactive Protein With Intracranial Aneurysm: A Mendelian Randomization and Genetic Correlation Study. Front Genet. 2021;12:679363.
Xu L, Hu L, Hu C, Liu J, Li B, Liao X, et al. Associations between Inflammatory Cytokine Gene Polymorphisms and Susceptibilities to Intracranial Aneurysm in Chinese Population. Biomed Res Int. 2021;2021:8865601.
Bowcock AM, Kidd JR, Lathrop GM, Daneshvar L, May LT, Ray A, et al. The human "interferon-beta 2/hepatocyte stimulating factor/interleukin-6" gene: DNA polymorphism studies and localization to chromosome 7p21. Genomics. 1988;3(1):8-16.
Rivera-Chavez FA, Peters-Hybki DL, Barber RC, O'Keefe GE. Interleukin-6 promoter haplotypes and interleukin-6 cytokine responses. Shock. 2003;20(3):218-23.
Brull DJ, Montgomery HE, Sanders J, Dhamrait S, Luong L, Rumley A, et al. 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. 2001;21(9):1458-63.
Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin JS, Humphries S, et al. 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(7):1369-76.
Bennermo M, Held C, Green F, Strandberg LE, Ericsson CG, Hansson LO, et al. Prognostic value of plasma interleukin-6 concentrations and the -174 G > C and -572 G > C promoter polymorphisms of the interleukin-6 gene in patients with acute myocardial infarction treated with thrombolysis. Atherosclerosis. 2004;174(1):157-63.
Smallwood L, Allcock R, van Bockxmeer F, Warrington N, Palmer LJ, Iacopetta B, et al. Polymorphisms of the interleukin-6 gene promoter and abdominal aortic aneurysm. Eur J Vasc Endovasc Surg. 2008;35(1):31-6.
Greisenegger S, Endler G, Haering D, Schillinger M, Lang W, Lalouschek W, 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):181-6.
Morgan L, Cooper J, Montgomery H, Kitchen N, Humphries SE. The interleukin-6 gene -174G>C and -572G>C promoter polymorphisms are related to cerebral aneurysms. J Neurol Neurosurg Psychiatry. 2006;77(8):915-7.
Fontanella M, Rainero I, Gallone S, Rubino E, Fenoglio P, Valfrè W, et al. Interleukin 6 gene polymorphisms are not associated with aneurysmal subarachnoid haemorrhage in an Italian population. J Neurol Neurosurg Psychiatry. 2008;79(4):471-3.
Sun H, Zhang D, Zhao J. The interleukin-6 gene -572G>C promoter polymorphism is related to intracranial aneurysms in Chinese Han nationality. Neurosci Lett. 2008;440(1):1-3.
Zhang G, Tu Y, Feng W, Huang L, Li M, Qi S. Association of interleukin-6-572G/C gene polymorphisms in the Cantonese population with intracranial aneurysms. J Neurol Sci. 2011;306(1-2):94-7.
Pera J, Dziedzic T, Adamski M, Jagiella J, Krupa M, Moskala M, et al. Interleukin 6-174G>C polymorphism and risk of aneurysmal subarachnoid hemorrhage: case-control study and meta-analysis. Acta Neurol Scand. 2012;125(2):111-5.
Liu Y, Sun J, Wu C, Cao X, He M, You C. The interleukin-6-572G/C gene polymorphism and the risk of intracranial aneurysms in a Chinese population. Genet Test Mol Biomarkers. 2012;16(7):822-6.
Sathyan S, Koshy LV, Srinivas L, Easwer HV, Premkumar S, Nair S, et al. Pathogenesis of intracranial aneurysm is mediated by proinflammatory cytokine TNFA and IFNG and through stochastic regulation of IL10 and TGFB1 by comorbid factors. J Neuroinflammation. 2015;12:135.
Bayri Y, Taşkin E, Ulus A, Bayrakli F, Altun A, Bagci H. Lack of Association Between Interleukin 6 Gene Promoter Polymorphisms and Aneurysmal Subarachnoid Hemorrhage in Turkish Population. Journal of Neurological Sciences. 2015;32:288-92.
Treska V, Topolcan O, Pecen L. Cytokines as plasma markers of abdominal aortic aneurysm. Clin Chem Lab Med. 2000;38(11):1161-4.
Lin CY, Lin CC, Hwang B, Chiang BN. Cytokines predict coronary aneurysm formation in Kawasaki disease patients. Eur J Pediatr. 1993;152(4):309-12.
Lindeman JH, Abdul-Hussien H, Schaapherder AF, Van Bockel JH, Von der Thüsen JH, Roelen DL, et al. Enhanced expression and activation of pro-inflammatory transcription factors distinguish aneurysmal from atherosclerotic aorta: IL-6- and IL-8-dominated inflammatory responses prevail in the human aneurysm. Clin Sci (Lond). 2008;114(11):687-97.
Fragoso J, Delgadillo H, Juárez-Cedillo T, Rodríguez-Pérez J, Vallejo M, Pérez-Méndez O, et al. The Interleukin 6 - 572 G>C (rs1800796) Polymorphism Is Associated with the Risk of Developing Acute Coronary Syndrome. Genetic testing and molecular biomarkers. 2010;14:759-63.
Hua Y, Guo X, Huang Q, Kong Y, Lu X. Association between interleukin-6 -174G/C polymorphism and the risk of Alzheimer's disease: a meta-analysis. Int J Neurosci. 2013;123(9):626-35.
Zheng GH, Chen HY, Xiong SQ. Polymorphisms of -174G>C and -572G>C in the interleukin 6 (IL-6) gene and coronary heart disease risk: a meta-analysis of 27 research studies. PLoS One. 2012;7(4):e34839.
Yin YW, Hu AM, Sun QQ, Liu HL, Wang Q, Zeng YH, et al. Association between interleukin-6 gene -174 G/C polymorphism and the risk of coronary heart disease: a meta-analysis of 20 studies including 9619 cases and 10,919 controls. Gene. 2012;503(1):25-30.
Frösen J, Tulamo R, Paetau A, Laaksamo E, Korja M, Laakso A, et al. Saccular intracranial aneurysm: pathology and mechanisms. Acta Neuropathol. 2012;123(6):773-86.
Tang G, Chiocca A. Gene transfer and delivery in central nervous system disease. Neurosurg Focus. 1997;3(3):e2.
Lim M, Weller M, Chiocca EA. Current State of Immune-Based Therapies for Glioblastoma. Am Soc Clin Oncol Educ Book. 2016;35:e132-9.
Reardon DA, Freeman G, Wu C, Chiocca EA, Wucherpfennig KW, Wen PY, et al. Immunotherapy advances for glioblastoma. Neuro Oncol. 2014;16(11):1441-58.
Samuel N, Radovanovic I. Genetic basis of intracranial aneurysm formation and rupture: clinical implications in the postgenomic era. Neurosurg Focus. 2019;47(1):E10.
Caranci F, Briganti F, Cirillo L, Leonardi M, Muto M. Epidemiology and genetics of intracranial aneurysms. Eur J Radiol. 2013;82(10):1598-605.
Giotta Lucifero A, Luzzi S, Brambilla I, Trabatti C, Mosconi M, Savasta S, et al. Innovative therapies for malignant brain tumors: the road to a tailored cure. Acta Biomed. 2020;91(7-s):5-17.
Luzzi S, Crovace AM, Del Maestro M, Giotta Lucifero A, Elbabaa SK, Cinque B, et al. The cell-based approach in neurosurgery: ongoing trends and future perspectives. Heliyon. 2019;5(11):e02818.
Luzzi S, Crovace AM, Lacitignola L, Valentini V, Francioso E, Rossi G, et al. Engraftment, neuroglial transdifferentiation and behavioral recovery after complete spinal cord transection in rats. Surg Neurol Int. 2018;9:19.
Palumbo P, Lombardi F, Augello FR, Giusti I, Luzzi S, Dolo V, et al. NOS2 inhibitor 1400W Induces Autophagic Flux and Influences Extracellular Vesicle Profile in Human Glioblastoma U87MG Cell Line. Int J Mol Sci. 2019;20(12).
Raysi Dehcordi S, Ricci A, Di Vitantonio H, De Paulis D, Luzzi S, Palumbo P, et al. Stemness Marker Detection in the Periphery of Glioblastoma and Ability of Glioblastoma to Generate Glioma Stem Cells: Clinical Correlations. World Neurosurg. 2017;105:895-905.
Savioli G, Ceresa IF, Macedonio S, Gerosa S, Belliato M, Iotti GA, et al. Trauma Coagulopathy and Its Outcomes. Medicina (Kaunas). 2020;56(4).
Giotta Lucifero A, Luzzi S. Against the Resilience of High-Grade Gliomas: The Immunotherapeutic Approach (Part I). Brain Sci. 2021;11(3).
Giotta Lucifero A, Luzzi S. Against the Resilience of High-Grade Gliomas: Gene Therapies (Part II). Brain Sci. 2021;11(8).
Garone G, Reale A, Vanacore N, Parisi P, Bondone C, Suppiej A, et al. Acute ataxia in paediatric emergency departments: a multicentre Italian study. Arch Dis Child. 2019;104(8):768-74.
Gastaldi M, Scaranzin S, Jarius S, Wildeman B, Zardini E, Mallucci G, et al. Cell-based assays for the detection of MOG antibodies: a comparative study. J Neurol. 2020;267(12):3555-64.
Foiadelli T, Piccorossi A, Sacchi L, De Amici M, Tucci M, Brambilla I, et al. Clinical characteristics of headache in Italian adolescents aged 11-16 years: a cross-sectional questionnaire school-based study. Ital J Pediatr. 2018;44(1):44.
Savasta S, Rossi A, Foiadelli T, Licari A, Elena Perini AM, Farello G, et al. Melkersson⁻Rosenthal Syndrome in Childhood: Report of Three Paediatric Cases and a Review of the Literature. Int J Environ Res Public Health. 2019;16(7).
Foiadelli T, Savasta S, Battistone A, Kota M, Passera C, Fiore S, et al. Nucleotide variation in Sabin type 3 poliovirus from an Albanian infant with agammaglobulinemia and vaccine associated poliomyelitis. BMC Infect Dis. 2016;16:277.
Savasta S, Rovida F, Foiadelli T, Campana AM, Percivalle E, Marseglia GL, et al. West-Nile virus encephalitis in an immunocompetent pediatric patient: successful recovery. Ital J Pediatr. 2018;44(1):140.
Michev A, Musso P, Foiadelli T, Trabatti C, Lozza A, Franciotta D, et al. Bickerstaff Brainstem Encephalitis and overlapping Guillain-Barré syndrome in children: Report of two cases and review of the literature. Eur J Paediatr Neurol. 2019;23(1):43-52.
Orsini A, Foiadelli T, Carli N, Costagliola G, Masini B, Bonuccelli A, et al. Rasmussen's encephalitis: From immune pathogenesis towards targeted-therapy. Seizure. 2020;81:76-83.
Katritsis D, Kaiktsis L, Chaniotis A, Pantos J, Efstathopoulos EP, Marmarelis V. Wall shear stress: theoretical considerations and methods of measurement. Prog Cardiovasc Dis. 2007;49(5):307-29.
Staarmann B, Smith M, Prestigiacomo CJ. Shear stress and aneurysms: a review. Neurosurg Focus. 2019;47(1):E2.
Sforza DM, Putman CM, Cebral JR. Hemodynamics of Cerebral Aneurysms. Annu Rev Fluid Mech. 2009;41:91-107.
Sakamoto N, Saito N, Han X, Ohashi T, Sato M. Effect of spatial gradient in fluid shear stress on morphological changes in endothelial cells in response to flow. Biochem Biophys Res Commun. 2010;395(2):264-9.
Turjman AS, Turjman F, Edelman ER. Role of fluid dynamics and inflammation in intracranial aneurysm formation. Circulation. 2014;129(3):373-82.
Frösen J. Smooth muscle cells and the formation, degeneration, and rupture of saccular intracranial aneurysm wall--a review of current pathophysiological knowledge. Transl Stroke Res. 2014;5(3):347-56.
Kataoka K, Taneda M, Asai T, Kinoshita A, Ito M, Kuroda R. Structural fragility and inflammatory response of ruptured cerebral aneurysms. A comparative study between ruptured and unruptured cerebral aneurysms. Stroke. 1999;30(7):1396-401.
Le JM, Vilcek J. Interleukin 6: a multifunctional cytokine regulating immune reactions and the acute phase protein response. Lab Invest. 1989;61(6):588-602.
Song M, Kellum JA. Interleukin-6. Crit Care Med. 2005;33(12 Suppl):S463-5.
Zheng S, Su A, Sun H, You C. The association between interleukin-6 gene polymorphisms and intracranial aneurysms: a meta-analysis. Hum Immunol. 2013;74(12):1679-83.
Hu L, Li B, Liao X, Yan J. Polymorphisms of Inflammatory Cytokine Genes and Risk for Intracranial Aneurysm: A Systematic Review and Meta-Analysis. Yonsei Med J. 2020;61(5):391-9.
Skirgaudas M, Awad IA, Kim J, Rothbart D, Criscuolo G. Expression of angiogenesis factors and selected vascular wall matrix proteins in intracranial saccular aneurysms. Neurosurgery. 1996;39(3):537-45; discussion 45-7.
Yoon BH, Jun JK, Romero R, Park KH, Gomez R, Choi JH, et al. Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha), neonatal brain white matter lesions, and cerebral palsy. Am J Obstet Gynecol. 1997;177(1):19-26.
Inder TE, Volpe JJ. Mechanisms of perinatal brain injury. Semin Neonatol. 2000;5(1):3-16.
Giacomini T, Foiadelli T, Annovazzi P, Nosadini M, Gastaldi M, Franciotta D, et al. Pediatric optic neuritis and anti MOG antibodies: a cohort of Italian patients. Mult Scler Relat Disord. 2019;39:101917.
Foiadelli T, Gastaldi M, Scaranzin S, Franciotta D, Savasta S. Seizures and myelin oligodendrocyte glycoprotein (MOG) antibodies: Two paradigmatic cases and a review of the literature. Mult Scler Relat Disord. 2020;41:102011.
Osuka K, Suzuki Y, Tanazawa T, Hattori K, Yamamoto N, Takayasu M, et al. Interleukin-6 and development of vasospasm after subarachnoid haemorrhage. Acta Neurochir (Wien). 1998;140(9):943-51.
Kwon KY, Jeon BC. Cytokine levels in cerebrospinal fluid and delayed ischemic deficits in patients with aneurysmal subarachnoid hemorrhage. J Korean Med Sci. 2001;16(6):774-80.
Downloads
Published
Issue
Section
License
Copyright (c) 2021 Alice Giotta Lucifero , Matias Baldoncini, Ilaria Brambilla , Monica Rutigliano, Gabriele Savioli, Renato Galzio, Alvaro Campero, Michael T. Lawton, Sabino Luzzi
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Transfer of Copyright and Permission to Reproduce Parts of Published Papers.
Authors retain the copyright for their published work. No formal permission will be required to reproduce parts (tables or illustrations) of published papers, provided the source is quoted appropriately and reproduction has no commercial intent. Reproductions with commercial intent will require written permission and payment of royalties.
How to Cite
