Gene Polymorphisms Increasing the Risk of Intracranial Aneurysms: Interleukin-1β -511C>T (Part I)

Gene Polymorphisms Increasing the Risk of Intracranial Aneurysms: Interleukin-1β -511C>T (Part I)

Authors

  • Alice Giotta Lucifero Neurosurgery Unit, Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
  • Matias Baldoncini Department of Neurological Surgery, Hospital San Fernando, Buenos Aires, Argentina
  • Thomas Foiadelli Pediatric Clinic, IRCCS Policlinico San Matteo Foundation, University of Pavia, Pavia, Italy
  • Ilaria Brambilla Pediatric Clinic, IRCCS Policlinico San Matteo Foundation, University of Pavia, Pavia, Italy
  • Gabriele Savioli Emergency Medicine and Surgery, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy
  • Renato Galzio Neurosurgery Unit, Maria Cecilia Hospital, Cotignola, Italy
  • Alvaro Campero Department of Neurosurgery, Hospital Padilla, San Miguel de Tucumán, Tucumán, Argentina
  • Michael T. Lawton Department of Neurosurgery, Barrow Neurological Institute (BNI), United States
  • Sabino Luzzi Neurosurgery Unit, Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy; Neurosurgery Unit, Department of Surgical Sciences, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

Keywords:

Allele Variations; Gene Polymorphisms; IL-1β; Inflammatory Cytokines; Interleukin-1β; Intracranial Aneurysm; Subarachnoid Hemorrhage.

Abstract

Introduction

Intracranial aneurysms (IAs) are devastating cerebrovascular diseases with multifactorial etiology. The role of inflammation is indisputable, and interleukins are pivotal in supporting local inflammatory pathways and endothelial dysfunction at the aneurysm wall.

In the light of insufficient evidence reported in the literature, this meta-analysis was aimed to investigate the genetic linkage between IL-1β (rs16944) -511C>T polymorphisms and IAs susceptibility.

Methods

A comprehensive online literature review was completed using the PubMed/Medline and Web of Science databases in accordance with the PRISMA guidelines. “Interleukin-1β,” “IL-1β,” “polymorphism,” “intracranial aneurysm,” and “subarachnoid hemorrhage” were the main keywords. Only human case-control studies, published from 2005 to 2021, written in English or translated, were screened. In the statistical analysis, we applied the fixed- and random-effect models, according to the level of heterogeneity, to assess the odds ratios (ORs) and 95% confidence intervals (CIs). RevMan 5.0 software was used for the statistics.

Results

Only 4 studies were eligible, with a total of 2070 patients, 1050 of which were assigned to the study group. Combined results showed a statistically significant association between the risk of IAs and -511CC (OR=0.79, 95% CI [0.65-0.95], p=0.01), and CT (OR=0.69, 95% CI [0.58-0.82], p<0.0001; OR=0.71, 95% CI [0.55-0.93], p=0.01) allele variations, both in the fixed- and random- models. No correlation was identified for the -511TT genotype (p=0.42; p=0.78). All the texts showed a low level of publication bias.

Conclusion

The present meta-analysis proved a potential role of IL-1β -511CC/CT genotypes in the pathogenesis of IAs. Additional studies are imperative to explain the underlying neuroimmune mechanisms, also allowing tailoring the potential inflammatory-target therapies for IAs.

References

Tricarico PM, Epate A, Celsi F, Crovella S. Alendronate treatment induces IL-1B expression and apoptosis in glioblastoma cell line. Inflammopharmacology. 2018;26(1):285-90.

Ho KH, Chen PH, Hsi E, Shih CM, Chang WC, Cheng CH, et al. Identification of IGF-1-enhanced cytokine expressions targeted by miR-181d in glioblastomas via an integrative miRNA/mRNA regulatory network analysis. Sci Rep. 2017;7(1):732.

Shonka N, Piao Y, Gilbert M, Yung A, Chang S, DeAngelis LM, et al. Cytokines associated with toxicity in the treatment of recurrent glioblastoma with aflibercept. Target Oncol. 2013;8(2):117-25.

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).

Savioli G, Ceresa IF, Macedonio S, Gerosa S, Belliato M, Iotti GA, et al. Trauma Coagulopathy and Its Outcomes. Medicina (Kaunas). 2020;56(4).

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.

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, 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.

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.

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.

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.

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).

Etminan N, Chang HS, Hackenberg K, de Rooij NK, Vergouwen MDI, Rinkel GJE, et al. Worldwide Incidence of Aneurysmal Subarachnoid Hemorrhage According to Region, Time Period, Blood Pressure, and Smoking Prevalence in the Population: A Systematic Review and Meta-analysis. JAMA Neurol. 2019;76(5):588-97.

van Gijn J, Kerr RS, Rinkel GJ. Subarachnoid haemorrhage. Lancet. 2007;369(9558):306-18.

Suarez JI, Tarr RW, Selman WR. Aneurysmal subarachnoid hemorrhage. N Engl J Med. 2006;354(4):387-96.

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, 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.

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.

Mrak RE, Griffin WS. Interleukin-1, neuroinflammation, and Alzheimer's disease. Neurobiol Aging. 2001;22(6):903-8.

Hall SK, Perregaux DG, Gabel CA, Woodworth T, Durham LK, Huizinga TW, et al. Correlation of polymorphic variation in the promoter region of the interleukin-1 beta gene with secretion of interleukin-1 beta protein. Arthritis Rheum. 2004;50(6):1976-83.

Basu A, Krady JK, Levison SW. Interleukin-1: a master regulator of neuroinflammation. J Neurosci Res. 2004;78(2):151-6.

Rothwell NJ, Luheshi GN. Interleukin 1 in the brain: biology, pathology and therapeutic target. Trends Neurosci. 2000;23(12):618-25.

Macdonald RL. Delayed neurological deterioration after subarachnoid haemorrhage. Nat Rev Neurol. 2014;10(1):44-58.

Shaftel SS, Griffin WS, O'Banion MK. The role of interleukin-1 in neuroinflammation and Alzheimer disease: an evolving perspective. J Neuroinflammation. 2008;5:7.

Nishimura M, Mizuta I, Mizuta E, Yamasaki S, Ohta M, Kuno S. Influence of interleukin-1beta gene polymorphisms on age-at-onset of sporadic Parkinson's disease. Neurosci Lett. 2000;284(1-2):73-6.

Bellantoni G, Guerrini F, Del Maestro M, Galzio R, Luzzi S. Simple schwannomatosis or an incomplete Coffin-Siris? Report of a particular case. eNeurologicalSci. 2019;14:31-3.

Ciappetta P, D'Urso P I, Luzzi S, Ingravallo G, Cimmino A, Resta L. Cystic dilation of the ventriculus terminalis in adults. J Neurosurg Spine. 2008;8(1):92-9.

Giotta Lucifero A, Luzzi S. Against the Resilience of High-Grade Gliomas: Gene Therapies (Part II). Brain Sci. 2021;11(8).

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, 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.

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.

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).

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.

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.

Luzzi S, Giotta Lucifero A, Brambilla I, Semeria Mantelli S, Mosconi M, Foiadelli T, et al. Targeting the medulloblastoma: a molecular-based approach. Acta Biomed. 2020;91(7-s):79-100.

Hendryk S, Jarzab B, Josko J. Increase of the IL-1 beta and IL-6 levels in CSF in patients with vasospasm following aneurysmal SAH. Neuro Endocrinol Lett. 2004;25(1-2):141-7.

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.

Slowik A, Borratynska A, Turaj W, Pera J, Dziedzic T, Wloch D, et al. Interleukin 1beta-511 C/T polymorphism and risk of aneurysmal subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry. 2006;77(2):279-80.

Fontanella M, Rainero I, Gallone S, Rubino E, Fornaro R, Fenoglio P, et al. Interleukin-1 cluster gene polymorphisms and aneurysmal subarachnoid hemorrhage. Neurosurgery. 2010;66(6):1058-62; discussion 62-3.

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.

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.

Geraghty JR, Testai FD. Delayed Cerebral Ischemia after Subarachnoid Hemorrhage: Beyond Vasospasm and Towards a Multifactorial Pathophysiology. Curr Atheroscler Rep. 2017;19(12):50.

Solenski NJ, Haley EC, Jr., Kassell NF, Kongable G, Germanson T, Truskowski L, et al. Medical complications of aneurysmal subarachnoid hemorrhage: a report of the multicenter, cooperative aneurysm study. Participants of the Multicenter Cooperative Aneurysm Study. Crit Care Med. 1995;23(6):1007-17.

Chaudhry SR, Güresir E, Vatter H, Kinfe TM, Dietrich D, Lamprecht A, et al. Aneurysmal subarachnoid hemorrhage lead to systemic upregulation of IL-23/IL-17 inflammatory axis. Cytokine. 2017;97:96-103.

Chaudhry SR, Hafez A, Rezai Jahromi B, Kinfe TM, Lamprecht A, Niemelä M, et al. Role of Damage Associated Molecular Pattern Molecules (DAMPs) in Aneurysmal Subarachnoid Hemorrhage (aSAH). Int J Mol Sci. 2018;19(7).

Muhammad S, Chaudhry SR, Kahlert UD, Lehecka M, Korja M, Niemelä M, et al. Targeting High Mobility Group Box 1 in Subarachnoid Hemorrhage: A Systematic Review. Int J Mol Sci. 2020;21(8).

Cahill J, Calvert JW, Solaroglu I, Zhang JH. Vasospasm and p53-induced apoptosis in an experimental model of subarachnoid hemorrhage. Stroke. 2006;37(7):1868-74.

Macdonald RL, Pluta RM, Zhang JH. Cerebral vasospasm after subarachnoid hemorrhage: the emerging revolution. Nat Clin Pract Neurol. 2007;3(5):256-63.

Cahill J, Zhang JH. Subarachnoid hemorrhage: is it time for a new direction? Stroke. 2009;40(3 Suppl):S86-7.

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.

Weiland J, Beez A, Westermaier T, Kunze E, Sirén AL, Lilla N. Neuroprotective Strategies in Aneurysmal Subarachnoid Hemorrhage (aSAH). Int J Mol Sci. 2021;22(11).

Chaudhry SR, Lehecka M, Niemelä M, Muhammad S. Sterile Inflammation, Potential Target in Aneurysmal Subarachnoid Hemorrhage. World Neurosurg. 2019;123:159-60.

Schneider UC, Xu R, Vajkoczy P. Inflammatory Events Following Subarachnoid Hemorrhage (SAH). Curr Neuropharmacol. 2018;16(9):1385-95.

Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010;140(6):805-20.

Hasan DM, Mahaney KB, Brown RD, Jr., Meissner I, Piepgras DG, Huston J, et al. Aspirin as a promising agent for decreasing incidence of cerebral aneurysm rupture. Stroke. 2011;42(11):3156-62.

Unruptured intracranial aneurysms--risk of rupture and risks of surgical intervention. N Engl J Med. 1998;339(24):1725-33.

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.

Gross BA, Rosalind Lai PM, Frerichs KU, Du R. Aspirin and Aneurysmal Subarachnoid Hemorrhage. World Neurosurgery. 2014;82(6):1127-30.

Yiqin Y, Meilin X, Jie X, Keping Z. Aspirin inhibits MMP-2 and MMP-9 expression and activity through PPARalpha/gamma and TIMP-1-mediated mechanisms in cultured mouse celiac macrophages. Inflammation. 2009;32(4):233-41.

Sánchez de Miguel L, de Frutos T, González-Fernández F, del Pozo V, Lahoz C, Jiménez A, et al. Aspirin inhibits inducible nitric oxide synthase expression and tumour necrosis factor-alpha release by cultured smooth muscle cells. Eur J Clin Invest. 1999;29(2):93-9.

Li S, Wang D, Tian Y, Wei H, Zhou Z, Liu L, et al. Aspirin Inhibits Degenerative Changes of Aneurysmal Wall in a Rat Model. Neurochem Res. 2015;40(7):1537-45.

Suzuki T, Kamio Y, Makino H, Hokamura K, Kimura T, Yamasaki T, et al. Prevention Effect of Antiplatelets on Aneurysm Rupture in a Mouse Intracranial Aneurysm Model. Cerebrovasc Dis. 2018;45(3-4):180-6.

Shen J, Huang KY, Zhu Y, Pan JW, Jiang H, Weng YX, et al. Effect of statin treatment on vasospasm-related morbidity and functional outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. J Neurosurg. 2017;127(2):291-301.

Lin J, Liu H, Jiang J, Jia C, Zhang B, Gao X. Clinical evidence of efficacy of simvastatin for aneurysmal subarachnoid hemorrhage. J Int Med Res. 2017;45(6):2128-38.

Marbacher S, Schläppi JA, Fung C, Hüsler J, Beck J, Raabe A. Do statins reduce the risk of aneurysm development? A case-control study. J Neurosurg. 2012;116(3):638-42.

Terceño M, Remollo S, Silva Y, Bashir S, Werner M, Vera-Monge VA, et al. Effect of combined acetylsalicylic acid and statins treatment on intracranial aneurysm rupture. PLoS One. 2021;16(2):e0247153.

Bruder M, Won SY, Wagner M, Brawanski N, Dinc N, Kashefiolasl S, et al. Continuous Acetylsalicylic Acid Treatment Does Not Influence Bleeding Pattern or Outcome of Aneurysmal Subarachnoid Hemorrhage: A Matched-Pair Analysis. World Neurosurg. 2018;113:e122-e8.

Bekelis K, Smith J, Zhou W, MacKenzie TA, Roberts DW, Skinner J, et al. Statins and subarachnoid hemorrhage in Medicare patients with unruptured cerebral aneurysms. Int J Stroke. 2015;10 Suppl A100(Suppl A100):38-45.

Li P, Gan Y, Sun BL, Zhang F, Lu B, Gao Y, et al. Adoptive regulatory T-cell therapy protects against cerebral ischemia. Ann Neurol. 2013;74(3):458-71.

Lei TY, Ye YZ, Zhu XQ, Smerin D, Gu LJ, Xiong XX, et al. The immune response of T cells and therapeutic targets related to regulating the levels of T helper cells after ischaemic stroke. J Neuroinflammation. 2021;18(1):25.

Mao L, Li P, Zhu W, Cai W, Liu Z, Wang Y, et al. Regulatory T cells ameliorate tissue plasminogen activator-induced brain haemorrhage after stroke. Brain. 2017;140(7):1914-31.

Zhang HF, Liang GB, Zhao MG, Zhao GF, Luo YH. Regulatory T cells demonstrate significantly increased functions following stimulation with IL-2 in a Tim-3-dependent manner in intracranial aneurysms. Int Immunopharmacol. 2018;65:342-7.

Luzzi S, Giotta Lucifero A, Brambilla I, Magistrali M, Mosconi M, Savasta S, et al. Adoptive immunotherapies in neuro-oncology: classification, recent advances, and translational challenges. Acta Biomed. 2020;91(7-s):18-31.

Han M, Cao Y, Guo X, Chu X, Li T, Xue H, et al. Mesenchymal stem cell-derived extracellular vesicles promote microglial M2 polarization after subarachnoid hemorrhage in rats and involve the AMPK/NF-κB signaling pathway. Biomed Pharmacother. 2021;133:111048.

Muhammad S, Chaudhry SR, Dobreva G, Lawton MT, Niemelä M, Hänggi D. Vascular Macrophages as Therapeutic Targets to Treat Intracranial Aneurysms. Front Immunol. 2021;12:630381.

Zhou K, Zhong Q, Wang YC, Xiong XY, Meng ZY, Zhao T, et al. Regulatory T cells ameliorate intracerebral hemorrhage-induced inflammatory injury by modulating microglia/macrophage polarization through the IL-10/GSK3β/PTEN axis. J Cereb Blood Flow Metab. 2017;37(3):967-79.

Luzzi S, Giotta Lucifero A, Brambilla I, Trabatti C, Mosconi M, Savasta S, et al. The impact of stem cells in neuro-oncology: applications, evidence, limitations and challenges. Acta Biomed. 2020;91(7-s):51-60.

Liu W, Li R, Yin J, Guo S, Chen Y, Fan H, et al. Mesenchymal stem cells alleviate the early brain injury of subarachnoid hemorrhage partly by suppression of Notch1-dependent neuroinflammation: involvement of Botch. J Neuroinflammation. 2019;16(1):8.

Turnbull MT, Zubair AC, Meschia JF, Freeman WD. Mesenchymal stem cells for hemorrhagic stroke: status of preclinical and clinical research. NPJ Regen Med. 2019;4:10.

Liu J, Kuwabara A, Kamio Y, Hu S, Park J, Hashimoto T, et al. Human Mesenchymal Stem Cell-Derived Microvesicles Prevent the Rupture of Intracranial Aneurysm in Part by Suppression of Mast Cell Activation via a PGE2-Dependent Mechanism. Stem Cells. 2016;34(12):2943-55.

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.

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.

Muhammad S, Haasbach E, Kotchourko M, Strigli A, Krenz A, Ridder DA, et al. Influenza virus infection aggravates stroke outcome. Stroke. 2011;42(3):783-91.

Muhammad S, Hänggi D. Inflammation and Anti-Inflammatory Targets after Aneurysmal Subarachnoid Hemorrhage. Int J Mol Sci. 2021;22(14).

Downloads

Published

21-03-2022

How to Cite

1.
Gene Polymorphisms Increasing the Risk of Intracranial Aneurysms: Interleukin-1β -511C>T (Part I). Acta Biomed [Internet]. 2022 Mar. 21 [cited 2024 Mar. 29];92(S4):e2021419. Available from: https://mattioli1885journals.com/index.php/actabiomedica/article/view/12668