Interleukin-1 Cluster Gene Polymorphisms and Aneurysmal Subarachnoid Hemorrhage

Fontanella, Marco Maria; Rainero, Innocenzo; Gallone, Salvatore; Rubino, Elisa; Fornaro, Riccardo; Fenoglio, Pierpaola; Valfrè, Walter; Vaula, Giovanna; Benevello, Chiara; Ducati, Alessandro; Pinessi, Lorenzo

doi:10.1227/01.neu.0000369187.95163.5d

Cited by 13 publications

(12 citation statements)

References 35 publications

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“…Earlier studies did provide evidence with contradictions for involvement of IL1 gene complex with IA. A study in Polish population has reported an association of IL1B rs16944 with IA, but this could not be replicated in Italian population [ 16 , 17 ]. IL1RN VNTR polymorphism has been widely implicated in ischemic stroke [ 32 ] and coronary artery disease (CAD) [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

“…All the previous studies which explored similar variants in genes involved in inflammatory and anti-inflammatory cytokines were included in this study. The meta-analysis included the most studied SNPs in immune response, rs1800796 of IL6 [ 10 – 14 ], rs3212227 of IL12B [ 15 ], and rs16944 of IL1B [ 16 , 17 ] (Additional file 1 : Table S2). The inconsistency index I 2 was used to assess between-study heterogeneity.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Pathogenesis of intracranial aneurysm is mediated by proinflammatory cytokine TNFA and IFNG and through stochastic regulation of IL10 and TGFB1 by comorbid factors

Sathyan

Koshy

Srinivas

et al. 2015

J Neuroinflammation

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BackgroundIntracranial aneurysm (IA) is often asymptomatic until the time of rupture resulting in subarachnoid hemorrhage (SAH).There is no precise biochemical or phenotype marker for diagnosis of aneurysm. Environmental risk factors that associate with IA can result in modifying the effect of inherited genetic factors and thereby increase the susceptibility to SAH. In addition subsequent to aneurismal rupture, the nature and quantum of inflammatory response might be critical for repair. Therefore, genetic liability to inflammatory response caused by polymorphisms in cytokine genes might be the common denominator for gene and environment in the development of aneurysm and complications associated with rupture.MethodsFunctionally relevant polymorphisms in the pro- and anti-inflammatory cytokine genes IL-1 complex (IL1A, IL1B, and IL1RN), TNFA, IFNG, IL3, IL6, IL12B, IL1RN, TGFB1, IL4, and IL10] were screened in radiologically confirmed 220 IA patients and 250 controls from genetically stratified Malayalam-speaking Dravidian ethnic population of south India. Subgroup analyses with genetic and environmental variables were also carried out.ResultsPro-inflammatory cytokines TNFA rs361525, IFNG rs2069718, and anti-inflammatory cytokine IL10 rs1800871 and rs1800872 were found to be significantly associated with IA, independent of epidemiological factors. TGFB1 rs1800469 polymorphism was observed to be associated with IA through co-modifying factors such as hypertension and gender. Functional prediction of all the associated SNPs of TNFA, IL10, and TGFB1 indicates their potential role in transcriptional regulation. Meta-analysis further reiterates that IL1 gene cluster and IL6 were not associated with IA.ConclusionsThe study suggests that chronic exposure to inflammatory response mediated by genetic variants in pro-inflammatory cytokines TNFA and IFNG could be a primary event, while stochastic regulation of IL10 and TGFB1 response mediated by comorbid factors such as hypertension may augment the pathogenesis of IA through vascular matrix degradation. The implication and interaction of these genetic variants under a specific environmental background will help us identify the resultant phenotypic variation in the pathogenesis of intracranial aneurysm. Identifying genetic risk factors for inflammation might also help in understanding and addressing the posttraumatic complications following the aneurismal rupture.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0354-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Pathogenesis of intracranial aneurysm is mediated by proinflammatory cytokine TNFA and IFNG and through stochastic regulation of IL10 and TGFB1 by comorbid factors

Sathyan

Koshy

Srinivas

et al. 2015

J Neuroinflammation

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“…In these studies, 3 articles investigated the associations between TNF-α rs1800629 polymorphism and risk of IA; 13,14,17 11 articles investigated the associations between IL gene (IL-1α, IL-1β, IL6, and IL-12B) polymorphisms and risk of IA. 11,12,[17][18][19][20][21][22][23][24][25] Detailed characteristics of the included studies are summarized in Table 2. A detailed flow chart of study selection is presented in Fig.…”

Section: Characteristics Of the Available Studiesmentioning

confidence: 99%

Polymorphisms of Inflammatory Cytokine Genes and Risk for Intracranial Aneurysm: A Systematic Review and Meta-Analysis

Liao

et al. 2020

Yonsei Med J

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Purpose: Inflammatory cytokines are thought to be involved in the pathogenesis of intracranial aneurysm (IA), although results among studies in the literature are inconsistent. This article sought to review studies on the associations among polymorphisms in inflammatory cytokine genes and IA risk and to provide recommendations for future research. Materials and Methods: A systematic search of PubMed, Embase, and Web of Science was conducted up to August 4, 2019. The associations between polymorphisms of inflammatory cytokine genes and IA risk were estimated by pooled odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup analyses were performed according to race. Qualitative systematic review was conducted for variants that were studied in only one study. All analyses were performed using STATA 12.0. Results: 13 studies investigating the associations between polymorphisms in five inflammatory cytokine genes (TNF-α, IL-1α, IL-1β, IL6, and IL-12B) and IA were reviewed. Combined results showed that the A allele of TNF-α rs1800629 polymorphism has a protective effect against IA (dominant model: OR=0.65, 95% CI=0.47-0.89, p=0.007). No associations were identified between polymorphisms in IL-1α rs1800587, IL-1β rs16944, IL6 rs1800795 and rs1800796, or IL-12B rs3212227 and IA risk. Conclusion: This review demonstrated an association between TNF-α rs1800629 polymorphism and IA in Caucasians, illustrating the potentially important role of genes involved in inflammation in IA.

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“…IL‐1β is a pro‐inflammatory cytokine highly produced by mononuclear phagocytes in response to injury and infection and is regarded as a master regulator of neuroinflammation . One study reported that in patients with aneurysmal subarachnoid hemorrhage, subjects carrying the T/T genotype of the IL‐1β gene showed a significant increase in the Hunt and Hess scores at hospital admission and a significant reduction in 6‐month Glasgow Outcome Scale scores , suggesting that IL‐1β may modify the complications of intracranial aneurysms. IL‐1β mRNA levels in cerebral arteries were increased in wild‐type C57BL/6 mice at both 2 weeks and 3 months after induction of intracranial aneurysm by ligation of a common carotid artery in combination with both hypertension and β‐aminopropionitrile administration .…”

Section: The Molecular Mechanisms Involved In Intracranial Aneurysm Dmentioning

confidence: 99%

Mouse Models of Intracranial Aneurysm

et al. 2014

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Subarachnoid hemorrhage secondary to rupture of an intracranial aneurysm is a highly lethal medical condition. Current management strategies for unruptured intracranial aneurysms involve radiological surveillance and neurosurgical or endovascular interventions. There is no pharmacological treatment available to decrease the risk of aneurysm rupture and subsequent subarachnoid hemorrhage. There is growing interest in the pathogenesis of intracranial aneurysm focused on the development of drug therapies to decrease the incidence of aneurysm rupture. The study of rodent models of intracranial aneurysms has the potential to improve our understanding of intracranial aneurysm development and progression. This review summarizes current mouse models of intact and ruptured intracranial aneurysms and discusses the relevance of these models to human intracranial aneurysms. The article also reviews the importance of these models in investigating the molecular mechanisms involved in the disease. Finally, potential pharmaceutical targets for intracranial aneurysm suggested by previous studies are discussed. Examples of potential drug targets include matrix metalloproteinases, stromal cell-derived factor-1, tumor necrosis factor-α, the renin-angiotensin system and the β-estrogen receptor. An agreed clear, precise and reproducible definition of what constitutes an aneurysm in the models would assist in their use to better understand the pathology of intracranial aneurysm and applying findings to patients.

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Interleukin-1 Cluster Gene Polymorphisms and Aneurysmal Subarachnoid Hemorrhage

Abstract: Our results do not support the hypothesis that genetic variation in select polymorphisms of the IL-1 cluster genes is associated with aneurysmal subarachnoid cerebral hemorrhage. However, the IL-1beta gene may modify disease severity and may be regarded as disease severity gene.

Cited by 13 publications

References 35 publications

Pathogenesis of intracranial aneurysm is mediated by proinflammatory cytokine TNFA and IFNG and through stochastic regulation of IL10 and TGFB1 by comorbid factors

Pathogenesis of intracranial aneurysm is mediated by proinflammatory cytokine TNFA and IFNG and through stochastic regulation of IL10 and TGFB1 by comorbid factors

Polymorphisms of Inflammatory Cytokine Genes and Risk for Intracranial Aneurysm: A Systematic Review and Meta-Analysis

Mouse Models of Intracranial Aneurysm

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