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

Abstract

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.

Lymphocytes influence intracranial aneurysm formation and rupture: role of extracellular matrix remodeling and phenotypic modulation of vascular smooth muscle cells

“…Increased systemic and local tissue expression of IL-6 has been well-characterized in clinical studies of IA, and although some suggest that lower IL-6 levels are synonymous with lower rates of IA rupture [ 31 , 32 ], other studies have shown that certain polymorphisms in the IL-6 gene can be protective against IA [ 33 ]. A meta-analysis of IA in a Southern Indian population showed that genetic variants in TNF and IFNγ but not IL-6 were associated with IA [ 34 ]. In this study, a significantly lower rate of IA rupture was seen with markedly higher IL-6 tissue expression at 2 weeks.…”

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

“…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.…”

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

“…Following publication of [ 1 ] it came to the authors’ attention that Lekshmy Srinivas’ name was displayed incorrectly. The correct spelling of their name is included in this erratum.…”