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Background  Intracranial 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.    Methods  Functionally 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.    Results  Pro-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.    Conclusions  The 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 material  The online version of this article (doi:10.1186/s12974-015-0354-0) contains supplementary material, which is available to authorized users.

journal of neuroinflammation

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