title: Pathogenesis of intracranial aneurysm is mediated by proinflammatory cytokine TNFA and IFNG and through stochastic regulation of IL10 and TGFB1 by comorbid factors.
abstract: 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.
authors.affiliation: Human Molecular Genetics Laboratory, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, 695014, Kerala, India. sanishsathyan@rgcb.res.in.
authors.forename: Sanish
authors.initials: S
authors.lastname: Sathyan
authors.affiliation: Human Molecular Genetics Laboratory, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, 695014, Kerala, India. lindakoshy@gmail.com.
authors.forename: Linda V
authors.initials: LV
authors.lastname: Koshy
authors.affiliation: Human Molecular Genetics Laboratory, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, 695014, Kerala, India. lekshmys@gmail.com.
authors.forename: Lekshmy
authors.initials: L
authors.lastname: Srinivas
authors.forename: Lekshmi
authors.initials: L
authors.lastname: Srinivas
authors.affiliation: Department of Neurosurgery, Sree Chitra Tirunal Institute for Medical Science and Technology, Thiruvananthapuram, Kerala, India. easwer@sctimst.ac.in.
authors.forename: H V
authors.initials: HV
authors.lastname: Easwer
authors.affiliation: Department of Neurosurgery, Calicut Medical College, Calicut, Kerala, India. drpremks@gmail.com.
authors.forename: S
authors.initials: S
authors.lastname: Premkumar
authors.affiliation: Department of Neurosurgery, Sree Chitra Tirunal Institute for Medical Science and Technology, Thiruvananthapuram, Kerala, India. snair@sctimst.ac.in.
authors.forename: Suresh
authors.initials: S
authors.lastname: Nair
authors.affiliation: Department of Neurosurgery, Sree Chitra Tirunal Institute for Medical Science and Technology, Thiruvananthapuram, Kerala, India. rnb@sctimst.ac.in.
authors.forename: R N
authors.initials: RN
authors.lastname: Bhattacharya
authors.affiliation: Department of Neurosurgery, Calicut Medical College, Calicut, Kerala, India. drjacobalapatt@yahoo.com.
authors.forename: Jacob P
authors.initials: JP
authors.lastname: Alapatt
authors.affiliation: Human Molecular Genetics Laboratory, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, 695014, Kerala, India. mbanerjee@rgcb.res.in.
authors.forename: Moinak
authors.initials: M
authors.lastname: Banerjee
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D015897:Comorbidity; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D006973:Hypertension / Q000235:genetics; D007371:Interferon-gamma / Q000235:genetics*; D016753:Interleukin-10 / Q000235:genetics*; D002532:Intracranial Aneurysm / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012737:Sex Factors; D012907:Smoking; D013269:Stochastic Processes; D013345:Subarachnoid Hemorrhage / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma