The genetics of sporadic ruptured and unruptured intracranial aneurysms: a genetic meta-analysis of 8 genes and 13 polymorphisms in approximately 20,000 individuals

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Intracranial aneurysms (IAs) are thought to have a multifactorial origin. The authors undertook a comprehensive meta-analysis on all genes investigated using a case-control model in ruptured (subarachnoid hemorrhage) and unruptured aneurysms.


Electronic databases were searched until and including July 2008 for any candidate gene studied in IA or subarachnoid hemorrhage using a case-control model. The ORs and 95% CIs were determined for each gene-disease association using fixed and random effect models.


Thirty studies of 8 genes and 13 polymorphisms were analyzed among 19,961 individuals (6622 cases and 13,339 controls). Two genes and 3 polymorphisms were associated with IA. The eNOS gene T786C polymorphism (OR 1.24, 95% CI 1.0–1.54; p = 0.05) and IL-6 gene G572C polymorphism (OR 7.08, 95% CI 2.85–17.57; p < 0.0001) both showed a significant association with ruptured/unruptured IA. The IL-6/G174C polymorphism exerted a significant protective effect against IA (OR 0.49, 95% CI 0.25–0.95; p = 0.04). The other candidate genes investigated (ACE, endoglin, APOE, elastin, MMP-3, and SERPINA3) showed no significant associations.


There is a likely genetic basis to sporadic IAs. However, the evidence base is small when compared against other complex disorders.

Abbreviations used in this paper: eNOS = endothelial nitric oxide synthase; IA = intracranial aneurysm; IL-6 = interleukin-6; NO = nitric oxide; PAR = population-attributable risk; pHet = probability test for heterogeneity; SAH = subarachnoid hemorrhage; SNP = single nucleotide polymorphism.

Article Information

Address correspondence to: Pankaj Sharma, M.D., Ph.D., F.R.C.P. email:

Please include this information when citing this paper: published online September 25, 2009; DOI: 10.3171/2009.8.JNS092.

© AANS, except where prohibited by US copyright law.



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    Flowchart illustrating number of studies included in the meta-analyses.

  • View in gallery

    Forest plot of pooled OR of eNOS 786C in IAs. The 95% CIs are drawn with the size of the box reflecting the weighting given to each study. M-H = Mantel-Haenszel.


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