Understanding the Genetic Susceptibility and Epidemiologic Risk Factors of Intracranial Aneurysms

Background and Objectives: Intracranial aneurysms affect up to 3% of the population and carry a high mortality and morbidity prognosis when presented with aneurysm rupture and spontaneous subarachnoid hemorrhage (SAH). Despite its severity on patient prognosis and cost to society, the pathologic mechanism of cerebral aneurysm formation and rupture remains unclear. The roles of genetics and epidemiology have been implicated to play major roles in the pathogenesis of aneurysm and patient outcome after SAH. Our studies serve to investigate both the genetic and epidemiologic factors associated with cerebral aneurysms through studying genome-wide association study (GWAS) of mitochondrial genes and the Nationwide Inpatient Sample (NIS) database. Methods: For our genetic study of cerebral aneurysms, we analyzed data from two existing GWAS databases targeting the nuclear-encoded mitochondrial gene loci. We identified single nucleotide polymorphisms (SNPs) within 500kb of 794 candidate nuclear-encoded mitochondrial proteins using the human mitochondrial protein and MitoProteome databases. Plink was used to identify SNPs associated with cerebral aneurysms and a meta-analysis approach was used to calculate the pooled odds ratio (OR) and 95% confidence interval (CI) of the two combined studies. In addition, gene expression analysis using three gene omnibus (GEO) databases (GSE15629, GSE26969, GSE46337) was used to identify differential expression of the genes associated with the significant SNPs. For our epidemiologic study of cerebral aneurysms, we analyzed patients using the NIS database from 2001 to 2010. Multivariate linear and logistic models were used to analyze the association between 1) cerebral aneurysm rupture and climatic factors, 2) cerebral aneurysm outcome and hospital teaching status, and 3) cerebral aneurysm outcome and patient insurance status. Results: Genetic studies: A new genome-wide significant SNP on chromosome 19 (rs7937, OR=2.71, 95%CI 1.81-4.05, p=3.46x10-5) was found to be associated with the formation of cerebral aneurysms. The expression of the gene associated with this SNP, RAB4B, was also found to be elevated in our subsequent differential gene expression analysis (RAB4B, OR=1.74, 95%CI 1.23-2.47, p=0.02). Epidemiologic studies: There were 38,843 hospitalizations for the treatment of unruptured and ruptured aneurysms. In the analysis of SAH rupture with meteorological pattern, decreased sunlight and lower relative humidity were associated with increased rate of admission (p<0.001). In ruptured cerebral aneurysms, the odds ratio of in-hospital death and non-routine discharges were 0.69 (95% CI 0.54-0.88) and 0.77 (95% CI 0.60-0.99) in teaching hospitals, independent of hospital aneurysm procedure volume. This difference was accentuated in patients who underwent microsurgical clipping. In the analysis of patient outcome with insurance status, the adjusted odds of in-hospital mortality were higher for Medicare (OR 1.23, p<0.001), Medicaid (OR 1.23, p<0.001), and uninsured patients (OR 1.49, p<0.001) compared with those with private insurance. Conclusion: In our genetics analysis of cerebral aneurysms, we demonstrated that mitochondrial genes may play an important role in the pathogenesis of cerebral aneurysm formation, and further research is necessary to confirm and validate the relationship between RAB4B and cerebral aneurysm formation. Our nationwide study was the first to suggest the association between decreased sunlight and lower relative humidity with admission of ruptured cerebral aneurysms. Furthermore, the studies also showed that both the hospital teaching status and patient insurance status have significant associations with the outcome cerebral aneurysm rupture.