Article
Genetic background in patients with aneurysmal subarachnoid hemorrhage
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Published: | June 9, 2017 |
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Objective: The risk for intracranial aneurysms (IA) and aneurysmatic subarachnoid hemorrhage (SAH) is increased among patient’s family members, however, the genetic background of the disease is still poorly understood. Although large genome wide association studies identified several single nucleotide polymorphisms, true pathogenic mutations have not been discovered yet. A better knowledge of the genetic background is essential to understand the molecular and cellular dysfunctions in SAH and to spot patients at risk for IA rupture.
Methods: We analyzed patients with SAH and multiple unruptured aneurysms from two families using Illumina HiSeqTM 2500 platform. In a next step we extended Whole Exome Sequencing analyses to a larger patient cohort (n=25). Diseases associated with SAH such as Marfan’s syndrome, Ehlers-Danlos syndrome or polycystic kidney disease were clinically excluded. Subsequently, statistical analyses using the Burrows Wheeler Aligner, Genome Analysis Toolkit, SAMtools and gene ranking were performed.
Results: WES and bioinformatic statistics revealed several candidate genes for SAH, which we ranked based on the identified mutation type and position as well as the pathophysiological relevance of the gene product. This resulted in PIK3R3 (coding for Phosphatidylinositol 3-Kinase, Regulatory subunit 3), COL5A1 and COL4A1 (coding for Collagen type V alpha 1 and type IV alpha 1, respectively) as top candidate disease genes.
Conclusion: Our analysis revealed PIK3R3 as a strong candidate disease gene for SAH, however, final verification of a phenocritical role for mutations in PIK3R3 has to be investigated. Notably, knockdown of PIK3R3 increases vascular smooth muscle cell proliferation and neointimal formation in a rat model. Taken together, these results emphasize the possible role of PIK3R3 in the pathophysiology of SAH and IA formation. Our findings might contribute to develop future tests to assess the risk of SAH in a routine clinical setting.