Yan J, Hitomi T, Takenaka K, Kato M, Kobayashi H, Okuda H, et al. Genetic Study of Intracranial Aneurysms. Stroke. 2015
The authors of this study delve into an interesting topic of determining the genetic predisposition of intracranial aneurysms (IA). Intracranial aneurysms when ruptured can lead to subarachnoid hemorrhage and can lead to devastating brain injury. Evaluation of the pathogenesis of aneurysms on the basis of luminal forces—such as high blood flow, shear stress and turbulence—alone may conceal other equally important abluminal factors, such as morphological or biological phenomena within the vessel wall, or the perianeurysmal environment.1-3 Microarray gene analyses of human tissue has found differential gene expression profiles between healthy arterial wall and aneurysm wall, with increased expression of genes related to infiltration of inflammatory cells, complement activation, apoptosis and inhibition of re-endothelialization in the aneurysm wall.4 Yan and colleagues attempted to determine the genetic component that contributes to the process of the development of intracranial aneurysms by performing whole exome sequencing of 42 cases with a definite phenotype of IA from 12 families.
They approached this daunting task by first establishing a large cohort of familial and sporadic IA cases from hospitals located in the western part of Japan. Using complex genetic analysis, they were able to determine via replicate association studies that only p.E133Q in ADAMTS15 was aggregated in the familial IA cases [odds ratio, 5.96; 95% confidence interval: 2.40–14.82; P=0.0001, significant after the Bonferroni correction (P =0.05/78=0.0006)]. Furthermore, they found that silencing ADAMTS15 and overexpression of ADAMTS15 p.E133Q accelerated endothelial cell migration, suggesting that ADAMTS15 may have antiangiogenic activity.
The authors take an important step forward in the cumbersome process of identifying possible genetic links that exist for intracranial aneurysms and this warrants further studies as well as genetic testing on patients that present with a familial history of intracranial aneurysms. Through genetic analysis, future targeting of these genes will go a long ways in reducing the burden of disease. I believe we have only touched the tip of the iceberg and gene therapy shall soon be entering its infant stages as further research is conducted.
References:
2. Wiebers, D. O. et al. Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet 362, 103–110 (2003).
3. Hashimoto, T., Meng, H. & Young, W. L. Intracranial aneurysms: links among inflammation, hemodynamics and vascular remodeling. Neurol. Res. 28, 372–380 (2006)
4. Burton, C. & Johnston, J. Multiple cerebral aneurysms and cardiac myxoma. N. Engl. J. Med. 282, 35–36 (1970).
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