Based on studies of twins, about 40% of cases of intracranial aneurysms are attributable to predisposing genes. Genome-wide association studies have identified polymorphisms in several genes that are associated with intracranial aneurysms, and these variants explain more than half of disease heritability.
Still, that suggests a significant role for nonheritable causes. Researchers at Brigham and Women’s Hospital recently reported in Neurology Genetics that somatic variants—specifically, somatic variants in the supervillin (SVIL) gene—increase susceptibility to intracranial aneurysms through changes in vascular smooth muscle cells (vSMCs).
The authors are Pui Man Rosalind Lai, MD, a former resident of the Department of Neurosurgery, Kai U. Frerichs, MD, director of Interventional Neuroradiology and Endovascular Neurosurgery at the Brigham, Rose Du, MD, PhD, director of Cerebrovascular Surgery, and colleagues.
At 13 centers, tissue from intracranial aneurysms of 30 patients (70% female, mean age 54) was obtained during surgical clipping. Whole-exome sequencing was performed on the tissue samples and matched peripheral blood samples. RNA sequencing and the CRISPR/Cas9 system were used later to explore the functional implications of the somatic mutations identified.
The key findings were:
- Five patients (17%) had variants related to SVIL, a gene on chromosome 7 that helps regulate cell–cell adhesion and extracellular matrix adhesion
- SVIL proved to have a role in the switching of vSMCs from the contractile phenotype to the synthetic phenotype
- The switch occurred with increased cell proliferation and migration via multiple pathways: p53/KLF4, PRAS40/MMP2 and MMP9, PDGF/HSP27, and RhoA/ROCK
- SVIL knockdown appeared to lead to migration of vSMCs because of increased expression of ROCK (Rho-associated, coiled-coil-containing protein kinase), and administration of a ROCK inhibitor called Y27632 suppressed the cells’ ability to migrate
ROCK inhibitors may prove to be a therapy—and perhaps even a preventive intervention—for intracranial aneurysms.