Genetic Markers and Predictive Factors Influencing the Aggressive Behavior of Cerebral Cavernous Malformation

Biological behavior of Cerebral Cavernous Malformation (CCM) is still controversial without clear-cut signature for biological mechanistic explanation of lesion aggressiveness. There is plenty evidence implicating dysregulated inflammatory and immune responses in vascular malformation pathogenesis, including CCM. In the present study, we evaluated the predictive capacity of the SNPs VDRrs7975232, VDRrs731236, VDR rs11568820 as well as expanded the analysis of PTPN2 rs72872125 and FCGR2Ars1801274 in relation to the aggressive behavior of CCM and its implications in biological processes. This was a single-site prospective observational cohort study with 103 patients enrolled, 42 had close follow-up visits for a period of 4 years, focused on 2 main aspects of the disease: (1) symptomatic event that composed both intracranial bleeding or epilepsy and (2) precocity of symptoms. We report a novel observation that the PTPN2 rs72872125 CT and the VDR rs7975232 CC genotype were independently associated with an asymptomatic phenotype. Additionally, PTPN2 rs72872125 CC genotype and serum level of GM-CSF could predict a diagnostic association with symptomatic phenotype in CCM patients, while the FCGR2Ars1801274 GG genotype could predict a symptomatic event during follow-up. The study also found a correlation between VDRrs731236 AA and VDR rs11568820 CC genotype to the time to first symptomatic event. In summary, this study provides valuable insights into the genetic markers that could potentially impact the development and advancement of CCM. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by CNPQ, CAPES, FAPERJ, Senator Romario Faria, MS and Casa Hunter ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Qualified researcher on human subjects conducted this study having been approved by the National Council for Ethics in Research (CAAE 69409617.9.0000.5258). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced are available online at