Genetic variants in FCGR2A, PTPN2, VDR as Predictive Signatures of Aggressive Phenotypes in Cerebral Cavernous Malformation

BACKGROUND: Cerebral Cavernous Malformation (CCM) is a disease that affects the central nervous system of 0.2-0.9% of the general population, which consists of vascular lesions and often results in significant hemorrhages and consequent neurological complications. Although significant advances have been made in understanding the natural history and pathogenic mechanisms of CCM, clinical and biological behavior is still controversial, with no clear signature for a biological mechanistic explanation of the aggressiveness of the lesion. There is much evidence implicating dysregulated inflammatory and immunological responses in the pathogenesis of vascular malformations.

METHODS: In this study, we evaluated the predictive capacity of the SNPs VDR^rs7975232, VDR^rs731236, VDR^rs11568820, PTPN2^rs72872125 and FCGR2A^rs1801274 concerning the aggressive behavior of CCM and its implications in biological processes. Genomic DNA was extracted from leukocytes for subsequent use in real-time PCR genotyping by TaqMan-PCR assay. This was a single-site prospective observational cohort study with 103 patients enrolled, 42 had close follow-up visits for 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.

RESULTS: 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 FCGR2A^rs1801274 GG genotype could predict a symptomatic event during follow-up. Also, we found a correlation between VDR^rs731236 AA and VDR^rs11568820 CC genotype at the time of to first symptomatic event.

CONCLUSIONS: This study provides significant insights into the genetic markers that could potentially impact the development and progression of CCM.