Association of Variants in FCGR2A, PTPN2 and GM-CSF with Cerebral Cavernous Malformation: Potential Biomarkers for Symptomatic Disease.

Backgrounds Cerebral cavernous malformations (CCM) predispose patients to a lifetime risk of seizures and symptomatic hemorrhage. Only a small percentage of affected people will develop clinical symptoms, and molecular mechanisms underlying lesional activity remain unclear. We have analyzed a panel of Single Nucleotide Polymorphisms (SNPs) in CCM patients and looked for plasmatic inflammatory cytokines checking for a pattern of plasmatic expression heterogeneity and any correlation with the genetic variation identified with different CCM clinical phenotypes. Methods This is a case-control study from a long-term follow-up cohort, including 23 CCM patients, 16 symptomatic, and 7 asymptomatic patients. A 200 SNP´s panel was performed through next-generation sequencing and eighteen different plasma molecules were assessed through a suspension array system. Results Fcγreceptor IIa rs1801274 (FCGR2A) and Protein tyrosine phosphatase non-receptor type 2 rs72872125 PTPN2 were found statically different between groups. Patients who had the combination of the presence of FCGR2A and the absence of PTPN2 also had symptoms earlier in their lifetime. The combination of the genetic polymorphisms and serum level of GM-CSF had resulted in the best diagnostic biomarker to distinguish symptomatic patients as formulated: [0.296*(FCGR2A)] + [-0.788*(PTPN2)] + [-0.107*(GM-CSF)]. Conclusion We have shown that SNPs in inflammation genes might be related to the symptomatic phenotype in CCM. We also demonstrated that a formula based on two of these polymorphisms (FCGR2A+ and PTPN2+) was possibly capable of predicting a symptomatic phenotype during a patient's lifetime.