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

• Published in: Current neurovascular research Vol. 18; no. 2; p. 172
• Main Authors: da Fontoura Galváo, Gustavo, Fontes-Dantas, Fabrícia Lima, da Silva, Elielson Veloso, Alves-Leon, Soniza Vieira, de Souza, Jorge Marcondes
• Format: Journal Article
• Language: English
• Published: United Arab Emirates 01-01-2021
• Subjects: Adult; Aged; Case-Control Studies; Female; Genetic Markers; Granulocyte-Macrophage Colony-Stimulating Factor - genetics; Hemangioma, Cavernous, Central Nervous System - genetics; High-Throughput Nucleotide Sequencing; Humans; Male; Middle Aged; Protein Tyrosine Phosphatase, Non-Receptor Type 2 - genetics; Receptors, IgG - genetics; Young Adult; cerebral cavernous malformation; peripheral plasma; GM-CSF; Fcγ receptor IIa; biomarkers; PTPN2
• DOI: 10.2174/1567202618666210603125630
• EISSN: 1875-5739

Cerebral Cavernous Malformations (CCM) predispose patients to a lifetime risk of seizures and symptomatic hemorrhage. Only a small percentage of people affected will develop clinical symptoms and the molecular mechanisms underlying lesional activity remain unclear. We analyzed a panel of Single Nucleotide Polymorphisms (SNPs) in CCM patients. We looked for plasmatic inflammatory cytokines, checking for a pattern of plasma expression heterogeneity and any correlation with genetic variations identified with different CCM clinical phenotypes.
This was a case-control study from a long-term follow-up cohort including 23 CCM patients, of which 16 were symptomatic, and 7 were asymptomatic. A 200-SNP panel was considered through next-generation sequencing and 18 different plasma molecules were assessed through a suspension array system.
Fcγ receptor IIa rs1801274 (FCGR2A) and protein tyrosine phosphatase non-receptor type 2 rs72872125 PTPN2 were statistically different between groups. Patients who had a combination of the presence of FCGR2A and the absence of PTPN2 also had symptoms earlier in life. The combination of genetic polymorphisms and serum level of GM-CSF showed the best diagnostic biomarker to distinguish symptomatic patients as formulated: [0.296*(FCGR2A)] + [-0.788*(PTPN2)] + [-0.107*(GM-CSF)].
We have shown that SNPs in inflammation genes might be related to a symptomatic phenotype in CCM. We also demonstrated that a formula based on two of these polymorphisms (FCGR2A+ and PTPN2+) is possibly capable of predicting a symptomatic phenotype during a patient's lifetime.