Association of VEGF-A and KDR polymorphisms with the development of schizophrenia

Several approaches indicate different blood flow disturbances in schizophrenia. VEGF-A is widely recognized as one of the key molecules involved in the angiogenesis process through mainly its receptor KDR. The current work was designed to investigate the potential association between three polymorphisms (rs699947; rs833061 and rs3025039) in VEGF-A gene and two SNPs (rs2305948 and rs1870377) within KDR gene and predisposition to schizophrenia among the Tunisian cohort.

We carried-out a case-control study composed of 200 patients with schizophrenia and 200 healthy subjects using PCR-RFLP.

Of all analyzed polymorphisms, only rs833061, rs3025039 and rs1870377) showed a significant risk for schizophrenia (P_Adjusted = 0.04, P_Adjusted=<0.001, P_Adjusted = 0.005 respectively). Following the stratified analysis, rs3025039 was more prevalent among undifferentiated form (P_Adjusted=<0.001) and more specifically with male sex (P_Adjusted=<0.001). Yet, rs1870377 was correlated with paranoid subtype (P_Adjusted = 0.002) and particularly with male sex (P_Adjusted = 0.005). We found also that rs699947 is associated to negative symptoms before and after treatment (P = 0.004; P = 0.001 respectively) and rs3025039 had an impact on positive and negative symptoms only after treatment (P = 0.03; P = 0.008 respectively). Haplotype analysis revealed a strong LD between rs833061 and rs3025039 only for controls and undifferentiated patients (P = 0.005). Moreover, the rs699947*C ∼ rs833061*T ∼ rs3025039*T haplotype, with only one mutated allele rs3025039*T, conferred a high risk to schizophrenia (P = 0.016) and, in particular, to undifferentiated and paranoid forms (P = 0.03; P = 0.02 respectively). Among the last-mentioned subgroup, we noticed another overrepresented haplotype (rs699947*A ∼ rs833061*T ∼ rs3025039*T; P = 0.01). Furthermore, the rs2305948*G ∼ rs1870377*T haplotype carrying the minor allele rs1870377*T displayed increased frequencies in the whole group of patients and particularly among paranoid subtype (P = 0.013; P=<0.001 respectively).

Our results show that all SNPs associated with the development or the severity of schizophrenia, were subsequently correlated with a decrease in the VEGF-A levels or influence KDR binding affinity. These data need to be strengthened by further independent analyses.