Genetic Polymorphisms Of TAM And Its Ligands Genes In Ocular Beh(?)et Disease

Purpose: TAM kinases(tyro3, axl, mer) family and its two ligands(gas6, protein S) have been revealed either independently or collectively to be associated with several autoimmune or immune-related modulation processes. The present study aimed to investigate whether the tag single-nucleotide polymorphisms(tag SNPs) of these 5 TAM signal related protein-coding genes(TYRO3, AXL, MERTK, GAS6, PROS1) are associated with ocular Beh?et disease(BD) in the Chinese Han origin population.Methods: A two-stage association study was performed in total 907 ocular BD patients and 1780 uveitis-free controls. Altogether 32 polymorphisms in TYRO3, AXL, MERTK, GAS6 and PROS1 genes were tested, using Sequenom MassARRAY genotyping method in the first stage and PCR-restriction fragment length polymorphism(PCR-RFLP) assay in the replication phase. Real-time PCR was performed to test the GAS6 and PROS1 relative mRNA expression level in peripheral blood mononuclear cells(PBMCs) from different SNP genotyped individuals. Cytokine production was measured by ELISA.Results: The study showed that SNP rs9577873 in GAS6 gene and rs4857037 in PROS1 gene were significantly associated with the risk of BD in Han Chinese. The C allele and CC genotype of rs9577873 in GAS6 gene(Pc=4.92×10-5,OR=1.598; Pc=1.91×10-5,OR=1.698, respectively) and the A allele and AA genotype of rs4857037 in PROS1 gene(Pc=1.85×10-6,OR=1.822; Pc=4.52×10-7,OR=1.945, respectively) is significantly higher in BD patients when compared with healthy controls, but none of the remaining tagSNPs involved in this study were associated with BD. GAS6 expression in CC carriers of rs9577873 was significantly lower than that in CT/TT individuals with untreated PBMCs(P=0.001). PROS1 expression in AA carriers of rs4857037 was significantly higher than that in AG/GG individuals with LPS-treated PBMCs(P=0.033). An elevated secretion of IL-6 and IFN-γ were detected in CC genotype when it compared to CT individuals(P=4.23×10-4, P=0.011, respectively).Conclusions: This study identified two risk SNPs, rs9577873/GAS6 and rs4857037/ PROS1 in Chinese Han ocular BD patients. Decreased expression of GAS6 and increased pro-inflammatory cytokines in individuals carrying the CC genotype suggest that TAM-GAS6/PROS1 signal pathway genes may be involved in the pathogenesis of BD.