| Uveitis is a group of heterogeneous ocular inflammatory diseases with complex phenotypes, which causes substantial visual impairment and accounts for about 10% of blindness worldwide among the working age group. Uveitis is generally accepted as an inflammatory condition and regulated by various endogenous immunological mechanisms. Moreover, uveitis can occur in individuals with genetic predisposition coupled with environmental factors. We target several molecular factors involved in the two major pathways to evaluate the genetic impact on susceptibility to uveitis, reveal potential disease mechanisms, and discover diagnostic markers.;Study 1: In a systemic review to explore recent genetic findings in uveitis susceptibility, we found several genes persistently associated with uveitis and involved in various pathways. They are genes expressing interleukin, chemokine, tumor necrosis factor, and genes involved in complement and oxidation pathways. Genetic polymorphisms were selected based on the immunological and inflammatory properties of uveitis. (1) Interleukin and CFH genes, involving in the T-cell response and complement system respectively. (2) CFB, as a competitor of CFH, involved in the alternative pathway of complement cascade together. (3) Investigation of C1INH ( SERPING1) in uveitis, with a view to elucidating the involvement of the classic pathway of complement cascade in uveitis development. (4) Evaluation of C3 and C5 genes in uveitis, due to their respective role of center component and downstream factor in the complement cascade.;Study 2: Genetic variations in the CFH, KIAA1109 and IL27 genes were examined. Our results showed an association between AU and CFH polymorphisms (rs800292 and rs1065489). The frequency of the CFH-rs800292 184G allele and GG homozygosity was higher in female patients than in controls. CFH-rs1065489 TT genotype was identified as a clinical marker associated with higher uveitis recurrence frequency. Interactions with HLA-B27 status in AU patients and different gender susceptibility were observed. In the second part of this study, these three candidate genes were examined in the other uveitic entity, NIPU, in our study cohort. CFH gene polymorphisms (rs1065489 and rs800292) were associated with NIPU patients. Specific association between KIAA1109-rs4505848 polymorphism and Behcet's disease was identified. There was also gender specific genetic difference. The dominant genotype of KIAA1109-rs4505848 in male NIPU patients was significantly more frequent than in male controls (GG/AG vs. AA).;Study 3: CFB, a competitor of CFH and participated in the same complement alternative pathway, was investigated. SNP rs1048709 in the C2/CFB region was associated with AU, and this genetic influence was affected by HLA-B27 status. Furthermore, one haplotype block across CFB (AATA) significantly predisposed AU with an increased risk of 1.97 (95% CI: 1.41-2.76; Pcorr=0.0005). Joint effects of CFB-rs1048709 with (CFH-rs800292 and CFH-rs1065489) were identified to be at a risk of 7.48 and 7.0 respectively. In addition, patients carrying rs1048709 (AG) were predicted to develop a higher degree of anterior chamber cells and higher proportion of keratic precipitate (KP) during AU course. For NIPU, association with CFB was detected for a different SNP, rs4151657, in female patients only.;Studies 4, 5, and 6: Three candidate genes (SERPING1, C3 and C5) across the complement cascade were orderly evaluated in the whole study cohort of AU, NIPU and controls. They did not show any significant associations with both two uveitis entities, although multiple in-depth analyses have been performed. (Abstract shortened by UMI.). |
