Uveitis genetics

Abstract

Uveitis is usually considered as a vision-threatening multiple system intraocular inflammatory disease. Among uveitis, Vogt-Koyanagi-Harada (VKH) disease and Behcet's disease (BD) are common non-infectious uveitis entities. Although the exact pathogenesis of uveitis is not yet clear, it is acknowledged that the combination of a certain genetic or epigenetic factors with an imbalance in the regulation of the immune response leads to the development of this disease. HLA genes show a strong association with both VKH disease (HLA-DR4, DRB1/DQA1) and BD (HLA-B51) in multiple ethnic populations. Candidate association studies based on a pathogenesis hypothesis laid the foundation for genetic research of uveitis and identified a large number of genes associated with VKH disease or BD including SUMO4, MCP-1, and CTLA4. Genome-wide association study (GWAS) provided a powerful tool for genome-wide level analysis to explore the genetic predisposition for uveitis and revealed several genes to be associated with uveitis including IL23R/C1orf141, STAT4 and ADO/ZNF365/EGR2. Another variant type, the so called copy number variants (CNV), in IL17F, IL23A and C4A also showed an association with uveitis. Additionally, epigenetic factors such as DNA methylation and ncRNAs play important roles in the development of uveitis. The application of new technologies such as whole exome sequencing and whole genome sequencing and other epigenetic modifications such as N6-methyl-adenosine (m6A) modification of mRNAs will be helpful to discover new pathogenic risk genes for uveitis. The understanding of the genetic and epigenetic mechanisms in uveitis may provide a foundation to find novel targets and to develop new strategies in the treatment of uveitis in the near future.