Identification of Novel Risk Loci for Behçet's Disease–Related Uveitis in a Chinese Population in a Genome‐Wide Association Study

Abstract

Objective To explore susceptibility loci associated with uveitis in Behçet's disease (BD). Methods We conducted a 2‐stage study, consisting of a genome‐wide association study (GWAS) stage and a replication stage, in a Chinese population. The GWAS stage included 978 cases with BD‐related uveitis and 4,388 controls, and the replication stage included 953 cases with BD‐related uveitis and 2,129 controls. Luciferase reporter analysis and chromatin immunoprecipitation assay were performed to explore the functional role of susceptibility genetic variants near ZMIZ1. Results Three independent HLA alleles (HLA–B51 [3.75 × 10−190], HLA–A26 [1.50 × 10−18], and HLA–C0704 [3.44 × 10−16]) were identified as having a genome‐wide association with BD‐related uveitis. In the non‐HLA region, in addition to confirming 7 previously reported loci, we identified 22 novel susceptibility variants located in 16 loci. Meta‐analysis of the Chinese cohort consisting of 1,931 cases and 6,517 controls and a published Japanese cohort of 611 cases and 737 controls showed genome‐wide significant associations with ZMIZ1, RPS6KA4, IL10RA, SIPA1‐FIBP‐FOSL1, and VAMP1. Functional experiments demonstrated that genetic variants of ZMIZ1 were associated with enhanced transcription activity and increased expression of ZMIZ1. Conclusion This GWAS study identified a novel set of genetic variants that are associated with susceptibility to uveitis in BD. These findings enrich our understanding of the contribution of genetic factors to the disease.

Genetics in Behcet’s Disease: An Update Review

“…Association between rs1518111 polymorphism of IL-10 and risk of BD was identified by multiple studies in various populations (11,27,30,34). A recent GWAS study of Chinese BD uveitis involving 978 patients and, 4388 controls also confirmed the risk factor role of the IL-10 variant (rs3021094) (52). In addition, two novel loci of IL10RA (rs2228054 and rs2228055) showed genome-wide significant association with BD uveitis in this study.…”

Atypical Cogan's Syndrome with Large-vessel Vasculitis Successfully Treated with Tocilizumab

“…LVV, such as vasculo-Behcet's disease and Takayasu's arteritis, has been reported to be associated with certain human leukocyte antigen (HLA) serotypes (vasculo-Behcet's disease with HLA-A26 and B51 and Takayasu's arteritis with HLA-B39 and B52) [16,17]. However, a definite association of HLA with Cogan's syndrome has not been reported.…”

Causal Association between Iritis or Uveitis and Glaucoma: A Two-Sample Mendelian Randomisation Study

“…The classification of glaucoma is based on anatomical and known-causal factors, with open-angle glaucoma (OAG) being the most common form according to the anatomical mechanism [ 4 ]. Uveitic glaucoma (UG) is a complex range of disorders characterized by the coexistence of iritis and glaucomatous optic neuropathy, which encompasses several diverse clinical entities with varying prognoses [ 5 , 6 , 7 ]. Nevertheless, not all patients with uveitis develop glaucoma, which can be caused by uveitis itself or occur as a side effect of treating inflammation.…”

“…Early stages of UG may present with open-angle and shared features of OAG. As uveitis and glaucoma are complex diseases with genetic predisposition and predisposing environmental factors [ 5 , 6 , 7 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ], further research using genetic data is required to gain additional information regarding the association between uveitis and OAG.…”