Genetic Dissection of Acute Anterior Uveitis Reveals Similarities and Differences in Associations Observed With Ankylosing Spondylitis

Abstract

Objective To use high density genotyping to investigate the genetic associations of acute anterior uveitis (AAU) in patients both with and without ankylosing spondylitis (AS). Method We genotyped 1,711 patients with AAU (either primary or with AAU and AS), 2,339 AS patients without AAU, and 10,000 controls on the Illumina Immunochip Infinium microarray. We also used data on AS patients from previous genomewide association studies to investigate the AS risk locus ANTXR2 for its putative effect in AAU. ANTXR2 expression in mouse eyes was investigated by RT-PCR. Results Comparing all AAU cases with HC, strong association was seen over HLA-B corresponding to the HLA-B27 tag SNP rs116488202. Three non-MHC loci IL23R, the intergenic region 2p15 and ERAP1 were associated at genome-wide significance (P < 5×10−8). Five loci harboring the immune-related genes IL10-IL19, IL18R1-IL1R1, IL6R, the chromosome 1q32 locus harboring KIF21B, as well as the eye related gene EYS, were also associated at a suggestive level of significance (P < 5×10−6). A number of previously confirmed AS associations demonstrated significant differences in effect size between AS patients with AAU and AS patients without AAU. ANTXR2 expression was found to vary across eye compartments. Conclusion These findings, with both novel AAU specific associations, and associations shared with AS demonstrate overlapping but also distinct genetic susceptibility loci for AAU and AS. The associations in IL10 and IL18R1 are shared with inflammatory bowel disease, suggesting common etiologic pathways.

Uveitis in spondyloarthritis including psoriatic arthritis, ankylosing spondylitis, and inflammatory bowel disease

“…Their disease tends to be much more persistent and is more likely to be associated with cataract or glaucoma. Several studies have identified genetic loci that affect the predisposition to uveitis in association with ankylosing spondylitis separately from affecting predisposition to joint disease [16,17]. These loci have not as yet been studied in the uveitis in association with psoriatic arthritis or IBD, and the rarity of these entities makes such a study difficult.…”

“…These loci have not as yet been studied in the uveitis in association with psoriatic arthritis or IBD, and the rarity of these entities makes such a study difficult. In addition to HLA B27, several genetic factors such as polymorphisms in the IL-23R are common to ankylosing spondylitis, inflammatory bowel disease, psoriatic arthritis, and uveitis [16,17].…”

Genetics of ankylosing spondylitis—insights into pathogenesis

“…The association of ERAP1 with acute anterior uveitis is stronger than its association with AS, suggesting that this pathway is even more centrally involved in uveitis pathogenesis than in AS predisposi tion. 69 In Behçet disease, the ASprotective haplotypes interact with HLA-B*51 to increase risk. Multiple weaker associations of ERAP1 have been reported with type 1 diabetes mellitus, cervical cancer, hypertension and multiple sclerosis, but these associations have yet to be demonstrated definitively, or have not been replicated in large studies.…”

Association of T-Bet, GATA-3, RORC, and FOXP3 Copy Number Variations With Acute Anterior Uveitis With or Without Ankylosing Spondylitis in Chinese Han

“…Besides the association with HLA-B27 (class I major histocompatibility complex [MHC]), evidence for an association of AAU with class II MHC genes has also been reported. 28 Recently, a high throughput genotyping method was used in a multicenter study 29 to investigate the genetic associations of AAU. The results showed that single nucleotide polymorphisms (SNPs) located in or around MHC class I or class II are associated with the susceptibility to AAU.…”