A genome wide scan identifies 3 loci predisposing to acute anterior uveitis including one locus unassociated with ankylosing spondylitis

Abstract

Abstract: : Purpose: To conduct a genome–wide scan to search for loci associated with acute anterior uveitis. Methods: Families with 2 or more members who have acute anterior uveitis and/or ankylosing spondylitis (AS) were recruited by investigators at the Casey Eye Institute or the North American Spondylitis Consortium (NASC, headed by Dr. Reveille). Genomic DNA extracted from blood cells was PCR–genotyped using the ABI Prism Linkage Map MD–10 system (Applied Biosystems, Foster City, CA). Evidence for linkage was determined by nonparametric multipoint linkage analysis using Gene Hunter Plus. The transmission disequilibrium test was also performed. The genome–wide scan for acute anterior uveitis was compared to one for AS performed by the NASC study. Results: Out of 978 individuals genotyped, 244 were affected with acute anterior uveitis. Where possible, the uveitis phenotype was verified by ophthalmology chart review. If no ophthalmology records were available, the assignment of a uveitis phenotype was based on self report AND documentation in a non–ophthalmological medical chart (usually noted by a rheumatologist). The data presented represent 76 affected sibling pairs for acute anterior uveitis. Of these, 6 sib pairs denied any symptoms of AS, 12 uveitis sib pairs were discordant for AS and the remaining 58 uveitis sib pairs were concordant for AS, either by self–report or by radiographic disease determination. A region at chromosome 9p showed a striking association with uveitis but not AS. The maximum LOD score at this region was 3.69 for uveitis, while the LOD score for the AS cohort was not significant (<1.0). Additional regions with significant linkage include the MHC locus on chromosome 6, and a region at chromosome 1q. However, these regions also showed significant linkage with AS. Transmission disequilibrium analyses supported the genome–wide scan linkage findings, including the 9p uveitis association. Conclusions: This is the first time that a genetic region for acute anterior uveitis has been identified by genome–wide scan. These data reveal a region on chromosome 9p as a predisposing factor in uveitis. Comparison to a companion AS scan indicates that this region is unique to the uveitis phenotype. Fine–mapping and/or candidate gene analyses should reveal the relevant gene(s) on chromosome 9.

Keywords: inflammation • genetics • linkage analysis