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T. M. Martin, D. M. Evans, P. Danoy, J. R. Smith, M. M. Ward, M. H. Weisman, The Australo-Anglo-American Spondylitis Consortium, J. D. Reveille, M. A. Brown, J. T. Rosenbaum; The Identification of New Genetic Associations for Acute Anterior Uveitis in a Genomewide Scan Comparison of Ankylosing Spondylitis Cases With vs. Without Uveitis. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3784.
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Acute anterior uveitis (AAU) and ankylosing spondylitis (AS) may occur independently or within the same patient. This study sought to (1) determine whether known AS genes also contribute to AAU, and (2) identify AAU-specific genetic associations.
Caucasian subjects with AS, AAU, or both were identified from a uveitis genetics study (OHSU) or via The Australo-Anglo-American Spondylitis Consortium (TASC). DNA was genotyped using either the Illumina 370CNV chip (TASC cases) or Illumina 610 chip (OHSU cases). The study utilized 952 uveitis cases (either with or without AS) and 1380 cases with validated AS (for whom uveitis was known to be absent from clinical records). Healthy controls of white European ancestry were from the Illumina iControl database. The AAU phenotype was validated from ophthalmology charts for a subset of the uveitis cases (n=153). Datasets were compared with the Cochrane-Armitage test for trend as implemented in PLINK. Study activities were performed in accordance with approved human subjects protocols and the Declaration of Helsinki.
A comparison of AS with uveitis vs. AS without uveitis revealed (1) the absence of differences at known AS loci; and (2) novel associations at 3 genetic regions. Association was observed at chromosome 1p35.1 in the gene CSMD2 (CUB and Sushi multiple domains 2; peak signal at SNP rs732889, P= 1.8x10-7). Associations were also observed at 4q32.3 and 15q22.1 with peak signficance at SNP rs11100530 (P=2.0x10-6) and rs1122208 (P=5.7x10-7), respectively. No genes reside in these regions. None of the 3 regions were associated with AS when compared to healthy controls.
This study confirms or reveals that genes involved in AS, including HLA-B27, IL23R, ERAP1, and IL1R2 are similarly associated with AAU. Three AAU-specific loci were also observed. One identified CSMD2 and 2 are in gene deserts. CSMD2 encodes a transmembrane protein with a large extracellular domain containing alternating CUB and Sushi motifs. It is reported to be expressed in brain and related tissues, including the ciliary ganglia. Additional studies are needed to confirm these results and explore the disease mechanisms involved.
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