POS0756 IDENTIFICATION OF GENETIC RISK FACTORS FOR JUVENILE IDIOPATHIC ARTHRITIS-ASSOCIATED UVEITIS
Authors: S. Angeles-Han, M. Pavlenko, M. Sudman, M. Marion, A. Duell, V. Utz, P. Nigrovic, M. Quinlan-Waters, G. Schulert, S. Thompson, C. Langefeld
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Uveitis is the most common extra-articular manifestation of juvenile idiopathic arthritis (JIA), affecting 10-20% of patients. Approximately 88% of patients with JIA-associated uveitis (JIA-U) present within the first 4 years of JIA. Despite adherence with ophthalmic screening examinations based on known clinical risk factors, 50% of children with JIA-U still develop ocular damage. Early detection of JIA-U is crucial for timely treatment to prevent vision-threatening complications. <h3>Objectives:</h3> To identify genetic risk factors associated with uveitis in children with JIA. <h3>Methods:</h3> We performed a genome wide association study (GWAS) of 144 patients with JIA (88 JIA without uveitis for ≥4 years and 56 JIA-U) of European ancestry from the Predicting Eye Disease in JIA-U (PEDIA-U) study. Ophthalmology examinations confirmed the presence of uveitis. Genotyping was done on the Affymetrix Genome-Wide Human SNP 6.0 array with standard quality control and population substructure, and tested for association via logistic regression adjusting for sex and age of onset of arthritis. <h3>Results:</h3> We identified multiple genomic regions with single nucleotide polymorphisms (SNP) associated with uveitis at p&lt;10<sup>-4</sup> (chromosome, SNP, odds ratio, p-value) that have proximal genes linked to ocular disease (Figures 1 and 2). Specifically, 1q23.3 contains rs2063140 (OR=3.7, P=2.75x10<sup>-5</sup>) which is intronic within <i>RGS4</i>, a regulator of g-protein signaling 4 and has a role in the development of chronic experimental autoimmune uveitis and neural tissue development. Within 4q25, rs243952 (OR=5.98, P=1.88 ×10<sup>-5</sup>) is an eQTL for <i>ENPEP</i> and <i>CASP6</i>. 6q16 contains rs17808421 (OR=4.67; P=4.54 ×10<sup>-6</sup>) which is near <i>LOC101927314</i>. On 8q11.21, rs3922033 (OR=0.17, P=2.57 ×10<sup>−5</sup>) is located within <i>SNTG1.</i> On 10q22.1, rs10999864 (OR=7.24, P<i>=</i>6.31 ×10<sup>−5</sup>) is within <i>CDH23</i>, a gene implicated in Usher syndrome. On 11q22.2, rs12575975 (OR=4.95, P<i>=</i>8.98 ×10<sup>−5</sup>) is located within <i>MMP7</i> and is an eQTL for <i>MMP7.</i> Matrix metalloproteinases such as <i>MMP7</i> are upregulated in a rat model of experimental autoimmune uveoretinitis, increase the permeability of the blood-brain barrier in an experimental autoimmune encephalomyelitis, and implicated in neovascular complications of age-related macular degeneration in humans. 14q23.3 (rs12589911, OR=10.11 P=5.36 ×10<sup>-5</sup>) is located near <i>FUT8</i>-<i>LINC00238</i>. On 15q22, rs12917403 (OR=5.91, P<i>=</i>3.17 ×10<sup>−5</sup>) is an eQTL in various tissues for multiple genes, including <i>CA12</i>, <i>LINC02568</i>, <i>HERC1</i>, and <i>RPS27L. CA12</i> is a carbonic anhydrase and zinc metalloenzyme that contributes to formation of aqueous humor and RPS27L is linked to retinitis pigmentosa 23. <h3>Conclusion:</h3> Even with this small GWAS, multiple genomic regions are associated with JIA-U compared to JIA without Uveitis, including regions with genes related to ocular function and disease. Expansion of the deeply phenotyped cohort is underway for validation and more power tests of associations. Identifying genetic polymorphisms may help identify important JIA-U pathways and pharmacologic targets. It will also lead to the development of genetic risk scores for JIA-U. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> <b>None declared.</b>