POS0034 ASSOCIATIONS OF 31 NOVEL COPA NON-SYNONYMOUS VARIANTS WITH AUTOIMMUNE AND INFLAMMATORY CLINICAL PHENOTYPES AMONG 160,365 INDIVIDUALS: DEFINING A COPA SPECTRUM DISORDER
Authors: P. A. Juge, V. L. Kronzer, C. David-Gabarre, M. L. Frémond, R. Kechiche, G. Mcdermott, X. Wang, K. Hayashi, J. Cui, K. Mueller, M. Own, H. Wobma, P. Y. Lee, S. Raychaudhuri, Z. S. Wallace, E. Karlson, P. Dieudé, J. A. Sparks
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> COPA syndrome is an autosomal dominant, severe, rare, monogenic autoimmune disorder, often affecting the lungs and joints, caused by loss-of-function mutations of <i>COPA</i> which are located in a specific locus (i.e., the <i>COPA</i> mutation hotspot, 7<sup>th</sup> to 10<sup>th</sup> exons). It is associated with autoimmune features and upregulation of both the type-1 interferon (IFN) pathway and T helper-17 cells. Clinical manifestations usually start during childhood, but late-onset symptoms have been described. <h3>Objectives:</h3> We aimed to identify additional novel non-synonymous variants (NSV) in <i>COPA</i> and to describe their associated phenotypes in two distinct adult biobanks. <h3>Methods:</h3> All individuals from two large institutional biobanks (Massachusetts General Brigham, [MGB] and Mayo Clinic Biobank) with available whole-exome sequencing (WES) data were included in this study. All NSV in the 7<sup>th</sup>, 8<sup>th</sup>, 9<sup>th</sup>, and 10<sup>th</sup> exons of <i>COPA</i> were identified and annotated according to allele frequency reported in GnomAD and functional predictive tools (SIFT, PLOYPHEN-2 and CADD score). Individuals with <i>COPA</i> NSV were matched to controls without <i>COPA</i> NSV from the same biobank by year of birth, sex, and race and ethnicity. Medical record review was performed in cases and controls to collect personal and familial medical history, results of autoantibodies, and chest computed tomography (CT) imaging results obtained through routine clinical care. Associations with the presence of <i>COPA</i> NSV were tested using logistic regression for categorical outcomes or an univariable linear regression for continuous outcomes. Functional impact of ten novel <i>COPA</i> NSV was tested by measuring type-1 IFN activity in cells transfected with mutant plasmids. <h3>Results:</h3> Among the 106,365 individuals with available WES data, 33 unique NSV were identified among a total of 85 individuals (0.08%); 59 were women (69.4%) and mean age at medical record review was 60.6 years (SD 18.5). Two individuals carried a NSV previously implicated in COPA syndrome (p.R281Q and p.R233H) but none of them had been clinically diagnosed with COPA syndrome. All other identified SNV were rare: 14 recorded rare variants (all with a frequency &lt;0.0001%) and 19 have never been previously described. NSV were predicted as deleterious by both SIFT and POLYPHEN-2 for 16 variants (48%). A history of autoimmune or inflammatory disease was reported for 38/85 carriers (45%) including 12 with inflammatory arthritis (14%), Table 1. Interstitial lung disease was observed in 11/85 patients (13%). Median age at autoimmune/inflammatory disease onset was 50.3 years IQR [39.5 – 63.5] with only 2 patients having childhood onset. Antinuclear antibodies, anti-CCP, and rheumatoid factor were positive for 15/27, 3/13, and 5/22 patients, respectively. A family history of autoimmune/inflammatory disease was reported in 17/68 patients (25%). When compared to matched controls, having a <i>COPA</i> NSV was significantly associated with increased risk for any autoimmune or inflammatory disease (OR = 1.73, 95%CI 1.05 to 2.87, p=0.03), any inflammatory arthritis (OR = 2.83, 95%CI 1.24 to 6.40, p=0.01), any ILD (OR = 6.17, 95%CI 2.27 to 18.4, p&lt;0.001), and having a family history of an autoimmune or an inflammatory disease (OR = 2.81, 95%CI 1.41 to 5.52, p=0.003), Table 1. Functional impact was confirmed for 2/10 of the novel <i>COPA</i> NSV, with a lower type-1 IFN activity compared to two <i>COPA</i> NSV previously as pathogenic mutations, Figure 1. <h3>Conclusion:</h3> We identified 31 novel NSV beyond the known causal mutations for COPA syndrome and described associations with autoimmune and/or inflammatory diseases, including ILD, most of which were adult-onset. In addition to the COPA syndrome, <i>COPA</i> variants could contribute to the genetic architecture of a spectrum of unrecognized adult-onset inflammatory and autoimmune diseases including ILD. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> Société Française de Rhumatologie, NIH, NIAMS. <h3>Disclosure of Interests:</h3> <b>None declared.</b>