AB0742 NON-HLA GENETIC ASSOCIATIONS WITH RADIOGRAPHIC OUTCOME IN RHEUMATOID ARTHRITIS
Authors: S. Sharma, N. Nair, R. Hum, L. Marshall, J. Bowes, A. Macgregor, S. Verstappen, A. Barton, R. Knevel, A. H. M. Van der Helm – Van Mil, S. Viatte
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> The shared epitope within the HLA-DRB1 gene and polymorphisms coding for valine at position 11 have been consistently associated with both susceptibility and radiographic outcome in Rheumatoid Arthritis (RA). [1-2] The extent to which single nucleotide polymorphisms (SNPs) outside the HLA are also shared predictors of RA susceptibility and outcome is not known. Few susceptibility genetic loci outside the HLA have been consistently associated with radiographic outcome. <h3>Objectives:</h3> (1)Determine whether non-HLA SNPs associated with RA susceptibility are also associated with radiographic outcome, using the Norfolk Arthritis Register (NOAR), a large cohort with available genome-wide data and radiographic outcome. (2)Conduct a systematic literature review to identify all non-HLA SNPs previously associated with radiographic outcomes and determine replication rate of these published associations in NOAR. <h3>Methods:</h3> NOAR is an inception cohort of patients with inflammatory polyarthritis recruited since 1989 and followed prospectively for up to 20 years. [1] Radiographic damage on longitudinal X-rays of hands and feet was quantified using the Larsen score. Patients were genotyped using the Illumina Human Core Exome array and 7.5 million SNPs were imputed using the Haplotype Reference Consortium. 152 known genetic associations with RA susceptibility were identified from the latest trans-ethnic meta-analysis (comprising 276,020 subjects) [3] and all previous studies. [4] Articles reporting genetic predictors of radiographic outcome were identified via 2 sources: a systematic review and a hand-search of reference lists of previous review articles. Association testing with the presence of erosions as a longitudinal binary variable was performed with generalized estimating equation models. Association testing was also performed with Larsen score as a longitudinal continuous variable by fitting a generalised linear latent and mixed model (GLLAMM) with discrete random effects and 3 latent classes. Additive and dominant models were used. <h3>Results:</h3> A total of 1884 participants (2198 radiographs) had both genetic and radiographic data available. Of 152 RA susceptibility SNPs, 41 (~27%) were associated with radiographic damage at nominal significance in at least one model. Table 1 shows the top 3 associations with Larsen Score. The systematic review identified 1169 records reporting non-HLA associations with radiographic outcome. A total of 133 SNPs were identified from 243 articles; 30 (~23%) were associated in at least one model. Table 2 shows the top 3 associations with Larsen Score. Results shown are under an additive model and are reported as β coefficients (representing change in Larsen score), with 95% confidence intervals (CI). <h3>Conclusion:</h3> In this large-scale study, we provide a systematic review and experimental validation of genetic predictors of radiographic damage in RA. Many associations with RA outcome are not shared with susceptibility and point towards different mechanisms of actions between disease susceptibility and severity. This approach demonstrates the importance of outcome studies in the identification of genetic markers for patients' stratification for precision medicine in rheumatology. <h3>REFERENCES:</h3> [1] S Viatte et al., Jama <b>313</b> (16), 1645 (2015). [2] HW van Steenbergen et al., Arthritis Rheumatol <b>67</b> (4), 877 (2015). [3] K Ishigaki et al., Nat Genet <b>54</b> (11), 1640 (2022). [4] L Padyukov, Semin Immunopathol <b>44</b> (1), 47 (2022). <h3>Acknowledgements:</h3> This work supported by the NIHR Manchester Biomedical Research Centre (NIHR203308). <h3>Disclosure of Interests:</h3> <b>None declared.</b>