OP0113 GENOME-WIDE ASSOCIATION STUDY OF Ro/SSA+ AND Ro/SSA-SJÖGREN’S CASES IN THE SJÖGREN’S GENETIC NETWORK (SGENE) DEMONSTRATES DIVERGENT GENETIC ARCHITECTURE IN PATIENT SUBPHENOTYPES
Authors: A. Rasmussen, M. Radziszewski, B. Khatri, K. L. Tessneer, E. Pontarini, M. Bombardieri, M. Rischmueller, M. Wahren-Herlenius, M. Kvarnström, T. Witte, H. Bootsma, G. M. Verstappen, F. G. M. Kroese, A. Vissink, S. Pringle, A. Tzioufas, C. Mavragani, A. Baer, M. Alarcon-Riquelme, J. Martin, X. Mariette, G. Nocturne, J. O. Pers, J. E. Gottenberg, W. F. Ng, C. Shiboski, K. E. Taylor, L. Criswell, B. M. Warner, A. D. Farris, J. A. James, R. H. Scofield, J. M. Guthridge, D. J. Wallace, S. Venuturupali, M. T. Brennan, J. Imgenberg-Kreuz, L. Ronnblom, E. Baecklund, M. L. Eloranta, L. A. Aqrawi, Ø. Palm, J. G. Brun, D. Hammenfors, M. V. Jonsson, S. Appel, S. M. Bucher, H. Forsblad-D’elia, T. Mandl, P. Eriksson, G. Nordmark, C. J. Lessard
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Sjögren's disease (SjD) is a complex systemic autoimmune disease with substantial morbidity and 21 known genetic associations. The International Sjögren's Genetics Network (SGENE) is a growing international collaboration focused on understanding how genetic variants influence SjD pathology. As sample sizes increase, we are focusing our efforts on the analyses of clinical subsets, which few studies have done. <h3>Objectives:</h3> Our genome-wide association study (GWAS) aimed to identify additional risk loci of genome-wide significance (GWS, p&lt;5E-08; suggestive, p&lt;5x10E-5) in European-derived subsets of SjD. <h3>Methods:</h3> This study was conducted with IRB/EC approvals. All SjD patients met the 2002 AECG criteria for SjD. A total of 5058 cases and 25943 controls were genotyped on GWAS arrays. After QC, 4855 cases and 25408 controls were included in the analyses. Logistic regression was calculated, adjusting for ancestry using the first 4 principal components to identify SjD-associated SNPs. Cases were split into Ro/SSA+ (n=2898) and Ro/SSA- (n=1313), and analyzed vs. each other, controls, and all-SjD. <h3>Results:</h3> We observed many differences in the genomic architecture of Ro/SSA- compared to Ro/SSA+ and all SjD (Figure 1a,b), most notably, a complete loss of the significance of the association with MHC on chromosome 6 in the Ro/SSA- cases(Figure 1b). The Ro/SSA+ subjects had a much stronger HLA association with OR ≈ 4 (Figure 1a), while the overall SjD showed OR ≈ 3. While none of the associations observed in the Ro/SSA- population reached GWS, 8 regions (near <i>PLXNA2</i>, <i>PCDH7</i>, <i>IRF5-TNPO3</i>, <i>DLD</i>, <i>LOC100134229</i>, <i>JAK3</i>, <i>LOC643529</i>, and <i>TMTC1</i>) show suggestive associations (Figure. 1a). Of these, only two, <i>IRF5-TNPO3</i> and <i>LOC643529</i>, are also suggestive in the Ro/SSA+ subset. However, while the Ro/SSA+ have both the <i>IRF5</i> promoter effect and the extended haplotype through <i>TNPO3</i>, the Ro/SSA- lack the <i>IRF5</i> promoter effect. Interestingly, previous studies have shown that lupus and systemic sclerosis have both haplotypes while primary biliary cholangitis only has the haplotype extending into <i>TNPO3</i>, similar to Ro/SSA- SjD [1]. When comparing Ro/SSA- to the all-SjD dataset, <i>PLXNA2</i> and <i>LOC100134229</i> showed no association; <i>PCDH7</i>, <i>DLD</i>, and <i>TMTC1</i> showed some association but did not reach suggestive levels; and <i>LOC643529</i>, <i>IRF5-TNPO3</i>, and <i>JAK3</i> surpassed the suggestive threshold, the latter two nearing or surpassing GWS. Two of the novel suggestive associations in Ro/SSA- are particularly intriguing. PLXNA2 is a member of a semaphorin co-receptor family that mediates repulsive effects on axon pathfinding during nervous system development; interestingly, Ro/SSA- SjD has a higher frequency of neurological involvement. JAK3 is a member of the Janus kinase (JAK) family of tyrosine kinases involved in cytokine receptor-mediated intracellular signal transduction; it is predominantly expressed in immune cells. Mutations in this gene are associated with autosomal severe combined immunodeficiency disease. Novel drugs target the JAK-STAT pathways, making this finding markedly relevant. <h3>Conclusion:</h3> Our findings highlight the relevance of expanding genetic studies to specific subphenotypes of the disease. While we continue to increase our GWAS sample size and explore other subphenotypes, more work is needed to increase the power of these studies to determine if the suggestive regions will surpass the GWS threshold. <h3>REFERENCES:</h3> [1] Kottyan LC, et al. <i>Hum Mol Genet</i>. 2015 Jan 15;24(2):582-96. <h3>Acknowledgements:</h3> NIH/NIAMS R01 AR073855, P50 AR060804; NIH/NIDCR U01DE028891; Sjögren's Foundation; Jerome L. Greene Foundation. <h3>Disclosure of Interests:</h3> Astrid Rasmussen: None declared, Marcin Radziszewski: None declared, Bhuwan Khatri: None declared, Kandice L Tessneer: None declared, Elena Pontarini: None declared, Michele Bombardieri: None declared, Maureen Rischmueller: None declared, Marie Wahren-Herlenius: None declared, Marika Kvarnström: None declared, Torsten Witte: None declared, Hendrika Bootsma: None declared, Gwenny M. Verstappen: None declared, Frans G.M. Kroese: None declared, Arjan Vissink: None declared, Sarah Pringle: None declared, Athanasios Tzioufas: None declared, Clio Mavragani: None declared, Alan Baer Received consulting fees from Bristol Myers Squibb (BMS) and iCell Gene Therapeutics., Marta Alarcon-Riquelme: None declared, Javier Martin: None declared, Xavier Mariette: None declared, Gaetane Nocturne: None declared, Jacques-Olivier Pers: None declared, Jacques-Eric Gottenberg: None declared, Wan-Fai Ng I have consulted for Novartis, BMS, Janssen, Sanofi, Abbvie, IQVIA, Argenx, Resolve Therapeutics., Caroline Shiboski: None declared, Kimberly E Taylor: None declared, Lindsey Criswell: None declared, Blake M Warner: None declared, A Darise Farris Grant/research support from Johnson and Johnson Innovative Medicine (formerly Janssen; ended 12/31/2023)., Judith A. James: None declared, R Hal Scofield Received consulting fees from Johnson and Johnson Innovative Medicine (formerly Janssen) and Merk Pharmaceuticals., Joel M Guthridge: None declared, Daniel J Wallace: None declared, Swamy Venuturupali: None declared, Michael T Brennan: None declared, Juliana Imgenberg-Kreuz: None declared, Lars Ronnblom: None declared, Eva Baecklund: None declared, Maija-leena Eloranta: None declared, Lara A Aqrawi: None declared, Øyvind Palm: None declared, Johan G Brun: None declared, Daniel Hammenfors: None declared, Malin V Jonsson: None declared, Silke Appel: None declared, Sara Magnusson Bucher: None declared, Helena Forsblad-d'Elia: None declared, Thomas Mandl Employee of UCB., Per Eriksson: None declared, Gunnel Nordmark: None declared, Christopher J Lessard Grant/research support from Johnson and Johnson Innovative Medicine (formerly Janssen; ended 12/31/2023).