ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 0884

Genetic Architecture Divergence in Sjögren’s Disease Subphenotypes and Populations: Genome-wide Association Study of Ro/SSA+ and Ro/SSA- Cases in European Populations

Marcin Radziszewski1, Astrid Rasmussen2, Bhuwan Khatri2, Kandice Tessneer2, Elena Pontarini3, Michele Bombardieri4, Maureen Rischmueller5, Marie Wahren-Herlenius6, Marika Kvarnström6, Torsten Witte7, Hendrika Bootsma8, Gwenny Verstappen9, Frans Kroese9, Arjan Vissink10, Sarah Pringle9, Athanasios Tzioufas11, Clio Mavragani12, Alan Baer13, Marta Alarcon-Riquelme14, Javier Martin15, Xavier Mariette16, Gaetane Nocturne16, Jacques-Olivier Pers17, Jacques-Eric Gottenberg18, Wan-Fai Ng19, Caroline Shiboski20, Kim Taylor21, Lindsey Criswell22, Blake M. Warner23, A. Darise Farris2, Judith James2, Robert Hal Scofield2, Joel Guthridge2, Daniel Wallace24, Swamy Venuturupalli25, Michael Brennan26, Juliana Imgenberg-Kreuz27, Lars Rönnblom27, Eva Baecklund27, Maija-Leena Eloranta27, Lara Aqrawi27, Øyvind Palm28, Johan Brun29, Daniel Hammenfors29, Malin Jonsson29, Silke Appel29, Sara Magnusson Bucher30, Helena Forsblad-d'Elia31, Thomas Mandl32 and Christopher Lessard2, 1University of Oklahoma Health Sciences Center, Oklahoma City, OK, 2Oklahoma Medical Research Foundation, Oklahoma City, OK, 3Queen Mary University of London, London, United Kingdom, 4Centre for Experimental Medicine and Rheumatology, The William Harvey Research Institute, Queen Mary University of London, London, United Kingdom, 5RheumatologySA, Adelaide, Australia, 6Karolinska Institutet, Stockholm, Sweden, 7Dept of Immunology and Rheumatology, Hannover, Germany, 8Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, Groningen, Netherlands, 9University Medical Center Groningen, Groningen, Netherlands, 10University Medical Center Groningen, Leek, Netherlands, 11LAIKO HOSPITAL, Athens, Greece, 12National and Kapodistrian University of Athens, Athens, Greece, 13Johns Hopkins University School of Medicine, Baltimore, MD, 14Fundación Progreso y Salud, Andalusian Government, Granada, Spain, 15Instituto de Parasitología y Biomedicina ‘López-Neyra’, CSIC, PTS Granada, Spain, Granada, Spain, 16Service de Rhumatologie, Hôpital Bicêtre, AP-HP, Le Kremlin Bicetre, France, 17University of Brest, Brest, France, 18Rheumatology Department, Strasbourg University Hospital,, Strasbourg, France, 19Institute of Cellular Medicine, Newcastle University, Gateshead, United Kingdom, 20University of California San Francisco, San Francisco, CA, 21University of California, San Francisco, CA, 22Genomics of Autoimmune Rheumatic Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, Bethesda, MD, 23National Institutes of Health, Bethesda, MD, 24Cedars Sinai Medical Center, Studio City, CA, 25Attune Health, Beverly Hills, CA, 26Atrium Health Carolinas Medical Center, Charlotte, NC, 27Uppsala University, Uppsala, Sweden, 28University of Oslo, Oslo, Norway, 29University of Bergen, Bergen, Norway, 30Universitetssjukhuset, Orebro, Sweden, 31University of Gothenburg, Gothenburg, Sweden, 32Lund University, Malmö, Sweden

Meeting: ACR Convergence 2024

Session Information

Date: Sunday, November 17, 2024

Title: Genetics, Genomics & Proteomics Poster

Session Type: Poster Session B

Session Time: 10:30AM-12:30PM

Background/Purpose: Sjögren’s disease (SjD) is a complex systemic autoimmune disease with 22 genome-wide significant (GWS) risk loci [1]. Historically, genomic research has focused on populations of European ancestry (86% of genome-wide association study (GWAS) populations) [2]. Only five of the 22 GWS SjD risk loci were identified using multi-ethnic, non-European populations (IRF5-TNPO3, STAT4, TNFAIP3, GTF21RD1-NCF1, IKZF1) [1]. The International Sjögren’s Genetics Network (SGENE) is focused on understanding how genetic variants influence SjD pathology. As sample sizes and ancestral diversity increase, we can improve analyses of clinical subsets, which few studies have done. The objective of this GWAS aims to identify new GWS risk loci (p< 5E-08; suggestive: p< 5x10E-5) across SjD cases of European ancestry, with and without anti-Ro/SSA antibodies (Ro/SSA).

Methods: Institutional IRB/EC approval was obtained. All cases met the 2002 AECG criteria for SjD. A cohort of 5058 cases and 25943 controls were genotyped on GWAS arrays. After sample quality control, 4855 cases and 25408 controls were analyzed by logistic regression using the first four principal components as covariates for ancestry. Analyzed subsets included Ro/SSA+ (n=2898), Ro/SSA- (n=1313) of European ancestry.

Results: GWAS results indicated different genetic architectures in Ro/SSA+ compared to Ro/SSA- cases. Ro/SSA+ cases showed significant association with the MHC region of chromosome 6 (top HLA SNP rs3130562, OR 3.66 [3.42-3.92], p=3.09E-308). This association was much lower in Ro/SSA- (top HLA SNP rs12664475, OR 1.25 [1.13-1.38], p=2.54E-5). Ro/SSA+ GWAS identified 15 GWS loci (Fig.1a). In the Ro/SSA- GWAS, none of the regions surpassed GWS threshold but 8 regions showed suggestive association: near PLXNA2, PCDH7, IRF5-TNPO3, DLD, LOC100134229, JAK3, LOC643529, and TMTC1 (Fig.1b). Only 2 of these loci (IRF5-TNPO3 and LOC643529) were in the Ro/SSA+ GWAS at the suggestive threshold. Deeper interrogation of the IRF5-TNPO3 locus revealed shared and distinct patterns, where the Ro/SSA- association was more similar to that of primary biliary cholangitis and the Ro/SSA+ association more similar to that of systemic sclerosis and lupus. The suggestive JAK3 risk locus was unique to the Ro/SSA- GWAS. Increased JAK3 expression in salivary gland epithelial cells and infiltrating immune cells was identified in SjD [3]. The Ro/SSA- GWAS risk SNPs are eQTLs to JAK3 in minor salivary gland and lymphoblastoid cell lines.

Conclusion: Our findings highlight the need to study specific subphenotypes to find new loci and understand the genetic basis of SjD heterogeneity. Our ongoing efforts aim to increase the sample size of disease subsets to reach GWS for Ro/SSA- of European ancestry. We also are increasing the sample size of SjD cases from non-European ancestries, including Asian ancestry (n=915).

References: [1] Khatri, et al. Nat Commun. 2022. DOI: 10.1038/s41467-022-30773-y. [2] Fatumo, et al. Nat Med. 2022. DOI: 10.1038/s41591-021-01672-4. [3] Gupta, et al. Nat Genet. 2023. DOI: 10.1038/s41588-023-01577-7.

Supporting image 1

Figure 1. Manhattan plot shows the summary data from the GWAS analysis of SjD Ro autoantibody subphenotypes: (A) Ro/SSA+ and (B) Ro/SSA-. The log10(P) for each SNP is plotted according to chromosome and base pair position. Loci that exceeded genome-wide significance (GWS; p<5xE-8 (red line) or suggestive GWS (p<5E-5 (blue line)) are annotated as the gene closest to the peak SNP.

Disclosures: M. Radziszewski: None; A. Rasmussen: None; B. Khatri: None; K. Tessneer: None; E. Pontarini: None; M. Bombardieri: None; M. Rischmueller: Abbvie, 1, 5, 6, Astra Zeneca, 5, BMS, 5, Boehringer-Ingelheim, 6, Eli Lilly, 5, GSK, 5, Horizon, 5, Janssen, 1, 5, LG Chemical, 5, Novatis, 1, 5, Pfizer, 6, Sandoz, 6, UCB, 5; M. Wahren-Herlenius: None; M. Kvarnström: None; T. Witte: AbbVie, 5, Amgen, 5, AstraZeneca, 6, Bristol-Myers Squibb, 5, Celgene, 5, Chugai, 5, Gilead, 5, GlaxoSmithKlein(GSK), 6, Janssen, 5, Lilly, 5, MSD, 5, Mylan, 5, Novartis, 5, Pfizer, 5, Roche, 5, UCB, 5; H. Bootsma: Argenx, 2, AstraZeneca, 2, 12, Funding, Bristol Myers Squibb, 2, 12, Funding, Galapagos, 2, Novartis, 2, 12, Funding, Roche, 2, 12, Funding, Sanofi, 2, UCB, 2; G. Verstappen: None; F. Kroese: None; A. Vissink: None; S. Pringle: None; A. Tzioufas: Pfizer, 2; C. Mavragani: None; A. Baer: Bristol-Myers Squibb(BMS), 2, iCell Gene Therapeutics, 2; M. Alarcon-Riquelme: None; J. Martin: None; X. Mariette: Bristol-Myers Squibb(BMS), 2, Galapagos, 2, GlaxoSmithKlein(GSK), 2, Novartis, 2, Pfizer, 2; G. Nocturne: AbbVie/Abbott, 12, Travel fees, Amgen, 12, Travel fees, Boehringer-Ingelheim, 6, Novartis, 6; J. Pers: None; J. Gottenberg: AbbVie, 2, BMS, 2, 5, Galapagos, 2, Gilead, 2, Lilly, 2, MSD, 2, Novartis, 2, Pfizer, 2, 5; W. Ng: Argenx, 2, Bristol Myers Squibb, 2, Flagship, 2, IQVIA, 2, Janssen, 2, Novartis, 2, Resolve Therapeutics, 2, Sanofi, 2; C. Shiboski: AI Therapeutics, 1; K. Taylor: None; L. Criswell: None; B. Warner: Mitobridge, Inc., a subsidiary of Astellas Bio, 2, 5, Pfizer, 2; A. Farris: Johnson and Johnson Innovative Medicine, 5; J. James: GlaxoSmithKlein(GSK), 1, Progentec Diagnostics, Inc., 5, 10; R. Scofield: Johnson and Johnson Innovative Medicine, 1, Merck, 1; J. Guthridge: AstraZeneca, 5, Bristol-Myers Squibb(BMS), 5; D. Wallace: None; S. Venuturupalli: None; M. Brennan: Lipella, 2, MeiraGTx, 2, SUN pharmaceuticals, 2; J. Imgenberg-Kreuz: None; L. Rönnblom: Ampel Biosolutions, 1, AstraZeneca, 1, 6, Bayer, 2, BMS, 1, UCB, 1; E. Baecklund: None; M. Eloranta: None; L. Aqrawi: None; Ø. Palm: None; J. Brun: None; D. Hammenfors: None; M. Jonsson: None; S. Appel: None; S. Magnusson Bucher: None; H. Forsblad-d'Elia: None; T. Mandl: UCB, 3; C. Lessard: Johnson and Johnson Innovative Medicine, 2, 5, Johnson and Johnson Sjögren's Disease Advisory Board, 1.

To cite this abstract in AMA style:

Radziszewski M, Rasmussen A, Khatri B, Tessneer K, Pontarini E, Bombardieri M, Rischmueller M, Wahren-Herlenius M, Kvarnström M, Witte T, Bootsma H, Verstappen G, Kroese F, Vissink A, Pringle S, Tzioufas A, Mavragani C, Baer A, Alarcon-Riquelme M, Martin J, Mariette X, Nocturne G, Pers J, Gottenberg J, Ng W, Shiboski C, Taylor K, Criswell L, Warner B, Farris A, James J, Scofield R, Guthridge J, Wallace D, Venuturupalli S, Brennan M, Imgenberg-Kreuz J, Rönnblom L, Baecklund E, Eloranta M, Aqrawi L, Palm Ø, Brun J, Hammenfors D, Jonsson M, Appel S, Magnusson Bucher S, Forsblad-d'Elia H, Mandl T, Lessard C. Genetic Architecture Divergence in Sjögren’s Disease Subphenotypes and Populations: Genome-wide Association Study of Ro/SSA+ and Ro/SSA- Cases in European Populations [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/genetic-architecture-divergence-in-sjogrens-disease-subphenotypes-and-populations-genome-wide-association-study-of-ro-ssa-and-ro-ssa-cases-in-european-populations/. Accessed .

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genetic-architecture-divergence-in-sjogrens-disease-subphenotypes-and-populations-genome-wide-association-study-of-ro-ssa-and-ro-ssa-cases-in-european-populations/