Effect on Lupus Outcomes of the Protective Allele at rs1876453 in the Complement Receptor 2 Gene

Ani Oganesyan¹, Rachel Sharp², Philip O’Neill³, Cynthia Aranow⁴, Laurent Arnaud⁵, Anca Askanase⁶, Sang-Cheol Bae⁷, Sasha Bernatsky⁸, Ian Bruce⁹, Jill Buyon¹⁰, Winn Chatham¹¹, Ann Clarke¹², Nathalie Costedoat-Chalumeau¹³, Mary Anne Dooley¹⁴, Paul R. Fortin¹⁵, Ellen Ginzler¹⁶, Dafna Gladman¹⁷, Caroline Gordon¹⁸, John G. Hanly¹⁹, Murat Inanç²⁰, David Isenberg²¹, Soren Jacobsen²², Andreas Jonsen²³, Kenneth Kalunian²⁴, Diane L. Kamen²⁵, S. Sam Lim²⁶, Anselm Mak²⁷, Eric Morand²⁸, Christine Peschken²⁹, Michelle Petri³⁰, Bernando A. Pons-Estel³¹, Anisur Rahman³², Rosalind Ramsey-Goldman³³, John Reynolds³⁴, Juanita Romero-Diaz³⁵, Guillermo Ruiz-Irastorza³⁶, Jorge Sanchez-Guerrero³⁷, Kristjan Steinsson³⁸, Murray Urowitz³⁹, Ronald van Vollenhoven⁴⁰, Evelyne Vinet⁴¹, Alexandre Voskuyl⁴², Daniel Wallace⁴³, Susan Manzi⁴⁴, Kenneth L. Jones⁴⁵ and Susan A. Boackle⁴⁶, ¹University of Colorado Anschutz Medical Campus, Aurora, CO, ²University of North Carolina at Chapel Hill, Chapel Hill, NC, ³University of Oklahoma Health Sciences Center, Oklahoma City, OK, ⁴Feinstein Institutes for Medical Research, Manhasset, NY, ⁵University Hospitals of Strasbourg, Strasbourg, France, ⁶Columbia University Medical Center, New York, NY, ⁷Hanyang University Hospital for Rheumatic Diseases and Hanyang University Institute for Rheumatology Research, Department of Rheumatology, Seoul, South Korea, ⁸Research Institute of the McGill University Health Centre, Montreal, QC, Canada, ⁹University of Manchester, Manchester, United Kingdom, ¹⁰NYU Grossman School of Medicine, New York, NY, ¹¹University of Alabama at Birmingham, Birmingham, AL, ¹²University of Calgary, Division of Rheumatology, Cumming School of Medicine, Calgary, AB, Canada, ¹³Inserm DR Paris 5, Paris, France, ¹⁴Raleigh Neurology Associates, Chapel Hill, NC, ¹⁵Centre ARThrite - CHU de Québec - Université Laval, Quebec City, QC, Canada, ¹⁶SUNY Downstate Health Sciences University, Brooklyn, NY, ¹⁷Schroeder Arthritis Institute, Krembil Research Institute, Toronto Western Hospital, Department of Medicine, University of Toronto, Toronto, ON, Canada, ¹⁸Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom, ¹⁹Dalhousie University, Halifax, NS, Canada, ²⁰Istanbul University, Istanbul, Turkey, ²¹University College London, London, United Kingdom, ²²Rigshospitalet, Copenhagen, Denmark, ²³Rheumatology, Department of Clinical Sciences, Lund University, Lund, Sweden, ²⁴University of California San Diego, La Jolla, CA, ²⁵Medical University of South Carolina, Charleston, SC, ²⁶Emory University, Atlanta, GA, ²⁷Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore, ²⁸Monash University, Centre for Inflammatory Diseases, Melbourne, Australia, ²⁹University of Manitoba, Winnipeg, MB, Canada, ³⁰Department of Medicine, Division of Rheumatology, Johns Hopkins University School of Medicine, Timonium, MD, ³¹Study Group of the Argentine Society of Rheumatology for Systemic Lupus Erythematosus, Buenos Aires, Argentina, ³²Centre for Rheumatology, Division of Medicine, University College London, London, United Kingdom, ³³Northwestern University, Chicago, IL, ³⁴University of Birmingham, Birmingham, United Kingdom, ³⁵Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico, ³⁶Hospital Universitario Cruces, Barakaldo, Spain, ³⁷University Health Network, Toronto, ON, Canada, ³⁸Landspitali University Hospital, Reykjavik, Iceland, ³⁹Schroeder Arthritis Institute, Krembil Research Institute; University of Toronto Lupus Clinic; Division of Rheumatology, Toronto, ON, Canada, ⁴⁰Amsterdam University Medical Centers, Amsterdam, Netherlands, ⁴¹McGill University Health Centre, Montréal, QC, Canada, ⁴²Amsterdam Rheumatology and Immunology Center, Amsterdam, Netherlands, ⁴³Cedars-Sinai Medical Center, Los Angeles, CA, ⁴⁴Lupus Center of Excellence, Autoimmunity Institute, Allegheny Health Network, Pittsburgh, PA, ⁴⁵Bioinformatics Solutions, Sheridan, WY, ⁴⁶None, Denver, CO

Meeting: ACR Convergence 2023

Keywords: complement, genetics, Outcome measures, Systemic lupus erythematosus (SLE)

Session Information

Date: Tuesday, November 14, 2023

Title: (2257–2325) SLE – Diagnosis, Manifestations, & Outcomes Poster III

Session Type: Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: Systemic lupus erythematosus is a heterogenous autoimmune disease characterized by inflammatory damage to multiple organ systems. We have shown that the single-nucleotide polymorphism (SNP) rs1876453 is associated with decreased risk of lupus, with a preferential effect on anti-double stranded (ds) DNA antibodies. Since anti-dsDNA antibodies develop prior to clinically apparent disease and are associated with more severe disease, we hypothesized that the minor A allele at rs1876453 would delay disease onset and improve clinical outcomes. We demonstrated a delay in lupus onset associated with the SNP using a large lupus association study [Large Lupus Association Study 2 (LLAS2)], and herein we explore the effects of the SNP on clinical outcomes using a longitudinal inception cohort.

Methods: Subjects genotyped using the Illumina platform from a longitudinal inception cohort [Systemic Lupus International Collaborating Clinics (SLICC), n=977] were studied. Age of onset was determined, and damage, disease activity, steroid exposure, and survival were assessed.

Results: As with the subjects in the LLAS2 cohort, the median age of diagnosis for subjects with the protective A allele at rs1876453 was significantly greater in the SLICC cohort [median (IQR), 33 (20) for GG, 36 (20) for AG, and 50 (31.5) for AA, p = 0.0167]. Subjects with the protective allele had similar scores for damage at 5 years, but their likelihood of developing damage by then was greater (41.6% for AG/AA vs 31.8% for GG at Year 5, p = 0.0270). This was not due to more severe disease, since they had lower disease activity [median SLEDAI (IQR) 2.5 (3.6) for GA/AA, 3.3 (3.8) for GG; p = 0.0163] and comparable steroid exposure. Although this was likely due in part to their older age at disease onset, there was a trend towards early damage even in patients younger than age 50 (p = 0.0762). Despite their older median age, their mortality rates were lower (p = 0.0414).

Conclusion: The minor allele at rs1876453 is associated with delayed onset, reduced overall disease activity, and lower mortality despite the increased probability of early damage. This increased risk of early damage may result from older age at disease onset or from a specific pathogenic mechanism in subjects with the protective SNP who develop lupus and will require further study.

Disclosures: A. Oganesyan: None; R. Sharp: None; P. O’Neill: None; C. Aranow: AstraZeneca, 2, Bristol-Myers Squibb(BMS), 2, GlaxoSmithKlein(GSK), 2, 5, kezar Inc, 2; L. Arnaud: AbbVie, 6, Alexion, 6, Alpine, 2, 6, Amgen, 6, AstraZeneca, 1, 2, 6, Biogen, 6, Boehringer Ingelheim, 6, Bristol-Myers Squibb(BMS), 2, 6, Eli Lilly, 6, GlaxoSmithKlein(GSK), 1, 2, 6, Grifols, 6, Janssen, 6, Kezar Life Sciences, 2, 6, LFB, 6, Medac, 6, Novartis, 2, 6, Pfizer, 6, Roche-Chugaï, 6, UCB, 6; A. Askanase: AbbVie, 2, Amgen, 2, AstraZeneca, 2, Aurinia, 2, Bristol-Myers Squibb, 2, Celgene, 2, Eli Lilly, 2, Genentech, 2, GSK, 2, Idorsia, 2, Janssen, 2, Mallinckrodt, 2, Pfizer, 2, UCB Pharma, 2; S. Bae: None; S. Bernatsky: None; I. Bruce: AstraZeneca, 1, 2, 5, 6, Aurinia, 2, GSK, 1, 2, 5, 6, Janssen, 5, 6, Lilly, 1, UCB, 6; J. Buyon: Bristol-Myers Squibb(BMS), 2, GlaxoSmithKlein(GSK), 2, Related Sciences, 1; W. Chatham: None; A. Clarke: AstraZeneca, 2, Bristol-Myers Squibb(BMS), 2, GlaxoSmithKlein(GSK), 2, 5, Otsuka, 2, Roche, 2; N. Costedoat-Chalumeau: None; M. Dooley: None; P. Fortin: AbbVie, 1, AstraZeneca, 1, 6, GlaxoSmithKlein(GSK), 1, 6, Roche-Genentech, 1; E. Ginzler: None; D. Gladman: AbbVie, 2, 5, Amgen, 2, 5, Bristol Myers Squibb, 2, Celgene, 2, 5, Eli Lilly, 2, 5, Galapagos, 2, Gilead Sciences, 2, Janssen, 2, 5, Novartis, 2, 5, Pfizer Inc, 2, 5, UCB, 2, 5; C. Gordon: AbbVie, 2, Alumis, 2, Amgen, 2, AstraZeneca, 2, Sanofi, 2, UCB Pharma, 2; J. Hanly: None; M. Inanç: Boehringer-Ingelheim, 6, Pfizer, 6, UCB, 6; D. Isenberg: None; S. Jacobsen: None; A. Jonsen: None; K. Kalunian: AbbVie/Abbott, 2, Amgen, 5, AstraZeneca, 2, Aurinia, 2, Bristol-Myers Squibb(BMS), 2, Eli Lilly, 2, EquilliumBio, 2, Genentech, 2, Gilead, 2, Janssen, 2, KezarBio, 1, Merck/MSD, 2, Novartis, 2, Pfizer, 2, Remegene, 2, Roche, 2, UCB, 5; D. Kamen: None; S. Lim: None; A. Mak: None; E. Morand: AbbVie, 2, 5, Amgen, 5, AstraZeneca, 2, 5, 6, Biogen, 2, 5, Bristol Myers Squibb, 2, 5, Eli Lilly, 2, 5, EMD Serono, 2, 5, Galapagos, 2, Genentech, 2, 5, GlaxoSmithKline, 2, 5, IgM, 2, Janssen, 2, 5, Novartis, 2, Servier, 2, Takeda, 2, UCB, 5; C. Peschken: AstraZeneca, 2, 5, GSK, 2, 5, Roche, 1, 2; M. Petri: Alexion, 1, Amgen, 1, AnaptysBio, 1, Annexon Bio, 1, Argenx, 1, Arhros-Focus Med/Ed, 6, AstraZeneca, 1, 5, Aurinia, 1, 5, 6, Axdev, 1, Biogen, 1, Boxer Capital, 2, Cabaletto Bio, 2, Caribou Biosciences, 2, CVS Health, 1, Eli Lilly, 1, 5, Emergent Biosolutions, 1, Exagen, 5, Exo Therapeutics, 2, Gilead Biosciences, 2, GlaxoSmithKlein(GSK), 1, 5, 6, Horizon Therapeutics, 2, Idorsia Pharmaceuticals, 2, IQVIA, 1, Janssen, 1, 5, Kira Pharmaceuticals, 2, MedShr, 6, Merck/EMD Serono, 1, Momenta Pharmaceuticals, 2, Nexstone Immunology, 2, Nimbus Lakshmi, 2, Proviant, 2, Sanofi, 2, Sinomab Biosciences, 2, Thermofisher, 5, UCB, 2; B. Pons-Estel: None; A. Rahman: None; R. Ramsey-Goldman: Ampel Solutions, 2, Calabetta, 2, Exagen, 2, Immunocor, 6; J. Reynolds: None; J. Romero-Diaz: None; G. Ruiz-Irastorza: None; J. Sanchez-Guerrero: None; K. Steinsson: None; M. Urowitz: None; R. van Vollenhoven: AbbVie, 2, 6, AstraZeneca, 2, 5, 6, Biogen, 6, Bristol-Myers Squibb(BMS), 2, 5, 6, Galapagos, 2, 5, 6, GlaxoSmithKline, 6, Janssen, 2, 6, MSD/Merck Sharp and Dohme, 5, Novartis, 5, Pfizer, 2, 5, 6, RemeGen, 2, Roche, 5, Sanofi, 5, UCB, 2, 5, 6; E. Vinet: None; A. Voskuyl: None; D. Wallace: None; S. Manzi: AbbVie, 5, Allegheny Singer Research Institute, 10, AstraZeneca, 2, 5, Exagen Diagnostics, Inc, 2, 9, 10, GSK, 2, 5, Lilly, 2, Lupus Foundation of America, 4, Novartis, 2, UCB Advisory Board, 2, Univiersity of Pittsburgh, 10; K. Jones: None; S. Boackle: None.

To cite this abstract in AMA style:

Oganesyan A, Sharp R, O’Neill P, Aranow C, Arnaud L, Askanase A, Bae S, Bernatsky S, Bruce I, Buyon J, Chatham W, Clarke A, Costedoat-Chalumeau N, Dooley M, Fortin P, Ginzler E, Gladman D, Gordon C, Hanly J, Inanç M, Isenberg D, Jacobsen S, Jonsen A, Kalunian K, Kamen D, Lim S, Mak A, Morand E, Peschken C, Petri M, Pons-Estel B, Rahman A, Ramsey-Goldman R, Reynolds J, Romero-Diaz J, Ruiz-Irastorza G, Sanchez-Guerrero J, Steinsson K, Urowitz M, van Vollenhoven R, Vinet E, Voskuyl A, Wallace D, Manzi S, Jones K, Boackle S. Effect on Lupus Outcomes of the Protective Allele at rs1876453 in the Complement Receptor 2 Gene [abstract]. Arthritis Rheumatol. 2023; 75 (suppl 9). https://acrabstracts.org/abstract/effect-on-lupus-outcomes-of-the-protective-allele-at-rs1876453-in-the-complement-receptor-2-gene/. Accessed .

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