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Abstract Number: 0299

The Minor Protective Allele at rs1876453 Is Associated with Increased Age of Onset of Systemic Lupus Erythematosus

Ani Oganesyan1, Jennifer Kelly2, Stuart Glenn2, Adam Adler2, Adrienne Williams3, Mary Comeau4, Julia Ziegler5, Miranda Marion5, Marta Alarcón-Riquelme6, Graciela Alarcón7, Juan-Manuel Anaya8, Sang-Cheol Bae9, Dam Kim9, Lee Hye-Soon9, Lindsey Criswell10, Barry Freedman11, Gary Gilkeson12, Joel Guthridge13, Chaim Jacob14, Judith James15, Diane Kamen16, Joan Merrill17, Kathy Moser Silvis18, Timothy Niewold19, Michelle Petri20, Rosalind Ramsey-Goldman21, John Reveille22, Hal Scofield23, Anne Stevens24, Luis Vilá25, Timothy Vyse26, Kenneth Kaufman27, John Harley28, Carl Langefeld5, Patrick Gaffney2, Elizabeth Brown29, Jeffrey Edberg7, Robert Kimberly7, Betty Tsao12, Daniela Ulgiati30, Kenneth Jones31 and Susan Boackle32, 1Division of Rheumatology, University of Colorado School of Medicine, Aurora, CO, 2Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 3Department of Biostatistical Sciences and Center for Public Health Genomics Wake Forest School of Medicine, Winston-Salem,, NC, 4Department of Biostatistical Sciences and Center for Public Health Genomics, Wake Forest School of Medicine; MC Analytics, Winston-Salem, NC, 5Department of Biostatistical Sciences and Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, NC, 6Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation;Centro Pfizer-Universidad de Granada-Junta de Andalucía de Genómica e Investigación Oncológica, Granada (GENYO), Granada, Spain, 7Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 8Center for Autoimmune Diseases Research (CREA), Universidad del Rosario, Bogotá, Colombia, 9Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Republic of Korea, 10Rosalind Russell/Ephraim P. Engleman Rheumatology Research Center, University of California San Francisco, San Francisco, CA, 11Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem,, NC, 12Division of Rheumatology, Medical University of South Carolina, Charleston, SC, 13Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oaklahoma, OK, 14Department of Medicine, University of Southern California, Los Angeles, CA, 15Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation;Department of Pathology, University of Oklahoma Health Sciences Center;Department of Medicine, University of Oklahoma Health Sciences Center, Edmond, OK, 16Medical University of South Carolina, Charleston, SC, 17Department of Clinical Pharmacology, Oklahoma Medical Research Foundation, Oklahoma City, OK, 18Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation; Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 19Colton Center for Autoimmunity, NYU School of Medicine, New York, NY, 20Johns Hopkins University School of Medicine, Baltimore, 21Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL, 22Department of Internal Medicine, University of Texas, Houston, TX, 23Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation; Department of Medicine, University of Oklahoma Health Sciences Center; US Department of Veterans Affairs Medical Center, Charleston, SD, 24Janssen Pharmaceuticals, Spring House, PA, 25Division of Rheumatology, Department of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico, 26Division of Genetics and Molecular Medicine and Immunology, King’s College, London, United Kingdom, 27Cincinnati Children’s Hospital Medical Center;US Department of Veterans Affairs Medical Center, Cincinnati, OH, 28Cincinnati Children's Hospital Medical Center/Univ of Cincinnati College of Medicine, Cincinnati, OH, 29Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, 30School of Pathology and Laboratory Medicine, Centre for Genetic Origins of Health and Disease, The University of Western Australia, Crawley, Australia, 31Harold Hamm Diabetes Center, University of Oklahoma Health Science Center, Oklahoma City, OK, 32Division of Rheumatology, University of Colorado School of Medicine; Denver Veterans Affairs Medical Center, Aurora, CO

Meeting: ACR Convergence 2020

Keywords: Autoantibody(ies), autoimmune diseases, genetics, immunology, Systemic lupus erythematosus (SLE)

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Session Information

Date: Friday, November 6, 2020

Title: SLE – Etiology & Pathogenesis Poster

Session Type: Poster Session A

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

Background/Purpose: Systemic lupus erythematosus (SLE) is a clinically heterogenous autoimmune disease characterized by autoantibody- and complement-mediated inflammatory damage to multiple organ systems. We previously showed that the single-nucleotide polymorphism (SNP) rs1876453, located in the first intron of complement receptor 2 (CR2/CD21), 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, we hypothesized that the minor A allele at rs1876453 would delay lupus onset.

Methods: DNA from individuals recruited from multiple sites was processed with institutional review board approval. All patients with SLE met the 1997 American College of Rheumatology revised classification criteria. Age of onset was collected by chart review. Genotyping was performed on the OMRF Illumina iSelect platform. Global ancestry was estimated based on the genotype of ancestry informative markers (AIMs), using principal components analysis and ADMIXMAP, and genetic outliers removed. Final clean data were from European Americans (EA), African Americans (AA; 7.5% Gullahs), Asians (AS; 74.6% Koreans, 16.1% Chinese, 9.3% Japanese and Singaporeans) and Hispanics (HS) enriched for Amerindian–European admixture.  Kruskal-Wallis and Mann-Whitney tests were used to detect differences between groups. A p value of < 0.05 was considered significant. Statistics and graphs were generated using GraphPad Prism software.

Results: The median age of lupus onset for subjects with AG or AA at rs1876453 was significantly higher than subjects with GG [median (interquartile range[IQR]) 40 (21) for AA (n=31), 32 (17) for AG (n=488), and 30 (19) for GG (n=5175), p < 0.0001].  When stratified based on sex, both females and males with the protective allele had significantly delayed disease onset [median (IQR) 40 (21.75) for AA (n=30), 32 (17) for AG (n=439), and 30 (18) for GG (n=4775) for females, p = 0.0006; median (IQR) 37.5 (21) for AA + AG (n=50) and 30 (23.75) for GG (n=400) for males, p = 0.0083].

Conclusion: The minor allele at rs1876453 delays lupus onset by 2-10 years. These data provide further support for a protective role for this SNP in lupus pathogenesis and suggest that novel therapies designed to mimic its mechanisms may prevent disease development in at-risk individuals.


Disclosure: A. Oganesyan, None; J. Kelly, None; S. Glenn, None; A. Adler, None; A. Williams, None; M. Comeau, None; J. Ziegler, None; M. Marion, None; M. Alarcón-Riquelme, None; G. Alarcón, None; J. Anaya, None; S. Bae, None; D. Kim, None; L. Hye-Soon, None; L. Criswell, None; B. Freedman, None; G. Gilkeson, None; J. Guthridge, None; C. Jacob, None; J. James, Progentec Diagnostics, Inc., 9; D. Kamen, None; J. Merrill, None; K. Moser Silvis, None; T. Niewold, None; M. Petri, AbbVie, 5, Amgen, 5, AstraZeneca, 2, 5, BMS, 5, Decision Resources, 5, GSK, 2, 5, INOVA, 5, IQVIA, 5, Janssen, 5, Eli Lilly, 2, 5, Merck EMD Serono, 5, Sanofi Japan, 5, Thermofisher, 5, UCB, 5, Exagen, 2; R. Ramsey-Goldman, None; J. Reveille, Eli Lilly, 2, UCB, 5, Janssen, 2; H. Scofield, None; A. Stevens, Janssen Pharmaceuticals, 3; L. Vilá, None; T. Vyse, None; K. Kaufman, None; J. Harley, Now Diagnostics, Inc, 1, 6, GSK, 5; C. Langefeld, None; P. Gaffney, None; E. Brown, None; J. Edberg, None; R. Kimberly, None; B. Tsao, None; D. Ulgiati, None; K. Jones, None; S. Boackle, None.

To cite this abstract in AMA style:

Oganesyan A, Kelly J, Glenn S, Adler A, Williams A, Comeau M, Ziegler J, Marion M, Alarcón-Riquelme M, Alarcón G, Anaya J, Bae S, Kim D, Hye-Soon L, Criswell L, Freedman B, Gilkeson G, Guthridge J, Jacob C, James J, Kamen D, Merrill J, Moser Silvis K, Niewold T, Petri M, Ramsey-Goldman R, Reveille J, Scofield H, Stevens A, Vilá L, Vyse T, Kaufman K, Harley J, Langefeld C, Gaffney P, Brown E, Edberg J, Kimberly R, Tsao B, Ulgiati D, Jones K, Boackle S. The Minor Protective Allele at rs1876453 Is Associated with Increased Age of Onset of Systemic Lupus Erythematosus [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/the-minor-protective-allele-at-rs1876453-is-associated-with-increased-age-of-onset-of-systemic-lupus-erythematosus/. Accessed .
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