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)

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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