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Background Autoantibodies (AAbs) are a hallmark of systemic lupus erythematosus (SLE). Common SLE AAbs show differences in specificities, levels and associations with clinical characteristics of disease which may be influenced by ethnicity.(1-2) NA SLE patients do not always exhibit classical AAb profiles.(2) Understanding how AAb profiles associate with clinical disease, including in NA patients, is important to better inform disease management. Objectives To identify patient subsets enriched for renal disease by clustering NA, AA and EA SLE patients into more homogeneous disease subsets based on expanded AAb profiles. Methods Serum samples from 49 NA, 49 AA, and 49 EA age, sex and ANA titer-matched SLE patients who met ACR classification and 10 sex and age matched controls from each ethnicity were tested for AAb reactivity by autoantigen microarray. Normalized fluorescence intensity (NFI) for AAb binding was determined for each individual for all autoantigens. Ratios of NFIs to total IgG were calculated and converted to Z-scores. Kruskal-Wallis analysis of Z-score transformed AAb ratios were used to identify AAbs that differed significantly between patients and controls for each ethnicity; these AAbs were used for hierarchal clustering of SLE subjects within each ethnicity. The enrichment of SLE clinical criteria within each cluster was determined by Fisher’s exact test. Results AAbs to nucleic acids and Ro52 were present in SLE patients of all three ethnicities. On average, NA SLE patients, but not EA or AA SLE patients, had lower levels of AAbs against extracellular matrix (ECM) antigens compared to controls. AA and EA, but not NA, SLE patients had significantly higher levels of AAbs to Sm, RNP and histones compared to matched controls. In each ethnicity four clusters of SLE subjects were identified by ethnicity-specific AAbs. All three groups had a cluster of subjects enriched in nucleic acid-specific AAbs and a cluster of subjects enriched in Ro52 AAbs. The NA group also had two clusters enriched in ECM AAbs. The AA group had an Sm/RNP AAb enriched cluster and a nucleolin/histone AAb enriched cluster. Two additional EA SLE clusters had similar levels of nucleic acid-specific AAbs and Ro52 AAbs, but were distinguished by significant differences in histone 2A (H2A) AAb levels. Renal manifestations were significantly enriched in the NA Ro52 cluster and the AA nucleolin/histone cluster compared to other SLE patient clusters of the same ethnicity. Conclusion Expanded AAb profiles can be used to identify SLE subsets that are more likely to have renal manifestations of disease. References [1] Sanchez E, et al. Impact of genetic ancestry and sociodemographic status on the clinical expression of systemic lupus erythematosus in American Indian-European populations. Arthritis Rheum. 2012;64(11):3687-94. [2] Kheir JM, et al. Unique clinical characteristics, autoantibodies and medication use in Native American patients with systemic lupus erythematosus. Lupus Sci. & Med. 2018;5:e000247. Acknowledgement This research supported by the National Institute of Allergy and Infectious Disease (U19AI082714), National Institute of Arthritis, Musculoskeletal and Skin Diseases (P30AR053483, P30AR073750), and National Institute of General Medical Sciences (U54GM104938) of the US NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the United States government. Disclosure of Interests None declared