AB0167 SINGLE CELL RNA EXPRESSION IN LUPUS NEPHRITIS COMPARING AFRICAN-AMERICAN AND CAUCASIAN PATIENTS IDENTIFIES DIFFERENTIAL EXPRESSION OF TYPE I INTERFERON PATHWAY
Authors: Andrea Fava, Yuji Zhang, Nir Hacohen, Arnon Arazi, Celine Berthier, Deepak Rao, Michael Brenner, David Wofsy, Anne Davidson, Matthias Kretzler, David Hildeman, E. Steve Woodle, Betty Diamond, Michelle A. Petri
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> African-American ethnicity is associated with a 3-fold higher risk of developing systemic lupus erythematosus (SLE). In addition, there is an increased risk of lupus nephritis (2-fold), high-risk histological features, and resistance to treatment. This may account for the increased mortality rate compared to Caucasian patients, especially in women. <h3>Objectives:</h3> In Phase One of the Accelerating Medicines Partnership (AMP) study, we used single-cell RNA sequencing on kidney biopsies from patients with active lupus nephritis to identify pathways that were differentially expressed in African-American patients. <h3>Methods:</h3> Single cell RNA sequencing was performed on renal biopsies obtained for clinical purpose for active nephritis using CEL-Seq2. Cell clusters with similar expression profile were identified using t-distributed stochastic neighbor embedding (t-SNE). First, the relative abundance of a cluster in AAs compared to Caucasian was determined using a logistic mixed model. Second, the differential expression profile was determined for each cell cluster and we applied Ingenuity Pathway Analysis (IPA) (QIAGEN Bioinformatics) to identify pathways of interest. <h3>Results:</h3> Samples from 13 AA and 7 Caucasian patients were obtained. Of the 3097 sequenced cell libraries, we used 2354 which passed our quality filter for a total of 30155 unique molecular identifiers. We identified 16 cell clusters including CD4, CD8, B and plasma cells, NK, myeloid cells, and tubular cells. We identified 2 cell clusters unique to African-American patients, a T and a B cell population with high expression of interferon inducible genes. We also identified that same cell populations may have differential gene expression profiles across ethnicity. For example, CD4 T cells in African-Americans have a higher expression of type 1 and type 2 interferon pathways. In contrast, myeloid cells have several upregulated pathways in Caucasians, including ERK/MAPK signaling. <h3>Conclusion:</h3> African-American lupus nephritis patients may have a stronger interferon pathway activation in infiltrating immune cells. Several other pathways, including ERK/MAPK, are differentially expressed in infiltrating cells based on ethnicity. These results suggest that ethnicity might predict a response to both current and upcoming treatments, paving the way for a more personalized approach to treatment in lupus nephritis. Further work in Phase 2 of AMP will confirm and extend these findings. <h3>Disclosure of Interests:</h3> Andrea Fava: None declared, Yuji Zhang: None declared, Nir Hacohen: None declared, Arnon Arazi: None declared, Celine Berthier: None declared, Deepak Rao: None declared, Michael Brenner Grant/research support from: Roche: sponsored research agreement on stromal cells (but has nothing to do with checkpoint related disease), Consultant for: GSK: consultant. (I am part of their immunology network, a group of about 8 immunologists who advise them regularly and broadly in the areas of inflammation and infection)., David Wofsy Consultant for: GlaxoSmithKline – Member, data safety monitoring board Novartis – Member, data safety monitoring board Celgene – member, scientific advisory board, Anne Davidson: None declared, Matthias Kretzler: None declared, David Hildeman: None declared, E. Steve Woodle: None declared, Betty Diamond: None declared, Michelle A Petri Shareholder of: Pfizer, Merck, Grant/research support from: AstraZeneca, Exagen, Consultant for: Eli Lilly, GSK, Merck EMD Serono, Janssen, Amgen, Novartis, Quintiles, Exagen, Inova Diagnostics, AstraZeneca, Blackrock, Glenmark, UCB, and the Annenberg Center for Health Sciences