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205 Single cell RNA expression in lupus nephritis comparing african-american and caucasian patients identifies differential expression of type I interferon pathway
  1. Andrea Fava1,
  2. Yuji Zhang2,
  3. Nir Hacohen3,
  4. Arnon Arazi4,
  5. Celine C Berthier5,
  6. Deepak Rao6,
  7. Michael Brenner7,
  8. David Wofsy8,
  9. Anne Davidson9,
  10. Matthias Kretzler10,
  11. David Hildeman11,
  12. E Steve Woodle12,
  13. Betty Diamond9 and
  14. Michelle Petri13
  1. 1Johns Hopkins University
  2. 2University of Maryland
  3. 3Harvard Medical School
  4. 4Broad Institute
  5. 5University of Michigan
  6. 6Brigham and Women’s Hospital/Harvard Medical School
  7. 7Brigham And Women’s Hospital
  8. 8Russell/Engleman Rheumatology Research Center, University of California, San Francisco, CA, USA
  9. 9Feinstein Institute for Medical Research
  10. 10University of Michigan Medical School
  11. 11University of Cincinnati Department of Pediatrics
  12. 12University of Cincinnati
  13. 13Johns Hopkins University School of Medicine


Background 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. 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.

Methods 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.

Results 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 30 155 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.

Conclusions 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.

Funding Source(s): NIH foundation partnership with AbbVie, Biogen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Johnson and Johnson, Lilly, Merck, Pfizer, Sanofi, Takeda, and Verily.

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