The disproportionate risk for idiopathic proteinuric podocytopathies in Black people is explained, in part, by the presence of two risk alleles (G1 or G2) in the APOL1 gene. The pathogenic mechanisms responsible for this genetic association remain incompletely understood. We analyzed glomerular RNASeq transcriptomes from patients with idiopathic nephrotic syndrome of which 72 had inferred African ancestry (AA) and 152 did not (noAA). Using gene coexpression networks we found a significant association between APOL1 risk allele number and the coexpression metamodule 2 (MM2), even after adjustment for eGFR and proteinuria at biopsy. Unadjusted Kaplan-Meier curves showed that unlike noAA, AA with the highest tertile of MM2 gene activation scores were less likely to achieve complete remission (p≤0.014). Characteristic direction (ChDir) identified a signature of 1481 genes, which separated patients with APOL1 risk alleles from those homozygous for reference APOL1. Only in AA, the tertile with the highest activation scores of these 1481 genes was less likely to achieve complete remission (p≤0.022) and showed a trend to faster progression to the composite event of kidney failure or loss of 40% eGFR (p≤0.099). The MM2 and ChDir genes significantly overlapped and were both enriched for Epithelial Mesenchymal Transition and inflammation terms. Finally, MM2 significantly overlapped with a parietal epithelial cell (PEC)-identity gene signature but not with a podocyte identity signature. Podocytes expressing variant APOL1s may generate inflammatory signals that activate PECs by paracrine mechanisms contributing to APOL1 nephropathy.

The authors have declared no competing interest.

This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants K01DK128304, 5T32DK07470, R01DK097836 and R01DK108329. The NEPTUNE consortium, U54-DK083912, is a part of the NIH Rare Disease Clinical Research Network (RDCRN), supported through collaboration between the Office of Rare Diseases Research, National Center for Advancing Translational Sciences, and the NIDDK. See Supplemental Acknowledgments for NEPTUNE consortium details. KPMP is a multiyear project funded by the NIDDK with the purpose of understanding and finding new ways to treat chronic kidney disease and acute kidney injury. See Supplemental Acknowledgments for KPMP consortium details. The Kidney Precision Medicine Project is funded by the following NIDDK grants: U01DK133081, U01DK133091, U01DK133092, U01DK133093, U01DK133095, U01DK133097, U01DK114866, U01DK114908, U01DK133090, U01DK133113, U01DK133766, U01DK133768, U01DK114907, U01DK114920, U01DK114923, U01DK114933, U24DK114886, UH3DK114926, UH3DK114861, UH3DK114915, and UH3DK114937.

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The NEPTUNE protocol is approved by the University of Michigan IRBMED central IRB (HUM00158219), and the Cleveland Clinic IRB (15-182). The KPMP study protocol is approved using a central IRB at the Human Research Protection Office of Washington University in St. Louis (IRB no. 201902013). NEPTUNE and KPMP participants provided written informed consent prior to enrollment.

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