A glomerular transcriptomic landscape of apolipoprotein L1 in Black patients with focal segmental glomerulosclerosis

Apolipoprotein L1 ( APOL1 )-associated focal segmental glomerulosclerosis (FSGS) is the dominant form of FSGS in Black people. There are no targeted therapies for this condition, in part because the molecular mechanisms underlying APOL1’s pathogenic contribution to FSGS are incompletely understood. Studying the transcriptomic landscape of APOL1 FSGS in patient kidneys is an important way to discover genes and molecular behaviors that are unique or most relevant to the human disease. With the hypothesis that the pathology driven by the high-risk (HR) APOL1 genotype is reflected in alteration of gene expression across the glomerular transcriptome, we compared expression and co-expression profiles of 15,703 genes in 16 Black FSGS patients with a HR vs 14 with a low-risk (“LR”) APOL1 genotype. Expression data from APOL1 -inducible HEK293 cells and normal human glomeruli were used to pursue genes and molecular pathways illuminated in these studies. We discovered (1) increased expression of APOL1 in HR and nine other significant differentially expressed genes, including stanniocalcin ( STC1) , which has a role in mitochondrial and calcium-related processes, (2) differential correlations between HR and LR APOL1 and metabolism pathway genes, but similar correlations with extracellular matrix- and immune-related genes, (3) significant loss of co-expression of mitochondrial genes in HR FSGS, and (4) an NF-κB -down-regulating gene, NKIRAS1 , as the most significant hub gene with strong differential correlations with NDUF family and immune-related genes. Overall, differences in mitochondrial gene regulation appear to underlie many differences observed between HR and LR FSGS. All data are available for secondary analysis through the “APOL1 Portal” (). ### Competing Interest Statement MGS has consulted for Maze Therapeutics and Janssen and is on the Scientific Advisory Board of Natera. DJF and MRP are inventors on patents related to APOL1, own equity in Apolo1bio, and receive research support and have consulted for Vertex. ### Funding Statement MS is supported by NIH RO1 DK108805, DK119380, and RC2 DK122397. DJ, NB, and JF are supported by 2 UM1 DK105554-06. The Nephrotic Syndrome Study Network Consortium (NEPTUNE), U54-DK-083912, is a part of the National Institutes of Health (NIH) Rare Disease Clinical Research Network (RDCRN), supported through a collaboration between the Office of Rare Diseases Research, National Center for Advancing Translational Sciences and the National Institute of Diabetes, Digestive, and Kidney Diseases. Additional funding and/or programmatic support for this project has also been provided by the University of Michigan, the NephCure Kidney International and the Halpin Foundation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This research was approved by the IRB of Boston Children's Hospital and the University of Michigan All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes We've created the APOL1 Portal (http://APOL1portal.org) to make all analyses in this paper and all of the data publicly available for browsing, download, and secondary analysis.