Kidney Week

Abstract: SA-PO605

APOL1 Glomerular Transcriptional Networks in Non-Black FSGS Patients

Session Information

• Noncystic Mendelian Diseases
  November 04, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Genetic Diseases of the Kidney

• 802 Non-Cystic Mendelian Diseases

Authors

• Fermin, D, University of Michigan, Ann Arbor, Michigan, United States

D Fermin,

• Yasutake, K, University of Michigan, Ann Arbor, Michigan, United States

K Yasutake,

• Sampson, Matt G., University of Michigan, Ann Arbor, Michigan, United States

Matt G. Sampson,

Group or Team Name

• NEPTUNE

Background

The “G1” & “G2” alleles of APOL1 are common in African-Americans and confer greatly increased risk for the development of FSGS. While these risk variants are essentially absent in non-blacks, APOL1 is substantially expressed in kidney tissue across races. Furthermore, experimental models have shown that increased expression of wild-type APOL1 is also associated with renal toxicity. Thus, we hypothesized that even when not harboring G1 & G2, glomerular APOL1 may have a role in NS pathogenesis. To pursue this, we contextualized APOL1 expression within glomerular transcriptional networks derived from whites with FSGS enrolled in the Nephrotic Syndrome Study Network (NEPTUNE).

Methods

Transcriptomic data was available from microdissected glomeruli of 18 white NEPTUNE participants with FSGS (100% wild-type APOL1). We measured APOL1 expression & then used “Weighted Gene Co-expression Network Analysis” (WCGNA) to identify genesets significantly correlated with its expression. To identify biologic processes associated with these genesets, we use gene-ontology term based enrichment analysis. To idenity key genes in these biologic processes, we constructed interaction networks.

Results

APOL1 was in the top 15^th percentile of expression of the 18,000 glomerular genes analyzed. There were 5 co-expression networks significantly correlated with APOL1. The most significant (r=-0.65, p=0.004) was enriched for GO terms related to anion transmembrane transport & metabolic processes. The 2^nd most correlated network (r=0.64, p=0.004) was enriched for development processes, particularly vascular & epithelial development. Viral responses & Type 1 Interferon signaling pathways, previously implicated in intrarenal transcriptomic studies of black NS patients with a HR APOL1 genotype, were enriched in the 5^th most correlated network (r=0.50, p=0.04). CD4 was a central hub in this network.

Conclusion

Our study of APOL1 in the glomeruli of white FSGS patients identified similarities to black patients with APOL1-attributed NS, both in expression level & co-regulated networks. But we also discovered highly correlated glomerular networks enriched for non-immune related biology. Some of these processes have been implicated in previous studies of APOL1, while others are novel. Further study of APOL1 glomerular transcriptional networks across races may help us discover the biologic mechanisms driving APOL1-attributed NS.

Funding

• NIDDK Support