Abstract: FR-PO317
Systems Genetics Approaches Uncover Pathway-Level Interactions in Mice Carrying APOL1 G0/G2 Transgene and Gstm1 Null Alleles
Session Information
- Genetic Diseases: Models, Mechanisms, Treatments
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1102 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Mychaleckyj, Josyf, University of Virginia Center for Public Health Genomics, Charlottesville, Virginia, United States
- Wang, Yves T., University of Rochester Medical Center, Rochester, New York, United States
- Le, Thu H., University of Rochester Medical Center, Rochester, New York, United States
Background
APOL1 G1/G2 and GSTM1 null alleles are associated with decline of kidney function but the cellular and molecular processes that effect the genetic risk remain poorly understood. We tested the interaction of an APOL1 podocyte-specific transgene and Gstm1 in cross-engineered mouse lines to examine the systems by which these two genes modulate kidney disease susceptibility.
Methods
We crossed FVB mouse lines carrying Gstm1(-/-) and podocyte specific APOL1 G0 or G2 transgenes (tg) in a 2x3 factorial design with 6-8 mice per group (Figure 1). RNA was extracted from kidney cortices and subjected to RNA-seq analysis. Sequence reads were aligned using a STAR/RSEM pipeline against an APOL1-spiked mouse genome. Analyses included cell-type deconvolution, differential expression, and independent components analysis to identify transcriptional gene modules. Differential gene sets and gene modules were tested for pathway enrichment and modular networks inferred (Figure 2).
Results
There was a significant increase in %neutrophils in Gstm1(-/-) mice compared to wild type (WT) (p=0.004), while tgG0 and tgG2 mice showed lower %nephron/duct cells (p=0.047/0.0078). There were 39 genes with altered expression at FDR< 0.05 in tgG2 vs tgG0 and 53 in Gstm1(-/-) vs WT. There was strong evidence for an interaction between the APOL1(tg) and Gstm1 genotypes through coordinated changes in pathways and gene sets, including cytochrome P450, glutathione, amino acid, and sphingolipid metabolism. In tgG2 vs tgG0, there were changes in oxidative phosphorylation, Th1/Th2/Th17 cell differentiation, neurodegeneration, diabetic cardiomyopathy-related, and AGE-RAGE signaling pathways. Functional cluster enrichment analysis of the modules recapitulated this through pervasive associations with immune response, innate immunity, cell adhesion, and synaptic response.
Conclusion
We have identified a complex of set of overlapping molecular and cellular processes that are dysregulated by these genotypic changes in APOL1 and Gstm1. The risk allele (G2 and Gstm1(-)) interaction suggests that additional genetic variability could be one source of the additional ‘hit’ needed to express a susceptibility phenotype within APOL1 G1/G2 risk carriers.
Funding
- NIDDK Support