Abstract: SA-PO575
Kidney Expression of Quantitative Trait Analysis Identified Tubule Caspase9 as a Kidney Disease Gene
Session Information
- Glomerular Diseases: Fibrosis, Extracellular Matrix
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix
Authors
- Doke, Tomohito, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Huang, Shizheng, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Seasock, Matthew J., University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Qiu, Chengxiang, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Susztak, Katalin, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Group or Team Name
- Susztak's lab
Background
Genome-wide association studies (GWAS) have identified sequence variations associated with kidney disease. However, finding causal genes, cell types and biological mechanisms underlying these associations remains a challenge. We generated expression of quantitative trait (eQTL) information for human kidney compartments to identify likely causal genes. Computational integration of the GWAS and eQTL datasets identified caspase 9 as a kidney disease risk gene. Caspase 9 is an initiator caspase in the apoptosis pathway found in many cells. Here we analyzed the role of caspase9 in kidney disease development.
Methods
We used a Bayesian colocalization method to integrate kidney eQTL data from 151 healthy individuals of European descent with CKD GWAS. We complemented our compartment-based eQTL studies with kidney-specific epigenome maps and single-cell specific RNA-sequencing results. We generated mice with heterozygous loss of caspase 9 (Casp9+/-). We characterized wild type and Casp9+/- mice at baseline and following folic acid induced kidney injury. Transcript levels for Caspase9 and fibrosis markers were determined by qPCR. Histological changes were characterized by Sirius Red and PAS staining.
Results
We found that the CKD risk variant of rs12124078 was associated with higher expression of caspase9 in microdissected human kidney glomerular and tubule samples. Similarly, in the folic acid kidney fibrosis model and in the APOL1 transgenic mouse model but not in the UUO induced kidney fibrosis model, the expression of cleaved Caspase9 was increased. Caspase 9 heterozygous mice appeared healthy without renal abnormalities. In the folic acid induce kidney injury model, not only the expression of cleaved Caspase9, but other effector caspases such as caspase3, caspase7, and expression of profibrotic genes were lower in Caspase 9 heterozygous mice.
Conclusion
GWAS and eQTL integration identified caspase 9 as CKD risk gene. Heterozygous loss of Caspase9 decreases apoptosis and fibrosis in models of kidney injury, indicating that Caspase9 is a kidney disease risk gene.
Funding
- NIDDK Support