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Kidney Week

Abstract: FR-OR069

Kidney Compartment Specific eQTL Studies Highlight Causal Genes and Pathways for Renal Disease Development

Session Information

Category: Genetic Diseases of the Kidney

  • 1002 Genetic Diseases of the Kidney: Non-Cystic

Authors

  • Qiu, Chengxiang, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Huang, Shizheng, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Park, Jihwan, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Park, Yoson, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Ko, Yi-An, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Seasock, Matthew J., University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Bryer, Joshua S., University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Song, Wenchao, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Palmer, Matthew, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Hill, Jonathan, Boehringer Ingelheim, Ridgefield, Connecticut, United States
  • Guarnieri, Paolo, Boehringer Ingelheim, Ridgefield, Connecticut, United States
  • Hawkins, Julie, Boehringer Ingelheim, Ridgefield, Connecticut, United States
  • Boustany, Carine, Boehringer Ingelheim, Ridgefield, Connecticut, United States
  • Pullen, Steven S., Boehringer Ingelheim, Ridgefield, Connecticut, United States
  • Susztak, Katalin, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Background

Chronic kidney disease (CKD) is a common disease condition affecting more than 1 in 10 people in the general population. Genome wide association studies (GWAS) have identified more than 100 regions where nucleotide variants are significantly and reproducibly associated with kidney function. Expression quantitative trait locus (eQTL) analysis aim to identify gene expression changes in cell and tissue samples driven by the underlying genetic variation. By combining GWAS and eQTL studies we can identify gene expression change driven by disease associated genetic variation. Genes for which expression are influenced by GWAS signals are likely candidates for disease development.

Methods

We conducted eQTL analyses separately on glomerular and tubular portions of healthy human kidney samples obtained from 151 subjects of European descent. We complemented our compartment-based eQTL studies with kidney-specific epigenome maps and single-cell RNA-sequencing results. Focusing on the DAB2-C9 CKD GWAS locus, we induced kidney injury by folic acid administration and unilateral ureter obstruction to test the effect of DAB2 and C9. To understand the mechanism of Dab2-induced kidney damage, we cultured primary renal tubule cells from Dab2flox/+ mice and infected them with Cre-eGFP or control adenovirus.

Results

We identified eQTLs and generated a searchable public eQTL database from human whole kidney, tubules and glomeruli samples. Kidney-specific eQTLs showed significant enrichment for genetic variants associated with renal traits. We identified eQTLs at 27 genes that colocalize with CKD GWAS signals. Putative causal genes were enriched for proximal tubule expression and endolysosomal function. DAB2 appeared to be a central gene among the putative causal genes. In vivo studies, using mice with reduced tubule epithelial-specific gene expression demonstrated that Dab2 protects mice from CKD development. In vitro results indicate that Dab2 in tubule cells plays an important role in TGFβ-induced profibrotic gene expression.

Conclusion

This in-depth follow-up analysis of CKD GWAS, defines a novel framework for CKD development, and identifies DAB2 and endolysosomal pathway as key mechanism for kidney disease pathogenesis.

Funding

  • NIDDK Support