Abstract: FR-PO928
Common Genetically Predicted Skipping of COL4A4 Exon 27 Is Associated with Hematuria and Albuminuria
Session Information
- CKD Epidemiology, Risk Factors, Prevention - II
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2301 CKD (Non-Dialysis): Epidemiology, Risk Factors, and Prevention
Authors
- Barua, Moumita, Toronto General Hospital, Toronto, Ontario, Canada
- Lona Durazo, Frida, Universite de Montreal Faculte de Medecine, Montreal, Quebec, Canada
- Omachi, Kohei, Washington University in St Louis School of Medicine, St Louis, Missouri, United States
- Fermin, Damian, University of Michigan Division of Nephrology, Ann Arbor, Michigan, United States
- Eichinger, Felix H., University of Michigan Division of Nephrology, Ann Arbor, Michigan, United States
- Troost, Jonathan P., Michigan Institute for Clinical and Health Research, Ann Arbor, Michigan, United States
- Miner, Jeffrey H., Washington University in St Louis School of Medicine, St Louis, Missouri, United States
- Paterson, Andrew, SickKids Research Institute, Toronto, Ontario, Canada
- Gagliano Taliun, Sarah A., Universite de Montreal Faculte de Medecine, Montreal, Quebec, Canada
Background
Hematuria is an established sign of glomerular disease and can be associated with kidney failure, but there has been limited scientific study of this trait.
Methods
Here, we combined genetic data from the UK Biobank with predicted gene expression and splicing from GTEx kidney cortex samples (n = 65) in a transcriptome-wide association study (TWAS) to identify additional biological mechanisms influencing hematuria.
Results
Our TWAS using kidney cortex identified significant associations for 5 genes in terms of expression and 3 significant splicing events. Notably, we identified an association between hematuria and the skipping of COL4A4 exon 27, which is genetically predicted by intronic rs11898094 (minor allele frequency 13%). The association was also found with urinary albumin excretion. We found independent evidence supporting the existence of this skipping event in glomeruli-derived mRNA transcriptomics data (n = 245) from the NEPTUNE dataset. The functional significance of loss of exon 27 was demonstrated using the split NanoLuc-based type IV collagen α3α4α5(IV) heterotrimer assay, in which heterotrimer formation was quantified by luminescence.
Conclusion
Altogether, our results highlight the value of investigating the role of non-coding sequence, an underexplored region, by integrating multiple data types to shed light on kidney traits and their underlying disease mechanisms.
Genomic overview of the exon 27 skipping event of COL4A4.
Funding
- NIDDK Support