Abstract: TH-OR032
Proportion of Allele-Specific Expression Is Different in Glomeruli and Tubulointerstitium of Proteinuric Kidneys and Correlated to Disease Progression
Session Information
- Genetics of Complex Kidney Traits
November 06, 2025 | Location: Room 360A, Convention Center
Abstract Time: 05:10 PM - 05:20 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Complex Kidney Traits
Authors
- Onuchic-Whitford, Ana C., Brigham and Women's Hospital, Boston, Massachusetts, United States
- Sung, Junmo, Brigham and Women's Hospital, Boston, Massachusetts, United States
- Sakkas, Erotokritos, Boston Children's Hospital, Boston, Massachusetts, United States
- McNulty, Michelle, Boston Children's Hospital, Boston, Massachusetts, United States
- Greenberg, Anya, Harvard Medical School, Boston, Massachusetts, United States
- Yoon, Jihoon, Yonsei University College of Medicine, Seodaemun-gu, Korea (the Republic of)
- Badina, Sowmya, The Apollo University, Chittoor, AP, India
- Bitzer, Markus, University of Michigan, Ann Arbor, Michigan, United States
- Mariani, Laura H., University of Michigan, Ann Arbor, Michigan, United States
- Sampson, Matt G., Boston Children's Hospital, Boston, Massachusetts, United States
- Lee, Dongwon, Boston Children's Hospital, Boston, Massachusetts, United States
Group or Team Name
- Nephrotic Syndrome Study Network (NEPTUNE).
Background
Allele-specific expression (ASE) is a key mechanism of gene regulation, through preferential expression of one gene copy. ASE occurs in all human tissues and is implicated in pathogenesis. ASE analysis in human kidneys has focused on non-diseased nephrectomy or post-mortem tissue. Here, we compare the ASE landscape among compartments of the human kidney, in both proteinuric and in non-diseased state, identifying systematic differences and correlation with disease course.
Methods
We performed genome-wide ASE analysis in 206 kidney biopsies from the Nephrotic Syndrome Study Network (NEPTUNE) and 36 non-diseased kidney samples with bulk RNA-seq from microdissected glomeruli (GLOM) and tubulointerstitium (TUBE). Based on systematic ASE differences in GLOM/TUBE, we ran survival analysis in NEPTUNE assessing the endpoint of end-stage kidney disease (ESKD) and/or ≥40% eGFR decline. We conducted differential gene expression (DEG) and gene set enrichment analysis (GSEA) to identify dysregulated molecular pathways.
Results
In NEPTUNE, the median proportion of genome-wide ASE (defined as number of ASE genes divided by the number of genes with coverage ≥20) was significantly higher in GLOM than TUBE (7.67% vs 5.27%, p<2.2x10-16). This was not seen in non-diseased samples, where ASE proportion was similar in GLOM and TUBE (6.47% vs 6.89%, p=0.75). We separated NEPTUNE into 2 equal groups based on the ratio of ASE proportion in GLOM relative to TUBE (low ratio 0.44 – 1.578, high 1.579 – 6.16). Kaplan-Meier analysis revealed the high-ratio group had slower progression to ESKD/eGFR endpoint (p=0.0016), with a Cox proportional hazard ratio of 0.39 (p=0.0023). DEG and GSEA showed upregulation of ribosome, ATP, and mitochondria-related pathways in the high-ratio group, with downregulation of immune and membrane-related terms.
Conclusion
Proteinuric kidneys, usually a result of glomerular disease, demonstrate more genome-wide ASE in GLOM than TUBE. A higher GLOM-to-TUBE ASE ratio was significantly associated with better disease course. DEG shows upregulation of ribosome and energy pathways in the high-ratio group, suggesting transcriptional/translational activation in GLOM may be driving increased ASE.
Funding
- NIDDK Support