Abstract: FR-PO651
Building a Biobank for Genetic Studies on Primary and Recurrent Focal Segmental Glomerulosclerosis
Session Information
- Genetic Kidney Diseases: Cohort Studies - Genetic Associations and Diagnoses
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Martinelli, Elena, Columbia University, Division of Nephrology, New York, United States
- Lim, Tze Yin, Columbia University, Division of Nephrology, New York, New York, United States
- Ke, Juntao, Columbia University, Division of Nephrology, New York, New York, United States
- Batal, Ibrahim, Columbia University, Division of Nephrology, New York, New York, United States
- Kiryluk, Krzysztof, Columbia University, Division of Nephrology, New York, New York, United States
- Sampson, Matt G., Division of Nephrology, Boston Children Hospital, Boston, Massachusetts, United States
- Saleem, Moin A., Division of Pediatric Nephrology, University of Bristol, Bristol, United Kingdom
- Pollak, Martin, Division of Nephrology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
- Hildebrandt, Friedhelm, Division of Nephrology, Boston Children Hospital, Boston, Massachusetts, United States
- Gharavi, Ali G., Columbia University, Division of Nephrology, New York, New York, United States
- Gbadegesin, Rasheed A., Division of Pediatric Nephrology, Duke University, Durham, North Carolina, United States
- Mohan, Sumit, Columbia University, Division of Nephrology, New York, New York, United States
- Sanna-Cherchi, Simone, Columbia University, Division of Nephrology, New York, New York, United States
Background
Primary and Recurrent focal segmental glomerulosclerosis (pFSGS/rFSGS) carry high burden of morbidity and graft loss after kidney transplant. Genetic studies are mostly directed to non-immune forms of FSGS leaving the complex genetic etiology of p/rFSGS unresolved. A hurdle in designing adequate genetic studies is the lack of large multiethnic cohorts. We propose a multicenter strategy to collect genetic data across lifespan and ancestries to perform genetic studies for unraveling targets amenable for drug development.
Methods
We ascertained 13,000 cases with nephrotic syndrome (NS)/FSGS from national and international centers across ages, response to immunosuppression and ancestries. DNA is available for all cases and genetic data have been generated in 60% of them. To identify p/rFSGS case we are conducting a sequential filtering by removal of cases with Mendelian/APOL1-FSGS, followed by chart review to remove secondary forms (prematurity, obesity, structural kidney anomalies, and other factors). Cases are further stratified in two tiers: 1) ESKD who have experienced post-transplant recurrence (rFSGS); 2) cases not transplanted but with predictors indicating high probability of rFSGS (full NS with >80% foot process effacement at EM, initial response to steroids with evolution to resistance, initial biopsy showing MCD and subsequent biopsy consistent with FSGS).
Results
A pilot analysis on 1,127 cases from 6 cohorts removed 202 cases with Mendelian/APOL1 FSGS (18%) and 121 cases with secondary FSGS, resulting in a group of 804 cases enriched for pFSGS. Database and chart review identified 52 individuals with rFSGS (Tier1): 63.3% pediatric (35/52), 65.4% male (34/52); across different genetic ancestries: European 55.1%, Admixed 12.2%, Latinx 10.2%, African 18.4%, Asian 4.1%. Tier2 analysis is ongoing.
Conclusion
Based on estimates from our pilot analysis we will identify at least 8,000 individuals with pFSGS for genome-wide association studies (GWAS) and exome-based rare variant burden analyses. We will then validate results on the Tier1 (estimated N>500) and Tier2 (N>2,000) subgroups individually or in aggregate. These datasets will power adequate genetic discovery studies for rare forms of FSGS.
Funding
- NIDDK Support