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Abstract: TH-PO245

Family-Based Whole-Genome Sequencing Identifies FRAS1 as a Novel Gene for Rapid Renal Decline in Diabetes

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Neeley, Matthew Brady, University of Utah, Division of Nephrology and Hypertension, Department of Internal Medicine, Salt Lake City, Utah, United States
  • Moore, Barry, University of Utah, Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, United States
  • Li, Shuwei, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Reilly, Dermot F., Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Lazaro guevara, Jose M., University of Utah, Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, United States
  • Pezzolesi, Melissa H., University of Utah, Division of Nephrology and Hypertension, Department of Internal Medicine, Salt Lake City, Utah, United States
  • Hernandez, Edgar Javier, University of Utah, Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, United States
  • Black, Mary Helen, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Yandell, Mark, University of Utah, Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, United States
  • Parrado, Antonio R., Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Pezzolesi, Marcus G., University of Utah, Division of Nephrology and Hypertension, Department of Internal Medicine, Salt Lake City, Utah, United States
Background

Progressive renal decline is the central manifestation of diabetic nephropathy (DN) and ultimately leads to end-stage renal disease. To accelerate discovery of novel genes that contribute to rapid renal decline and DN, we developed an innovative family-based approach that integrates electronic medical record data, a unique population-based genealogy resource, and next-generation sequencing.

Methods

Kindred-specific risk of rapid renal decline was used to quantify the familial standardized incidence ratio and identify pedigrees with excess clustering of rapid renal decline. Whole genome sequencing (WGS) was performed in 60 individuals from 6 pedigrees ascertained for the Utah Diabetes Study, followed by unified linkage analysis and rare variant association testing. To replicate findings, we performed variant-/gene-level association tests using whole exome sequencing (WES, n=450K), WGS (n=150K), renal function biomarkers, and kidney disease endpoints available in the UK Biobank.

Results

Among these pedigrees, we identified a rare pathogenic variant in FRAS1 shared by 5 affected members of one family. Sanger sequencing confirmed the carrier status of these affected family members and identified 2 additional carriers (including 1 with impaired renal function) and 4 non-carriers of the FRAS1 variant in this family. In the UK Biobank, a population-based cohort of primarily healthy individuals at the time of baseline blood draw, we observed nominal variant association with increased risk of CKD, nephrotic syndrome, and glomerulonephritis (all p<5x10-3). FRAS1 putative loss-of-function and deleterious singletons in aggregation were nominally associated with reduced eGFR (p<5x10-3).

Conclusion

These data suggest that rare pathogenic variants in FRAS1 contribute to increased risk of DN and, importantly, progression of rapid renal decline. FRAS1 encodes an extracellular matrix protein that mediates integrity of glomeruli and is downregulated in glomeruli of mice with DN; further supporting FRAS1’s potential role in kidney disease in individuals with diabetes. These findings highlight the power of family-based genetics in well-phenotyped cohorts and its ability to discover novel genes that contribute to rapid renal decline and DN.

Funding

  • NIDDK Support –