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Abstract: SA-PO252

Gene-Based Burden Analysis of De Novo Sphingolipid Pathway Genes Identifies CERS3 as a Potential Risk Gene in Advanced Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Simeone, Christopher A., University of Utah, Department of Human Genetics, Salt Lake City, Utah, United States
  • Wilkerson, Joseph L., University of Utah, Department of Nutrition and Integrative Physiology, Salt Lake City, Utah, United States
  • Summers, Scott, University of Utah, Department of Nutrition and Integrative Physiology, Salt Lake City, Utah, United States
  • Pezzolesi, Marcus G., University of Utah, Department of Human Genetics, Salt Lake City, Utah, United States
Background

Identifying the genetic factors influencing diabetic kidney disease (DKD) susceptibility remains challenging. Recent studies have demonstrated that ceramides, a class of sphingolipids, are antagonists for insulin signaling and drivers of DKD progression. Sphingolipid profiles have been explored in DKD, although little is known about the genetic architecture underlying aberrant sphingolipid levels in DKD. Here, we investigated the burden of rare, pathogenic variants in genes within the de novo sphingolipid pathway in patients with advanced DKD.

Methods

We examined 33 genes in two cohorts with advanced DKD (eGFR < 30): The Chronic Renal Insufficiency Cohort (CRIC, n=656) and the Utah Kidney Study (UKS, n=185). Genotype data from CRIC was imputed (R2 ≥ 0.4) using the Michigan Imputation Server and variants localized to genes of interest were selected, while targeted sequencing of these same genes was performed for participants of the UKS. Using summary data from gnomAD (71,702 control genomes), we performed a two-stage, gene-based burden analysis of rare variants (gnomAD global AF filter < 0.01) using the TRAPD software package to identify reproducible candidate genes across cohorts. We performed immunofluorescence in kidneys and functional analyses of the top candidate gene identified in these analyses.

Results

Gene-based burden analyses identified CERS3 as a significant, reproducible candidate gene in both the CRIC and UKS cohorts. Nominal significance was observed in two ORMDL genes after filtering variants for CADD score ≥ 20. Immunofluorescence demonstrated the presence of CERS3 in the tubules of mouse and human kidney tissues. Additionally, metabolic flux assays suggest that genetic variation in CERS3 reduces Cer d18:1/26:0 produced in HEK293T cells.

Conclusion

CERS3 is a ceramide synthase that produces longer acyl chain ceramides (≥C26). Interestingly, common variants in a similar family member, CERS2, have also been associated with renal phenotypes in patients with diabetes, suggesting that this family of enzymes may play a role in DKD susceptibility. Further examination is necessary to fully characterize the influence of CERS3 on DKD progression.

Funding

  • NIDDK Support