Kidney Week

Abstract: SA-PO260

Transcriptomic Analysis of mRNA Expression in Peripheral White Blood Cells of Genes Encoding Circulating Proteins Associated with the Development of ESKD in Diabetes

Session Information

• Diabetic Kidney Disease: Basic - 2
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 701 Diabetic Kidney Disease: Basic

Authors

• Pezzolesi, Marcus G., University of Utah Health, Salt Lake City, Utah, United States

Marcus G. Pezzolesi, PhD, MPH

• Ihara, Katsuhito, Joslin Diabetes Center, Boston, Massachusetts, United States

Katsuhito Ihara, MD, MPH

• Satake, Eiichiro, Joslin Diabetes Center, Boston, Massachusetts, United States

Eiichiro Satake, MD, PhD

• Md Dom, Zaipul, Joslin Diabetes Center, Boston, Massachusetts, United States

Zaipul Md Dom, PhD

• Krolewski, Bozena, Joslin Diabetes Center, Boston, Massachusetts, United States

Bozena Krolewski, PhD

• Krolewski, Andrzej S., Joslin Diabetes Center, Boston, Massachusetts, United States

Andrzej S. Krolewski, MD, PhD

Background

Using global-untargeted proteomics, we recently identified 46 circulating proteins robustly associated the risk of development of end-stage kidney disease (ESKD) in individuals with Type 1 (T1D) or Type 2 diabetes (T2D) during 7-15 years of follow-up. In the present study, we performed transcriptomic analysis on mRNA to examine whether circulating levels of these proteins derive from expression of the risk-associated protein encoding genes in peripheral white blood cells (WBC).

Methods

RNA sequencing was performed on total RNA isolated from peripheral blood from a subset of individuals enrolled in the Joslin Kidney Study (23 T1D and 48 T2D). During 7-15 years of follow-up, 16 of these individuals developed ESKD and 55 remained without ESKD. The resulting sequencing reads were aligned to the GRCh38/hg38 reference genome and annotated using Ensembl (release 102). Differential gene expression analysis was then performed between controls and cases who progressed to ESKD during follow-up or had fast kidney function declining (eGFR slope <-5.0 ml/min/year).

Results

Transcriptome-wide, 4 out of ~22,000 genes (GRB10, IGKV1-9, IGKV1-39, and NAV3) were found to be differentially expressed between the two groups after correcting for multiple testing (Bonferroni-adjusted p <2.26x10^-6). Out of the 46 circulating proteins associated with risk of development of ESKD, 11 genes encoding these proteins were not expressed in WBC, 10 had low expression and 26 had moderate or high expression. Strikingly, and in contrast with our proteomic findings where concentrations of 10 ESKD risk-associated proteins in plasma collected at the same time as these WBC were significantly upregulated in cases relative to controls, expression of these genes was identical in those who progressed and those who did not progressed to ESKD.

Conclusion

These negative transcriptomic findings in WBC contrast with significant statistical differences in concentration of ESKD risk-associated proteins in plasma. These findings suggest that the high concentrations of ESKD risk associated proteins in circulation cannot be accounted for by increased transcription of these genes in WBCs.

Funding

• NIDDK Support