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Abstract: TH-PO430

Identification and Characterization of Biomarkers from Cell-Free DNA Methylation in ADPKD Patients

Session Information

Category: Genetic Diseases of the Kidneys

  • 1201 Genetic Diseases of the Kidneys: Cystic

Authors

  • Li, Xiaoyan, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, United States
  • Zhou, Xia, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, United States
  • Hanna, Christian, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, United States
  • Harris, Peter C., Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, United States
  • Li, Xiaogang, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, United States
Background

ADPKD is caused by mutations of PKD1/PKD2. However, there is no proper biomarker for this disease. Recently, circulating cell-free (cf) DNA has attracted attention as biomarkers in the context of prediction, prognostication, and monitoring of drug response in human diseases.

Methods

We isolated cfDNA from plasma and urine and performed EM-Sequencing to identify cfDNA methylation signatures and the differential methylation regions (DMRs) with 5% methylation difference between the pediatric ADPKD patients and age-matched healthy individuals. The DMRs associated signaling pathways were analyzed with gene set enrichment analysis (GSEA).

Results

We identified 2,054 and 30,511 DMRs in cfDNA from plasma and urine, in which 1,409 (69%) and 24,707 (81%) DMRs were aligned to protein-coding genes, 43 (3%) and 7453 (30%) DMRs were located on the promoters of those protein-coding genes, and 26 of 43 (60%) and 7365 of 7453 (99%) DMRs were hypomethylated in ADPKD patients. The criteria used to identify DMRs as biomarkers include that, 1) their methylation is three times more than the initial 5% differential methylation in ADPKD patients versus healthy controls in either plasma or urine; 2) they are located to the promoter regions of protein-coding genes; and/or 3) they are constantly hypo- or hyper-methylated in both plasma and urine. We identified 7 hypo- and 5 hyper-methylated DMRs in plasma only, and 1754 hypo- and 55 hypermethylated DMRs in urine only, and those DMRs only matched criteria 1 and 2. Importantly, we identified 19 DMRs in both plasma and urine, and 10 of these 19 DMRs matched all three criteria. These 10 DMRs associated protein-coding genes encode inflammatory cytokine (CD70), metabolic related proteins (PON1, LOXL1, CERS3, ENOSF1), neurological synapse related factor (SDK1), epigenetic regulators (PRDM8, CMTR2) and transcriptional regulators (CIZ1, NBL1), which were all hypomethylated and their mRNA levels were increased in Pkd1 mutant mouse kidneys. The diverse function of these 10 proteins/factors and the associated pathways supports the roles in regulation of cyst growth in ADPKD.

Conclusion

This study identifies cfDNA methylation signatures and the differential methylation regions in ADPKD patients, and the 10 candidate DMRs and the associated genes and pathways are potential biomarkers and novel mechanisms for ADPKD progression.

Funding

  • NIDDK Support