PUBLICATION
Whole-Genome Sequencing of Finnish Type 1 Diabetic Siblings Discordant for Kidney Disease Reveals DNA Variants associated with Diabetic Nephropathy
- Authors
- Guo, J., Rackham, O.J.L., Sandholm, N., He, B., Österholm, A.M., Valo, E., Harjutsalo, V., Forsblom, C., Toppila, I., Parkkonen, M., Li, Q., Zhu, W., Harmston, N., Chothani, S., Öhman, M.K., Eng, E., Sun, Y., Petretto, E., Groop, P.H., Tryggvason, K.
- ID
- ZDB-PUB-200905-9
- Date
- 2020
- Source
- Journal of the American Society of Nephrology : JASN 31: 309-323 (Journal)
- Registered Authors
- Keywords
- association test, diabetic kidney diseases, diabetic nephropathy, discordant sibling pairs, whole genome sequencing
- MeSH Terms
-
- Female
- Child, Preschool
- Male
- Zebrafish
- Protein Kinase C/physiology
- PubMed
- 31919106 Full text @ J. Am. Soc. Nephrol.
Abstract
Background Several genetic susceptibility loci associated with diabetic nephropathy have been documented, but no causative variants implying novel pathogenetic mechanisms have been elucidated.
Methods We carried out whole-genome sequencing of a discovery cohort of Finnish siblings with type 1 diabetes who were discordant for the presence (case) or absence (control) of diabetic nephropathy. Controls had diabetes without complications for 15-37 years. We analyzed and annotated variants at genome, gene, and single-nucleotide variant levels. We then replicated the associated variants, genes, and regions in a replication cohort from the Finnish Diabetic Nephropathy study that included 3531 unrelated Finns with type 1 diabetes.
Results We observed protein-altering variants and an enrichment of variants in regions associated with the presence or absence of diabetic nephropathy. The replication cohort confirmed variants in both regulatory and protein-coding regions. We also observed that diabetic nephropathy-associated variants, when clustered at the gene level, are enriched in a core protein-interaction network representing proteins essential for podocyte function. These genes include protein kinases (protein kinase C isoforms ε and ι) and protein tyrosine kinase 2.
Conclusions Our comprehensive analysis of a diabetic nephropathy cohort of siblings with type 1 diabetes who were discordant for kidney disease points to variants and genes that are potentially causative or protective for diabetic nephropathy. This includes variants in two isoforms of the protein kinase C family not previously linked to diabetic nephropathy, adding support to previous hypotheses that the protein kinase C family members play a role in diabetic nephropathy and might be attractive therapeutic targets.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping