Dataset Information
Whole-Genome Sequencing of Finnish Type 1 Diabetic Siblings Discordant for Kidney Disease Reveals DNA Variants associated with Diabetic Nephropathy.
Ontology highlight
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 ? and ?) 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.
SUBMITTER: Guo J
PROVIDER: S-EPMC7003303 | biostudies-literature | 2020 Feb
REPOSITORIES: biostudies-literature
Publications
Whole-Genome Sequencing of Finnish Type 1 Diabetic Siblings Discordant for Kidney Disease Reveals DNA Variants associated with Diabetic Nephropathy.
Journal of the American Society of Nephrology : JASN 20200109 2
<h4>Background</h4>Several genetic susceptibility loci associated with diabetic nephropathy have been documented, but no causative variants implying novel pathogenetic mechanisms have been elucidated.<h4>Methods</h4>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 varia ...[more]
