Background Several genetic susceptibility loci associatedwith 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. ResultsWeobserved protein-altering variants and an enrichment of variants in regions associatedwith 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 i) 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 andmight be attractive therapeutic targets.
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