In:
Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 31, No. 2 ( 2020-2), p. 309-323
Abstract:
Although diabetic nephropathy is partly genetic in nature, the underlying pathogenetic mechanisms are obscure. The authors assembled from the homogeneous Finnish population a cohort of 76 sibling pairs with type 1 diabetes who were discordant for diabetic nephropathy. Using whole-genome sequencing and multiple analytic approaches, they identified DNA variants associated with nephropathy or its absence and validated their findings in a 3531-member cohort of unrelated Finns with type 1 diabetes. The genes most strongly associated with diabetic nephropathy encode two protein kinase C isoforms (isoforms ε and ι ) not previously implicated in the condition. Besides providing a resource for studies on diabetic complications, these findings support previous hypotheses that the protein kinase C family plays a role in diabetic nephropathy and suggest potential targets for treatment. 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.
Type of Medium:
Online Resource
ISSN:
1046-6673
,
1533-3450
DOI:
10.1681/ASN.2019030289
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2020
detail.hit.zdb_id:
2029124-3
Permalink