A study of the genomes of 152 Finnish people with diabetes has found several genes potentially involved in the development of diabetic nephropathy, a condition that affects about 25 percent of people with Type 1 or Type 2 diabetes. Yet, finding the genetic links between the two diseases has been challenging.
Finns have the highest rate of Type 1 diabetes globally. As such, they were chosen as the study population to look for the genetic underpinnings of diabetic kidney disease through whole-genome sequencing.
In the study, researchers first compared the genomes of 76 Finnish sibling pairs, where both siblings had Type 1 diabetes for more than 15 years but only one had developed diabetic nephropathy. They looked for differences between the siblings at the genome, gene, and single mutation (SNP) level. Next, the researchers confirmed their findings by comparing the genomes of over 3,500 unrelated Finns with Type 1 diabetes, of whom about 40% had diabetic kidney disease.
Published in a paper in the Journal of the American Society of Nephrology, their research ultimately focused on DNA variants in several genes involved in regulatory and protein-coding regions, especially genes coding for protein kinase C (PKC). Two PKC isoforms, PRKCE and PRKCI,were strongly implicated with diabetic nephropathy, as were genes for PTK2, ABTB1, and ALOX5.
Hyperglycemia-induced metabolic pathways are known to lead to diabetic vascular complications in diabetes, like nephropathy, retinopathy, and neuropathy. Many mechanisms for hyperglycemia-related vascular complications have been proposed, high among them is activation of the diaclglycerol (DAG)-PKC pathway.
Variants in the two PKC isoforms have not previously been linked to diabetic nephropathy. Taken together with the knowledge that PKC proteins play a role in diabetic nephropathy, the study authors suggest that proteins produced by the PKC pathway may represent desirable therapeutic targets to preventing or treat diabetes-related kidney disease.
To further validate these findings, the research team from Duke University their international collaborators is studying the genomes of 1,000 patients with diabetes in Singapore who are part of the Diabetes Study in Nephropathy and other Microvascular Complications (DYNAMO) in Singapore.