Genetic predisposition unveiled in diabetic kidney disease

One out of four adults with diabetes will ultimately develop kidney disease that can lead to kidney failure. These patients are often told that keeping their blood sugar levels under control should keep diabetic kidney disease (DKD) at bay. However, even when they do this, many patients still end up developing DKD. A new study that examined the genetics of nearly 20,000 participants, reveals several regions in the genome that may increase the risk of DKD, regardless of blood glucose-control.

Current treatment options can at most slow the progression of DKD but are unable to stop or reverse the disease. Past research suggests that DKD is heritable and genetics may predispose some people to develop the disease, but until recently the genetic basis of DKD was unknown. 

Reporting in the Journal of the American Society of Nephrology, an international team of researchers discovered 16 new genetic regions that are linked to DKD and are independent of the degree of glucose control. These regions may provide critical insights into the understanding of DKD and help identify potential biological targets for future therapeutics and disease prevention. 

The study examined the largest ever cohort for DKD genetics research and was done under the auspices of the Diabetes Nephropathy Collaborative Research Initiative. It followed up on a previous genome-wide analysis study of around 6,000 participants, led by the GENIE Consortium.   

“This is really a game-changer in the genetics of diabetic kidney disease,” said lead author and institute member Jose Florez, who is also the co-director of the Metabolism Program at the Broad Institute of MIT and Harvard, the chief of the Endocrine Division and the Diabetes Unit at the Massachusetts General Hospital, and professor of medicine at Harvard Medical School (HMS). “The large cohort size, almost triple that of our previous genome-wide association study, fundamentally enabled the success of this current study.”

To look for gene variants linked with DKD, the researchers analyzed the genomes of 19,406 individuals of European descent who all had type 1 diabetes but only some had DKD. 

The researchers identified a gene variant that seems to protect the kidney from the harmful effects of high blood sugar levels. The variant was in the COL4A3 gene that encodes for a collagen protein, a major structural component of the nephron, the filtering unit of the kidney. Mutations in this gene lead to progressive loss of kidney function. The researchers say the COL4A3 variant they identified warrants further study, and this gene could be a promising drug target. 

“The findings associated with the collagen protein highlights new biology that we think is compelling and needs future investigations in the context of a therapeutic target,” said co-senior author and institute member Joel Hirschhorn, who is also co-director of the Broad Metabolism Program, the Concordia Professor of Pediatrics and professor of genetics at Boston Children’s Hospital and HMS. 

The authors say that future genetic studies of DKD should include large numbers of people with diverse ancestries as well as patients with type 2 diabetes to further the understanding of DKD genetics. 

Other co-senior authors include Per-Henrik Groop at University of Helsinki and Stephen Rich at the University of Virginia, Charlottesville. The study’s co-first authors are Rany Salem at the University of California, San Diego, Jennifer Todd currently at the University of Vermont, Niina Sandholm at the University of Helsinki, and Joanne Cole at the Broad. 

This study was supported by grants from the Juvenile Diabetes Research Foundation and the National Institute of Diabetes and Digestive and Kidney Diseases.