Today, more than 500 million adults live with diabetes. Of these, approximately 1 in 4 will develop kidney disease. Kidney disease is far more common in people with diabetes than in people without the condition. Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and reflects the increasing prevalence of diabetes worldwide. More than 80% of cases of end-stage renal disease are caused by diabetes which is also a risk for hypertension.

However, despite the tremendous advances in genetic testing, no risk genes for diabetic kidney disease have been identified. Therefore, Professor Sam El-Osta, a Danish Diabetes Academy Visiting Professor and leader of the Human Epigenetics team at the Department of Diabetes at Monash University, set out to use innovative sequencing techniques and to develop gene methylation risk scores that are tightly associated with early detection and the development of diabetic kidney disease.

Based on the largest-ever international study on type 1 diabetes, his team made a significant new finding. In adults with diabetes, the loss of DNA methylation in several disease related genes appears to be associated with the loss of protection and more aggressive development of diabetic kidney disease (DKD) and a poorer chance of survival.

The study, ‘Reduced methylation correlates with diabetic nephropathy risk in type 1 diabetes’, (Journal of Clinical Investigation, 15 Feb 2023) takes an unprecedented look at methylation testing of disease genes in Danish, Finnish and Asian diabetes cohorts, offering important clues that reduced DNA methylation is closely associated with the increased risk of DKD.

The multi-national study identified predictive genes associated with the development and progression of diabetic kidney disease using methylation sequencing technology.

“These discoveries will influence how we screen patients with diabetes and improve risk stratification, disease prediction and diagnosis”, says Professor Sam El-Osta, who has led the study.

Reliable Method Improving Predictive Risk and Diagnostic Accuracy

Scientists searching for blood-based biomarkers in diabetes cohorts originating from Finland, Denmark, Hong Kong and Thailand, found surprising commonality in gene methylation risk scores. They note that the innovative sequencing technologies developed using the internal collaboration revealed missing methylation data that was ultimately used to develop a predictive test for diabetic kidney disease.  

“The standard assays used in the clinic rely on assessing kidney function and the level of damage to the kidney caused by diabetes. While these assays have been the mainstay of detecting progressed diabetic kidney disease, the early stages of the disease are typically without symptoms. We have developed a reliable method that improves predictive risk and diagnostic accuracy,” says the study’s first author Dr Ishant Khurana.

Reduced methylation in diabetes cohorts using the KDIGO (kidney disease improving global outcomes) guidelines and risk categories tightly correspond with the development and progression of diabetic kidney disease. Elevated DNA methylation of core genes suppress pathways implicated with diabetic kidney disease and the loss of DNA methylation protection activates the same disease related pathways.

The researchers hope that routine gene methylation testing for diabetic complications such as kidney disease will soon be a standard part of the treatment plan, as it is for more common cancers.

“As far as technological advancements in methods are concerned, epigenetic testing is going to be the new standard for early detection and DKD care,“ says Dr El-Osta. “Renal biopsies are difficult to procure and the novel blood-based test means the test can be readily available and used in remote areas with the added advantage of being more stable than methods measuring other biological indices.”

The total number of people living with diabetes is projected to rise to 643 million by 2030 and 783 million by 2045.

Study Background

This study was conducted by an international consortium comprising scientists at the Human Epigenetics team at Monash University and collaborative partners in the Department of Nephrology, University of Helsinki and Helsinki University Hospital, Finland; Steno Diabetes Center Copenhagen, Denmark; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, and the Diabetes and Thyroid Center, Theptarin Hospital, Bangkok, Thailand.

This work was supported in part by a research grant from the Danish Diabetes Academy to Professor El-Osta, which is funded by the Novo Nordisk Foundation, grant number NNF17SA0031406.

Contact Information

Prof. Sam El-Osta
Human Epigenetics, Department of Diabetes, Central Clinical School, Monash University
E-mail: sam.el-osta@monash.edu

The study, ‘Reduced methylation correlates with diabetic nephropathy risk in type 1 diabetes’, (Journal of Clinical Investigation, 15 Feb 2023) takes an unprecedented look at methylation testing of disease genes in Danish, Finnish and Asian diabetes cohorts, offering important clues that reduced DNA methylation is closely associated with the increased risk of DKD.