People with type 1 diabetes who develop kidney disease have 32 epigenetically dysfunctional genes

Therapy Breakthroughs 23. jul 2023 3 min Senior Scientist Niina Sandholm, Postdoctoral Fellow Emma Dahlström Written by Kristian Sjøgren

Researchers have identified 32 genes in which the regulation of genetic expression is associated with the link between type 1 diabetes and the development of kidney disease. Researchers say that this improves understanding of the connection between type 1 diabetes and kidney disease, which is necessary for developing new drugs for diabetic kidney disease.

Nine million people worldwide have type 1 diabetes, in which the immune system destroys the insulin-producing cells in the pancreas.

However, type 1 diabetes leads to other illnesses, with 40% of people with type 1 diabetes developing kidney disease during their lifetime.

More and more recent studies have indicated that epigenetic regulation of genes affects the interaction between type 1 diabetes and kidney disease, and researchers have now identified some of these genes, providing insight into how the diseases are linked.

“We have learned which genes are involved when type 1 diabetes leads to the development of kidney disease. This can potentially identify new drug targets for diabetes-related kidney disease and improve understanding of the mechanisms behind the link between the diseases,” explains a researcher behind the study Niina Sandholm, Senior Scientist, Folkhälsan Research Center, Helsinki, and University of Helsinki, Finland.

The research has been published in Nature Communications.

Epigenetics can make people sick or healthy

Epigenetics affects how genes function. For example, two identical strands of DNA may differ in expression because each is controlled by different epigenetic factors.

Methylation is the most common epigenetic factor, in which a methyl group is attached to the genetic material, which can make it easier or harder for the cellular machinery to read the genetic code and translate it into proteins.

Thus, epigenetics can turn genes on and off and thereby maintain health or cause dysregulation and disease.

The researchers wanted to determine whether the epigenetic regulation differs between individuals with type 1 diabetes who are diagnosed versus those not diagnosed with kidney disease.

“Treating people with diabetes focuses on more than lowering blood glucose. We are increasingly interested in the complications associated with diabetes. Kidney disease is a major comorbidity, because no drugs can treat people with both type 1 diabetes and kidney disease. However, developing new drugs for diabetes-related kidney disease requires determining which signalling pathways are involved in developing the disease and whether these signalling pathways have any relevant drug targets,” says another researcher involved in the study, Emma Dahlström, Postdoctoral Fellow, Folkhälsan Research Center, Helsinki, and University of Helsinki, Finland.

Epigenetic alterations in 32 genes

The researchers compared the degree of DNA methylation at 800 sites between people with type 1 diabetes who either have or do not have kidney disease.

The researchers had data from two carefully studied cohorts of people with type 1 diabetes from Finland and from the United Kingdom and Ireland and examined the epigenetic expression of 1,304 of these people.

The results show that the DNA methylation differs at 32 or more sites between people with type 1 diabetes who either have or do not have kidney disease.

At most of the 32 sites, people with type 1 diabetes who had kidney disease had lower levels of methylation; 21 of the 32 genes were associated with an increased risk of developing kidney failure, and 18 of the 32 differences in methylation were in genes that are all expressed in the kidney and are often associated with the pathological features of kidney disease.

The region with the strongest association between type 1 diabetes and developing kidney disease was on chromosome 19.

“Not much is known about this gene, but it has previously been associated with the development of diabetes-related kidney disease. Another site on the genome near the gene REV1 turned out to be one of the most important in determining later onset of diabetes-related kidney disease, and we also found causality. In the other 31 genes, we found an association but did not find direct causality,” explains Niina Sandholm.

Developing an epigenetic risk score

According to the researchers, these 32 potentially relevant genes for the risk of developing diabetes-related kidney disease should now be investigated for their potential role.

Emma Dahlström says that many factors can influence whether one gene becomes methylated or demethylated in a direction leading to illness, including blood pressure, blood lipids, body mass index, smoking and other factors.

The aim of understanding these links is not only to develop new treatments for people with diabetes-related kidney disease but also to establish tools to estimate a risk score for developing kidney disease among people with type 1 diabetes.

“We do not yet have drugs that affect the degree of methylation in all the body’s cells. But if we can identify changes in DNA methylation that lead to diabetes-related kidney disease, we can identify genes that can be targets for new drugs. In addition, there are clear opportunities to develop an epigenetic risk score, which appears to have greater potential than a genetic risk score for determining the risk of kidney disease among people with type 1 diabetes,” concludes Niina Sandholm.

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