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Q&A: Genetics and epigenetics of diabetic complications


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3 minutes

Genetic variation provides a partial explanation for the occurrence of diabetes and its complications. But genetics alone cannot explain the heterogeneity of diabetes or its many complications. Epigenetic variation has a role, as well. spoke with two of the researchers who will review the latest findings in this area during the Tuesday morning symposium Genetics and Epigenetics of Diabetic Complications, which will begin at 7:30 a.m. in S-154 (South, Upper Mezzanine Level).

What’s the difference between genetic and epigenetic variation?

Niina Sandholm, DSc
Niina Sandholm, DSc

Niina Sandholm, DSc, Co-Principal Investigator of the FinnDiane Study Group at Folkhälsan Research Center in Helsinki, Finland: Genetic variants are changes in DNA present from birth. By identifying genetic variants that increase the risk of disease, we can better understand the biological processes leading to the disease and maybe find a way to modify a pathway to stop the negative effects of the variant.

Epigenetic variants affect the expression of genes. The gene does not change, but the way it functions changes in response to external factors such as the environment, diet, or physical activity. We might be able to change those external factors to improve outcomes.

In terms of diabetes complications, what are the relative contributions of genetic and epigenetic changes?

Rama Natarajan, PhD, Professor and Chair of the Department of Diabetes Complications and Metabolism at City of Hope and Beckman Research Center: There are at least five different types of diabetes with distinct features and risk of complications. Genetic changes make a difference in some forms of diabetes and some complications, but epigenetic changes also play an important role because they are affected by environmental factors.

How can genetic changes affect diabetic complications?

Dr. Sandholm: About a third of patients with type 1 diabetes have diabetic nephropathy. FinnDiane (Finnish Diabetic Nephropathy Study) is a long-term, cross-sectional study of complications in about 6,000 individuals with type 1 diabetes. One of our surprises is a relatively common variant in a collagen gene that changes the protein structure and protects against kidney disease in type 1 diabetes. This alpha-3 subunit of type IV collagen is a major structural component of the glomerular basement membrane. Rare variants in the same gene are responsible for rare complications such as Goodpasture’s syndrome, an autoimmune condition that can lead to kidney failure and severe hemorrhage in lungs.

How do epigenetic changes play out in diabetic complications?

Rama Natarajan, PhD
Rama Natarajan, PhD

Dr. Natarajan: We have shown that many inflammatory and fibrotic genes associated with diabetic complications are regulated by epigenetic mechanisms in diabetes. We’re also working with the DCCT (Diabetes Control and Complications Trial) and its ongoing follow-up EDIC (Epidemiology of Diabetes Interventions and Complications) study of subjects with type 1 diabetes. The initial DCCT trial was stopped when it became clear that if you bring A1C closer to normal, the progression of complications is vastly reduced. The original intensively treated patients are still getting fewer complications, whereas the conventional treatment patients are still getting more complications, despite both groups having similar A1C levels. Active epigenetic chromatin changes are higher in blood cells of the conventional treatment group and DNA methylation variations present at the end of DCCT in 1993 were still evident in blood cells 17 years later in the same patient, a kind of metabolic memory.

These long-lasting epigenetic changes are in significant genes that affect islet dysfunction, as well as kidney, eye, and cardiovascular complications. They appear to be highly associated with a history of elevated A1C and hyperglycemia over a number of years. Even if you are born with good genes, you can change things for the worse via epigenetics, and vice versa.