We are not a finished product. We are born with a specific set of DNA, with an underlying program, but that’s not the end of it. Like experiences, the decisions we take regarding health habits, diet, our environment, etc., make their mark on the structure of the genes that cause these genes to express or not. This is the exciting and still little studied field of epigenetics - one of the areas of research of the IMIM Neurovascular research group.

Carolina Soriano, the doctor of genetics in this group, and researcher and neurologist at Hospital del Mar, Jordi Jiménez Conde, in collaboration with the research group on Epidemiology and Cardiovascular Genetics, decided to investigate the epigenetic biomarkers on genes linked to neurovascular disease and specifically, diabetes, one of the diseases associated with them. Using the bank of biological samples of blood and serum of the more than 7000 people who were admitted with stroke and who voluntarily provided samples for research, a study of 355 patients was begun to determine the existence of a link between type 2 diabetes mellitus and abnormal DNA methylation, which is one of the most thoroughly studied mechanisms of epigenetic change. There was no prior hypothesis. The researchers aimed to search for potential variations that might be linked to glucose regulation in blood.

 

The results of the study evoke the theory of metabolic memory, which says that people in whom diabetes is detected after a year and a half and with poor management or treatment suffer from more problems deriving from the disease than patients in whom the disease is detected and treated early because the body remembers the damaged that occurs over this time.

 

The hunt for epigenetic variations

Using a state-of-the-art technique, the researchers analyzed more than 45,000 methylation loci on the genome and carried out a statistical analysis to compare the genes that were significantly abnormal in people with diabetes with those that were not. To prevent the bias that may result from spot measurements of glucose levels, hemoglobin glycosylate levels were included, which provide the mean value of glucose levels of the patient in the previous three months and which are used to diagnose diabetes and to determine whether the patient is managing the disease correctly. The results could therefore be linked to people who were or were not diabetic (half of the participants were diabetic) and could be divided by their level of glucose management.

The initial results were promising: diabetic patients showed a couple of genes that appeared to show abnormal methylation that was not present in patients without the disease. However, to correct for random false positives, the study was replicated in two new cohorts of 167 and 645 patients, respectively, in order to apply any corrections. They then processed the results and were able to confirm their find: the gene TXNIP is definitively linked to glucose homeostasis, as it is hypomethylated in diabetic patients and, specifically, in patients with poor management of the disease, while it does not appear in properly managed patients.

 

Hypomethylation and metabolic memory

This find suggests that hypomethylation may be a biomarker for poor regulation of diabetes. We can also deduce that this abnormality is a result and not a cause, as it is not found in properly managed patients. It may therefore be a very useful biomarker for early detection of the disease and to evaluate the efficiency of treatments in the personalized medicine of the near future.

The results of the study evoke the theory of metabolic memory, which says that people in whom diabetes is detected after a year and a half and with poor management or treatment suffer from more problems deriving from the disease than patients in whom the disease is detected and treated early because the body remembers the damaged that occurs over this time. Epigenetic signs of hypomethylation may simply be the signal that the body has been exposed to this damage, or they may be the switch that affects recovery. To demonstrate whether this switch can be turned off, it would be necessary to follow up healthy people over their lifetimes and, in those who develop diabetes, determine what is happening at the epigenetic level and therefore discover whether proper management of changes of lifestyle can cause these markers to disappear.

 

 

Reference article

Soriano C, Jiménez-Conde J, Giralt E, Mola M, Vivanco R, Ois A, Rodríguez-Campello A, Cuadrado E, Sayols-Baixeras S, Elosua R, Roquer J, on behalf of the GENESTROKE Consortium. Epigenome-wide association study identifies TXNIP gene associated with Type 2 diabetes mellitus and sustained hyperglycemia. Hum Mol Genet 2015.

https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddv493