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Epigenetic biomarkers for prediction of vascular complications and response to treatment in subjects with diabetes

Periodic Reporting for period 1 - EpiHope (Epigenetic biomarkers for prediction of vascular complications and response to treatment in subjects with diabetes)

Reporting period: 2016-06-01 to 2018-05-31

Metformin is the first-line therapy of type 2 diabetes (T2D), but among T2D patients, ~30% are classified as glycemic non-responders. Currently no clinical phenotype successfully predicts the glycemic response to metformin. Therefore, our aim was to identify blood-based epigenetic biomarkers that successfully predicts metformin response in drug-naïve T2D patients. This research is of high importance since the epigenetic biomarkers could be used in the clinics in all newly T2D patients to discriminate which diabetics cannot receive metformin since they will not respond to this drug. This biomarker kit will progress personalized treatment for T2D using pharmacoepigenetics for the prediction of glycemic response to metformin treatment in newly diagnosed patients with T2D. Therefore, it will be essential for clinical decision making in T2D treatment.

On the other hand, T2D increases the risk for cardiovascular disease (CVD) and mortality. However, it is not known why some diabetic individuals develop these complications whereas others not. Hence, we aimed to identify blood-based epigenetic biomarkers that successfully predict coronary events and stroke in T2D subjects. Notably, our epigenetic biomarkers will provide a useful tool to identify T2D subjects at high risk of developing CVD to prevent at an early stage the progression to a macrovascular event. In fact, prevention is possible since early intensive glycemic control of T2D reduce in the long-term the number of macrovascular complications.

Overall, the identified epigenetic biomarkers of clinical relevance from this project predicting metformin response and macrovascular complications in people with T2D could provide a valuable tool for personalized medicine.
We have analyzed DNA methylation of approximately 850,000 CpG sites using the Infinium MethylationEPIC BeadChip (Illumina) in DNA extracted from blood in drug naïve subjects with T2D and in newly diagnosed T2D patients with no clinical history of CVD when blood was taken from the ANDIS cohort (All New Diabetics in Scania, http://andis.ludc.med.lu.se/).

We have identified 25 epigenetic markers that could predict response to metformin in drug naïve subjects with T2D. When a methylation risk score was generated based on these markers, it could better predict metformin response than the individual markers. Moreover, we observed that these epigenetic markers might have a role in metabolically relevant tissues for T2D, since they showed differential methylation and gene expression between diabetics and non-diabetics in human adipose tissue, pancreatic islets, skeletal muscle and/or liver.

We found ~500 epigenetic markers that could predict macrovascular complications in newly diagnosed T2D individuals. We have observed that the identified epigenetic biomarkers improved the ROC curve compared to just known clinical risk factors (age, sex, lipid profile, smoking and the use of antihypertensives, statins and diabetes medication).

Replication of these findings is still needed in additional individuals and we are in the processing of analysing these results. For disseminating the results, two publications are planned during 2019 in high-impact journals.
The identification and development of these new epigenetic biomarker kits constitute a fundamental and innovative way to stop the alarming growing of T2D and macrovascular complications. The impact of T2D complications is threatening health systems, the social and economic implications are enormous and current therapeutic options are insufficient to face this chronic disease. However, the complications can be reduced through early and appropriate preventive and therapeutic interventions. Therefore, one of the most important contribution of EpiHope is the development of a panel of high-quality epigenetic biomarkers, thus aiming to give a new reliable clinical tool for early prevention of macrovascular complications in T2D patients. Besides, EpiHope represents an original opportunity to progress in personalized treatment for T2D, proposing for the first time pharmacoepigenetics for the prediction of response to metformin treatment in newly diagnosed patients with T2D. Receiving an optimal therapy and thereby a better glycemic control may reduce future cardiovascular complications, suffering for the patients and costs for society.

This research shows that epigenetics could be a promising biomarker in T2D treatment and macrovascular complications although replication and further research is needed to translate our identified epigenetic biomarkers findings to T2D patients in the clinics.
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