Mental disorders vary on symptomology and clinical presentation. These include depression, bipolar disorder, schizophrenia, and other forms of psychosis. If mental illnesses are not diagnosed and treated in a timely and effective manner, they bear significant socio-economic consequences. The worst outcome of depression and other mental disorders, such as schizophrenia, is suicide. In Greece, according to data of the Hellenic Statistical Authority in 2014, 4.7% of the population suffered from depression, while compared to 2012 an increase of 80.8% was observed in the frequency of the disease. At the same time, a significant increase was observed in the number of suicides, especially during the period of economic crisis (increase by 11.7% from 2011 to 2013). There are effective therapeutic methods, both pharmaceutical and psychotherapeutic, to deal with mental disorders. However, a significant percentage of patients with mental disorders do not respond positively to pharmacotherapy, as significant diversity is observed both in the range of effective doses between patients and in the therapeutic effect of each pharmacotherapy. The contribution of genetic factors is particularly important both in the diverse response to medication and in the causation of the occurrence of mental disease. The  Unit, in tandem with the other units of IMPReS, will contribute to:

• the simultaneous genotyping of polymorphisms in genes encoding cytochrome P450 (CYP450) enzymes, which play an important role in the metabolism of psychiatric drugs and in the analysis of genes of target molecules of psychiatric drugs, which participate in mechanisms of action giving the complete pharmacogenomic profile of each patient
• the simultaneous genotyping of gene polymorphisms of systems involved in neurotransmission and related to the onset of psychiatric diseases and the severity of symptoms
• determine the epigenomic profile of psychiatric patients and its association with response to pharmacotherapy and disease causation
• determine metabolites related to the intensity of symptoms and are indicative of response to pharmacotherapy
• determine the therapeutic levels of antidepressant and antipsychotic drugs administered that are not measurable

For the genomic and pharmacogenomic study of psychiatric diseases, there is already an established collaboration with the university psychiatric clinic of PGNA, which will be significantly upgraded with the new infrastructure.

Atrial fibrillation (AF) is the most common arrhythmia in clinical practice and one of the main aggravating factors of stroke and mortality. The incidence of AF has been increasing the last decades. In Greece, it is estimated that more than 150,000 patients exhibit AF, a number that corresponds to 3% of the adult population. For the prevention of stroke and pulmonary embolism in patients with AF, long-term daily administration of oral anticoagulants (OACs) is necessary. For many years, OACs included only the coumarinic oral anticoagulants (COAs) warfarin, acenocoumarol (ACE), and phenprocoumon, which have been in therapeutic use since the 1950s. In the last decade, the therapeutic quiver of OACs has been enriched with a series of new drugs, direct oral anticoagulants (DOACs). DOACs approved in the US, Europe and Greece include the direct thrombin inhibitor dabigatran (PRADAXA) and the factor Xa inhibitors rivaroxaban (XARELTO) and apixaban (ELIQUIS). Administration of DOACs has gained ground in the treatment of AF with a continuous upward trend in administration over coumarin anticoagulants. It is characteristic that apixaban and rivaroxaban are among the 10 bestselling drugs worldwide for 2018, while they also show a significant increase in sales compared to 2017. Apixaban is the 2nd bestselling drug (33.5% increase in sales) and rivaroxaban 10th (5.8% increase in sales). These two DOACs together exceed $16 billion in sales. For COAs, including ACE mainly administered in Greece, it is well known that there is great variability in response and required drug dose among patients and that this variability is significantly influenced by the genetic composition of individuals. In contrast, pharmacogenomics of DOACs has been poorly studied. At the same time, for this class of drugs there is no indicator of their anticoagulant effect, while it is imperative to determine the therapeutic levels of the drugs in order to limit the incidence of hemorrhagic episodes. The Medical Precision Unit will contribute to interaction with the other units of the IMPReS Center to:

• the identification of easily measurable epigenetic markers (biomolecules) in peripheral blood and more specifically the response to anticoagulant pharmacotherapy with DOACs and COAs
• development of new innovative products related to the response to pharmacotherapy with new anticoagulants
• development of an innovative algorithm for the selection of anticoagulant therapy according to clinical, epigenetic and pharmacogenomic characteristics
• generating modern knowledge around the key genes associated with response to pharmacotherapy
• highlight gene, gene/environment interaction networks as a tool for managing complex biological information
• identify the molecular mechanisms underlying anticoagulation with DOACs and identification of possible differences between the three different drugs of this class

Atrial fibrillation (AF) is the most common arrhythmia in clinical practice and one of the main aggravating factors of stroke and mortality. Genome and identification of mutations or gene polymorphisms can explain a small degree of heritability in AF but cannot provide information on the dynamics of gene expression in cardiac tissue and the changes in gene expression during establishment of AF in the heart. For the tissue-specific molecular study of AF, the analysis of the regulators of gene expression at different levels is needed; Epigenomics, Transcriptomics and Post-transcriptomics. The Unit will contribute, in tandem with the other units of the IMPReS Center, in the tissue-specific molecular analysis of gene expression in AF and the comparison of expression signatures with those imprinted in peripheral blood by studying epigenomics (DNA methylation), transcriptomics and post-transcriptomics factors. More specific our objectives are:

• to study gene expression tissue specifically in the cardiac sinus and to compare between patients with AF and individuals in normal heart rhythm, as well as between patients with different types of AF
• to compare the gene expression signature of cardiac tissue with the signature in peripheral blood of the same participants to find peripheral blood markers to be used as prognostic and/or diagnostic markers
• To establish "gene-mRNA" and "miRNA-mRNA-gene" regulatory networks related to the onset of AF

Goal is to identify the molecular mechanisms and signaling pathways that govern AF and to retarget drugs to them in order to change the molecular signature of AF.

For these tissue-specific studies, there is already an established collaboration with the Cardiothoracic Surgery Clinic of PGNA.

Patients undergoing percutaneous biologic aortic valve implantation (TAVI) face risks associated with thrombosis of the implanted valve which may cause ischemic events such as acute myocardial infarction (AMI) and acute cerebrovascular accident (ACE). So far, there is no absolute agreement regarding the optimal anti-thrombotic treatment after percutaneous biological valve implantation, while different qualitative and temporal combinations of anti-platelet and anti-coagulant treatment have been proposed. The study of miRNAs is attracting intense research interest as they are easily accessible circulating biomarkers that could be used to identify individuals who have an increased predisposition to thrombosis or bleeding. The Unit, in collaboration with the Clinic of Cardiology of PGNA, will conduct pharmacoepigenomic analyses investigating a) the discriminatory ability of epigenomic markers to detect high thrombotic risk patients undergoing TAVI and b) whether these patients - selected using the epigenomic analysis markers - will benefit more with the use of dual antithrombotic therapy (DOAC + ASA) compared to the use of single antiplatelet therapy.

It is widely accepted that a wide interindividual variability exists in patient response to analgesics. Pharmacogenomics is being implemented into clinical pain management practice through genotyping of CYP450 isoenzymes that are involved in opioid (codeine and tramadol) and non-steroidal anti-inflammatory drugs (NSAIDs) metabolism. In IMPREs center we analyze the CYP450s genetic variations associated with response to opioids and NSAIDs to individialize both drug choice and drug dosing by use of FDA, CPIC and DPWG pharmacogenomic recommendations.

Our laboratory, with years of experience in human pharmacogenomics, is now introducing this field in dogs. Polymorphism identification methods have been developed and are continuously being developed along with multiple clinical studies for determining the optimal dose of chemotherapeutic agents (anticancer drugs), antiparasitics and anesthetics in dogs. By combining methods of molecular genetics and high-precision bioanalytical chemistry, laboratory results can be translated into clinical oncology and anesthesiology results in order to study personalized chemotherapy treatment in cancer dog patients, plan a safer antiparasitic treatment and anesthetic procedure by taking into consideration patient breed status and disease profile . In the prospect of a holistic approach, apart from genotyping, our laboratory provides personalized advising based on the results of DNA testing.