Precision medicine in diabetes prevention, classification and management.

Diabetes has become a major burden of healthcare expenditure. Diabetes management following a uniform treatment algorithm is often associated with progressive treatment failure and development of diabetic complications. Recent advances in our understanding of the genomic architecture of diabetes and its complications have provided the framework for development of precision medicine to personalize diabetes prevention and management. In the present review, we summarized recent advances in the understanding of the genetic basis of diabetes and its complications. From a clinician's perspective, we attempted to provide a balanced perspective on the utility of genomic medicine in the field of diabetes. Using genetic information to guide management of monogenic forms of diabetes represents the best-known examples of genomic medicine for diabetes. Although major strides have been made in genetic research for diabetes, its complications and pharmacogenetics, ongoing efforts are required to translate these findings into practice by incorporating genetic information into a risk prediction model for prioritization of treatment strategies, as well as using multi-omic analyses to discover novel drug targets with companion diagnostics. Further research is also required to ensure the appropriate use of this information to empower individuals and healthcare professionals to make personalized decisions for achieving the optimal outcome.

Personalized treatment of schizophrenia in everyday clinical practice: reality or fiction?

Each day clinical practice tries to follow the idea and principles of personalized medicine. Besides predicting an individual's sensibility or predisposition for developing schizophrenia, pharmacogenetic and pharmacogenomic approaches attempt to define and acknowledge important indicators of clinical response to antipsychotics namely their efficacy and adverse effects. The main focus of our article were not facts regarding the role CYP450 liver enzymes have in this; our purpose is introducing other, new genetic and epigenetic factors which could introduce important biomarkers in diagnostics of the disease itself, the efficacy and tolerance for antipsychotics. There is still a huge gap between gathering and collecting information and using them for the personalized treatment of schizophrenia. From the genetic point of view personalized treatment of schizophrenia is the field we need to focus on and successfully incorporate it our everyday clinical practice in the future.

Medicina individualizada aplicada à cardiologia / Personalized medicine applied to cardiology

Atualmente, a farmacogenômica está recebendo grande atenção da comunidade médica e do público em geral devido à promessa da medicina personalizada. Aincorporação dos conceitos da farmacogenética já estão fortemente presentes no dia a dia da oncologia e começam a ser aceitos na prática cardiológica. A base racional da farmacogenética envolve o desenvolvimento de medicamentos específicos para determindado grupo de pacientes, maximizando a resposta terapêutica e reduzindo efeitos adversos. Este artigo de atualização visa a reunir as principais informações da biologia molecular aplicadas à cardiologia.

Pharmacogenomics of statin responsiveness.

Statins are widely prescribed and are established as first-line therapy for the primary and secondary prevention of coronary artery disease. However, the benefit of treatment varies between patients. Genetic variation can contribute to interindividual variations in clinical efficacy of drug therapy, and significant progress has been made in identifying common genetic polymorphisms that influence responsiveness to statin therapy. To date, >30 candidate genes related to pharmacokinetics and pharmacodynamics of statins have been investigated as potential determinants of drug responsiveness in terms of low-density lipoprotein cholesterol lowering. Genetic variation at gene loci that affect intestinal cholesterol absorption include apolipoprotein (apo) E; adenosine triphosphate-binding cassette transporter G5 and G8; cholesterol production, such as 3-hydroxy-3-methylglutaryl coenzyme A reductase; and lipoprotein catabolism, such as apoB and the low-density lipoprotein receptor, all may play a role in modulating responsivesness as well genes involved in metabolism of statins such as cytochrome P450. However, there is considerable variation in results reported, and the data suggest that combined analysis of multiple genetic variants in several genes, all of which have possible functional significance, is more likely to give significant results than single gene studies in small sample populations. In the future, pharmacogenomic studies with a greater number of participants (>2,000 participants) should provide a better picture as to who is most likely and who is least likely to benefit from statin therapy.

Genetic basis of drug metabolism.

The application of pharmacogenetics in identifying single nucleotide polymorphisms (SNPs) in DNA sequences that cause clinically significant alterations in drug-metabolizing enzyme activities is discussed. Recent advances in pharmacogenomic research have begun to elucidate the inherited nature of interindividual differences in drug-induced adverse reactions, toxicity, and therapeutic responses. In one particular area of study, variations in DNA sequences (i.e., genetic polymorphisms) explain some of the variability in drug-metabolizing enzyme activities which contribute to alterations in drug clearance and impact patients' response to drug therapy. Historical and current examples of several extensively studied SNPs include the genes encoding for glucose-6-phosphate dehydrogenase, N-acetyltransferase, and the superfamily of cytochrome P-450 (CYP) isoenzymes. Because CYP isoenzymes metabolize a large number of structurally diverse drugs and chemicals, most of the variant genotypes of the CYP2D6, CYP2C9, CYP2C19, and CYP3A families have been identified and studied. Individuals with aberrant genes for these enzymes may experience diminished efficacy or increased toxicity in response to certain drugs because of the different levels of activities associated with variant genotypes. The frequency of variant alleles for drug-metabolizing enzymes often differs among ethnic groups. Continued research in pharmacogenetics will further our understanding in interindividual differences in drug disposition. The application of this knowledge will ultimately help individualize drug dosing and drug therapy selection, predict toxicity or therapeutic failure, and improve clinical outcomes. Pharmacogenetics has elucidated the genetic basis for interindividual variability in drug response and will continue to play a key role in defining strategies to optimize drug therapy.

Pharmacogenetics and pharmacogenomics: why is this relevant to the clinical geneticist?

Adverse drug reactions, due at least in part to interindividual variability in drug response, rank between the 4th and 6th leading causes of death in the USA. The field of 'pharmacogenetics', which is 'the study of variability in drug response due to heredity', should help in reducing drug-caused morbidity and mortality. The recently coined term 'pharmacogenomics' usually refers to 'the field of new drug development based on our rapidly increasing knowledge of all genes in the human genome'. However, the two terms - pharmacogenetics and pharmacogenomics - are often used interchangeably. A classification of more than five dozen pharmacogenetic differences is presented here. Most of these variations occur in drug-metabolizing enzyme (DME) genes, with some presumed to exist in the DME receptor and drug transporter genes, and others have not yet been explained on a molecular basis. A method for unequivocally defining a quantitative phenotype (drug efficacy, toxicity, etc.) is proposed; this is where help from the clinical geneticist can be especially important. Our current appreciation of the degree of variability (including single-nucleotide polymorphisms, SNPs) in the human genome is described, with emphasis on the need to prove that a particular genotype is indeed the cause of a specific phenotype; this topic has been termed 'functional genomics'. Furthermore, the current amount of admixture amongst almost all ethnic groups will obviously make studies of gene-drug interactions more complicated, as will the withholding of ethnic information about DNA samples during any molecular epidemiologic study. DME genes and DME receptor and drug transporter genes can be regarded as 'modifier genes', because they influence disorders as diverse as risk of cancer, bone marrow toxicity resulting from occupational exposure, and Parkinson's disease; for this reason, the clinical geneticist, as well as the medical genetics counselor, should be knowledgeable in the rapidly expanding fields of pharmacogenetics and pharmacogenomics.