Current Pharmacogenomics and Personalized Medicine (Formerly Current Pharmacogenomics) - Volume 8, Issue 3, 2010

Full text available

Full text available

Existing treatments for depression usually take several weeks to achieve their antidepressant effects, and a significant number of patients do not have adequate improvement or are treatment refractory even after long-term drug administration. Moreover, the increased risk of suicide is a serious public health concern that can occur particularly during the initial stages of antidepressant pharmacotherapy. Thus, there is an urgent need for therapeutics with improved efficacy that can exert their effects within hours or days of their administration. The pteridine tetrahydrobiopterin (BH4) is an essential co-factor for production of many neurotransmitters including serotonin. Given the pivotal role of BH4 in several processes fundamental to the pathobiology of mood disorders and the mechanisms of action of mood-regulating drugs, it is surprising that only a few studies have examined the potential role of BH4 pathway genes in individual variability in susceptibility to mood disorders and their treatment outcomes. Although previous studies have examined BH4 in these contexts, there were methodological shortcomings, as well as conflicting findings. However, more recent studies have provided new evidence for the importance of the BH4 pathway in mood disorders and their treatment. For example, the recent finding that the SSRI antidepressant paroxetine substantially affects the level of the protein sepiapterin reductase, which catalyzes the final step in the biosynthesis of BH4, in neural cells, has suggested a need to re-examine the BH4 pathway in the context of the pathobiology of mood disorders and, more importantly, as a potential target for mood-regulating drugs.

After the completion of the human genome sequence, international efforts have been directed to the characterization of the genomes of human-associated resident microbes. The Human Microbiome Project was launched in 2007 with the aim of sequencing the resident microbiota from different sites of the human body. In this paper, we introduce the Human Microbiome Project, the role of the human microbiome in health and disease, and the implications of the microbiome variations in personalized medicine and in pharmacomicrobiomics, which we define as the effect of microbiome variations on drug disposition, action, and toxicity.

There have been a number of notable strides in Hungary in the field of population pharmacogenomics. This paper aims to summarize and share the recent experiences in population genomics and personalized medicine in Hungary with leaders of the Genomic National Technology Platform. The present day Hungary differs from other populations in the region as Hungary was established some 1100 years ago, with founders of the ancestral Hungarian population originating from the east side of the Urals. Additionally, the Roma population of about 700,000 represents the largest ethnic minority living in Hungary. In a series of investigations, we found significant differences between the Hungarian and Roma populations in clinically relevant pharmacogenomics targets such as VKORC1 and CYP2C9 genes. Pharmacogenomics applications are also of interest from the standpoint of biomarker-guided drug discovery in Hungary which we highlight briefly in this paper. Regulatory, ethical and economic aspects of genomics are other dimensions crucial for efficient transition of basic genomics discoveries from laboratory to the clinic. Importantly, Hungary has a Parliamental Act for regulation of genetic diagnostic and research test procedures, and for regulation of biobanks since 2008. Diagnostic molecular pharmacogenomics tests are reimbursed from the same insurance budget as with the other molecular biology based tests in Hungary. Personalized medicine diagnostics require further considerations on how best to integrate and reimburse them in routine healthcare as this new field evolves in Hungary.

The high-throughput ‘omics’ technologies and especially metabolomics can play a major role in advancing the field of personalized medicine and associated fields like nutrition science. Current nutrition research is not mechanism driven making it difficult to fully understand (or forecast) the effects of diet and nutritional interventions. The omics biotechnology platforms can offer a more complete understanding of the complexity of biological systems, which is important for developing personalized nutrition strategies. Unlike transcriptomics and proteomics, metabolomics data encode the genotype and the phenotype. In order to fully understand the effects of diet on overall health status, it is important to be able to define the phenotype and show how it is affected by dietary factors. To this end, the gut microflora composition will also have an impact on the overall phenotype of an individual especially with regards to how nutrients are absorbed and utilized in the body. Metabolomics is uniquely suited to not only provide phenotype-specific information, but also to monitor dynamic changes in nutritional phenotypes, including variations over time, and how interventions such as dietary supplements may return phenotypes back into a normal range. This article provides an introduction to the field of metabolomics and how it may impact nutrition research especially with regards to defining mechanisms of action of bioactive food components, the role of the gut microflora, and the impact of nutritional interventions such as vitamin supplementation. Additionally, the challenges that must be overcome in order to apply metabolomics to its full potential in personalized nutrition are discussed.

While the role of accumulations of mutations has been historically emphasized in the etiology of human cancers, converging evidence strongly implicates contributory epigenetic mechanisms as well. Recently, there have been accumulating observations on the role which epigenetics plays in the regulation of ABCB1 drug transporter expression and its ability to contribute to cancer incidence and multi-drug resistance (MDR) to a wide variety of therapeutic agents. As the development and use of epigenetic therapies for the prevention and treatment of cancer increase, the effect of these interventions on ABCB1 expression (and the related development of MDR) needs to be addressed. The potential for such agents and chemotherapy drugs to induce ABCB1 expression and drug resistance within the cancers they are attempting to treat or prevent is high. Thus, monitoring ABCB1 promoter methylation may be of particular importance when chemotherapy and epigenetic therapies are used, in particular if such agents induce ABCB1 expression. This information could improve our ability to distinguish between drug-sensitive tumours and MDR tumours. In addition, monitoring epigenetic changes within the promoters of ABCB1 and other genes implicated in chemotherapy resistance could help guide patient management by epigenetic agents and/or chemotherapy. The potential for monitoring dynamic changes in promoter methylation for genes associated with drug response using blood samples, rather than tumour core biopsies from cancer patients, makes this an extremely attractive approach for pharmacoepigenomics applications in the clinic.

It is well established that major psychosis (schizophrenia and bipolar disorder) has a strong hereditary basis. However, no unequivocal genetic mutation or polymorphism underlying these disorders has been identified thus far. This paper discusses the role of epigenetics (heritable changes in gene expression not involving changes in DNA sequence) in the pathogenesis of the major psychoses. Importantly, epigenetics offers a conceptual interface between the environment and the genome in the pathogenesis of these disorders. The paper discusses the epigenetically modified genes that are thought to predispose to the development of the major psychoses. The putative environmental factors that can epigenetically modify the genes underlying these disorders are also presented. Finally, the paper offers a framework for epigenetics research applications with considerations over diagnosis, treatment, and prevention of these disorders that have a substantial public health burden throughout the world including the Asia-Pacific region.