Current Pharmacogenomics and Personalized Medicine (Formerly Current Pharmacogenomics) - Volume 8, Issue 4, 2010

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Nutrition research has traditionally focused on providing adequate amounts of nutrients to nourish populations and prevent nutrient deficiencies. Modern nutrition science explores health-related aspects of bioactive components in foodstuffs at a subgroup rather than population level. Today's nutrition research focuses on promoting health, preventing or delaying the onset of disease, optimizing performance and assessing risk in individuals or subpopulations. Personalized nutrition means adapting food to individual needs, depending on host biological variation as well as life stage, style and situation. Nutrigenomics and nutrigenetics comprise the science to understand human genomic/genetic variability in preferences, requirements, and responses to diet and may become the future tools for personalized nutrition, health maintenance and disease prevention. The novel field of nutriproteomics builds upon and complements the field of nutrigenomics/ nutrigenetics. Nutriproteomics has great potential as a tool for personalized nutrition. Specifically, nutriproteomics delivers two essential outputs for molecular nutrition research and applications in personalized nutrition: (1) the characterization and quantification of food-derived bioactive peptides and proteins and (2) the elucidation of biomarkers for mechanism- of-action, efficacy and side effects of nutritional interventions. This article introduces the new field of nutriproteomics in the context of nutrition and health research and discusses protein- and peptide-derived bioactives and biomarkers, highlights human proteome variability and how best to translate this field into personalized nutrition. The paper concludes with a status quo and outlook on nutriproteomics studies and technologies.

It has been suggested that personalized medicine era is fast approaching based on recent applied genomics and life sciences findings. But are the tools to enable personalized therapeutics and multiplexed diagnostics at hand? Nearly a decade after the first full publication of the human genome sequence and the media hype around numerous related medical promises, biologists are still facing crucial questions about biological complexity and its reverse engineering. A biological system is considered more complex not on the basis of the number of its components but rather on the number and strength of interactions between the components. The challenge is to obtain a comprehensive picture of cell functioning. The general mechanisms regarding the cellular information have been now uncovered. The past decade has seen small RNAs on the news, their cellular importance being directly related to an early phase of life evolution. Besides the discoveries of siRNAs and riboswitch RNAs, biologists have appreciated the importance of taking biological noise into account. Systems biology approaches are aimed at understanding the emergent collective properties of the biological constituents of the cell or the whole organism. Synthetic biology is aimed at engineering living systems to create living micromanufactures and bio-derived nanomachines. The recent report in May 2010 of the creation of new Mycoplasma mycoides cells with a synthetic digitized chromosome by Gibson and co-workers is the first major milestone in this new biotechnology era. Current conceptual changes in systems and synthetic biology are illustrated in this paper with several examples related to personalized medicine: from diagnostics to individualized drug therapies.

Over the past several years, it has become evident that not all patients respond optimally to standard dosing of the antiplatelet medication clopidogrel. With the aid of pharmacogenetics research, polymorphisms in the CYP2C19 gene (*2, *3, *4, *5,*6, *7, *8) have been linked with the poor conversion of clopidogrel to its active metabolite and reduced clopidogrel efficacy. Poor response to clopidogrel therapy as evidenced by high platelet reactivity, particularly after stent implantation, has been linked with an increase in major adverse cardiac events. Intermediate and poor metabolism of clopidogrel can potentially be overcome with additional loading doses and higher maintenance doses, or switching to alternative antiplatelet medications. We suggest that the use of genotyping for guiding patient-specific pharmacotherapy is more useful and practical for clopidogrel than for warfarin but interpretation of the testing results can be difficult. To this end, a model for interpretation of pharmacogenetic testing results is proposed. Additionally, point-of-care testing, such as a P2Y12 inhibition assay, can reveal the percentage of platelet inhibition following clopidogrel dosing and is a tool that can be used to achieve optimal clopidogrel dosing.

In the past decade, treatment for multiple sclerosis (MS), especially with respect to disease modifying therapies (DMTs), has substantially improved. Responses to DMTs, such as interferon β and glatiramer acetate, are not uniform, with considerable variability seen in efficacy and toxicity. Furthermore, unexpected serious side effects have been reported for recently developed therapies. There are currently no reliable markers for the interindividual differences in drug response prior to the initiation of therapy for MS. It would therefore be profoundly useful if we could apply genomic based personalized therapy to MS patients. Here, we review the current literature on the pharmacogenomics of MS and discuss the future application of pharmacogenomics as a potential guide for clinical decision making.

Infection due to hepatitis B virus (HBV) is a global public health issue. With effective treatment, it is possible to prevent disease progression to cirrhosis and hepatocellular carcinoma in chronic hepatitis B patients. Several viral factors have been documented to be associated with disease progression and treatment response, including HBV genotype and several naturally occurring HBV mutants, such as precore stop codon mutation (G1896A) and basal core promoter mutation (A1762T/G1764A). Recent studies suggested that responses to standard interferon or peginterferon are more favourable in patients infected with the HBV virus of genotype A or B than the genotype C or D infection. In contrast, therapeutic responses to nucleos(t)ide analogues are generally comparable between HBV genotypes. In addition to the viral genotype, BCP mutation (A1762T/G1764A) is likely to be associated with a higher sustained viral response in HBeAg-positive patients receiving interferon or peginterferon treatment. In conclusion, therapeutic differences seem to exist among HBV genotypes and genetic variations. However, the definite contribution of each viral factor still remains unclear. Since the majority of current studies included small numbers of patients and were not powered to answer such critical questions, the role of viral genetic variation for treatment outcomes awaits further studies before personalized treatment strategies can be planned.

MicroRNAs (miRNAs), a class of short endogenous RNAs, act as post-transcriptional regulators of gene expression. A vast literature has emerged over the past decade about miRNAs and their pivotal roles as negative regulators of gene expression in a wide array of (patho)physiological processes. Recent observations have revealed that many miRNAs are implicated in common human cancers through a variety of mechanisms. miRNA expression can be altered in cancer through chromosomal changes, epigenetic defects, mutations and alterations in the miRNA genes and in the machinery involved in miRNA biogenesis. Detection and monitoring of tumors are now becoming possible by evaluation of tumor-derived secretory miRNAs. Moreover, the term microRNA polymorphisms (miR-polymorphisms) was coined, defined as a novel class of polymorphisms that interfere with the function of a miRNA leading to loss of the miRNAmediated regulation of target genes. miR-polymorphisms can be classified in three major categories: (1) miRpolymorphisms involving the gene silencing machinery; (2) miR-polymorphisms in pri-miRNAs, pre-miRNAs and mat-miRNAs; (3) miR-polymorphisms in miRNA target sites. The new term “miR-pharmacogenomics” can be defined as the study of miRNAs and miR-polymorphisms in their target genes affecting drug behavior in order to improve efficiency of drugs. This paper discusses the recent progress in the field of miR-polymorphisms, miR-pharmacogenomics and their roles in cancer.

The polymorphic cytochrome P450 2D6 (CYP2D6) enzyme, a member of the cytochrome P450 mixed-function oxidase system, is one of the clinically most important enzymes involved in the metabolism of drugs and other xenobiotics. This highly polymorphic enzyme exhibits vastly different phenotypes: poor metabolizers show no enzyme activity, whilst ultrarapid metabolizers exhibit a significantly higher activity. Between these two extremes, there are the extensive and intermediate metabolizers, two heterogeneous groups with overlapping boundaries concerning CYP2D6 activity. These different phenotype groups can be correlated partly to the genotype of an individual. More than 70 different CYP2D6 alleles have been described to date, which encode for null alleles, have a decreased activity or carry gene duplications. However, there is a need for guidelines to translate different CYP2D6 allele combinations into phenotypes. We hereby summarize the current state of the knowledge concerning the relationship between CYP2D6 genotype and phenotype. Clinical relevance of CYP2D6 variation is highlighted with respect to both drugs and putative endogenous ligands. Looking forward, we present a practical genotype interpretation tool, which may help to implement CYP2D6 pharmacogenetics in medical practice. Additionally, we discuss CYP2D6 activity measurement in the context of the recent efforts for multiplexed phenotyping of drug metabolism in vivo.

The reader will find below the list of guest referees who dedicated their time and expertise to the peer review process of the Journal over the past year. Rigorous, objective and timely peer review is crucial to sustain the high publication standards of the CPPM. We also recognize that pharmacogenomics and personalized medicine is a field of inquiry drawing from diverse disciplines and expert colleagues in different global regions. We are glad to take this opportunity to thank the CPPM editors, the international editorial advisory board and the guest referees for their availability, promptness and valuable comments that support the editorial goals of addressing the complexities and nuances of pharmacogenomics and personalized medicine for an international readership.