Current Pharmacogenomics and Personalized Medicine - Volume 8, Issue 2, 2010

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Sepsis is one of the most complex human diseases that continue to be associated with high mortality rates and substantial medical costs. It is an infection-induced, complex traits systemic syndrome that engages most of the body's systems and organs. Whereas several etiologic agents can elicit sepsis, disease susceptibility, severity and therapeutic outcomes are modulated by a complex interaction of numerous environmental and constitutive (e.g., genomic) factors. To effectively understand and treat different types of sepsis in susceptible individuals, we need to adopt holistic systems approaches that utilize network-based investigations to integrate disease related complex traits, themselves affected by variations in the host genomic and epigenetic contexts, physiogenomic, metabolomic status as well as by variations in the pathogen. Importantly, a systems approach to sepsis can provide a roadmap to help identify both the host and the pathogen pathways underlying sepsis or variable therapeutic responses to sepsis. This paper introduces the emerging field of “septomics” - i.e., the application of high-throughput omics technologies to sepsis related complex traits - in diagnosing and/or modulating susceptibility and outcomes of sepsis. Additionally, we discuss how unbiased, network-based systems approaches and biotools can help better understand novel gene-by-environment interactions in sepsis, and identify genetic, physiologic and soluble (e.g., proteomics) biomarkers that can precisely predict disease susceptibility, progression or response to therapeutic interventions. Finally, we note that septomics also signals a new application of genome-based medicine in the context of global public health against existing and emerging infectious diseases that are greatly affecting the world populations in both developed and developing countries.

There has been a fundamental shift in biopharmaceutical research from a linear, systematic investigation to a more whole organism, systems-oriented analysis program. The impetus behind this change is an acknowledgment that the current novel target and drug discovery model was flawed due in part to an overly simplified view of disease biology, i.e., a unidirectional path from one gene to one protein to one mechanism of action. Fortunately, recent technological advancements in whole genome analysis, DNA, RNA, proteome sequencing and mathematical modeling have permanently altered the target discovery landscape. These improvements in high throughput knowledge-creation have facilitated the multi-dimensional interrogation of disease in the context of the whole organism. One of the recently described mechanisms for helping to bridge these investigational studies with clinical medicine has been through the introduction of an analytic modeling platform known as “systems pathology”. The derived systems-based pathology models use the patients' own clinical data and intact tissue specimens to construct a baseline phenotype for defining a clinical risk state. These biologic-quantitative models also provide a biomarker profile which can be linked to treatment and health outcomes. This paper presents the rationale and implementation of systems biology in the area of translational medicine and a practical clinical application, i.e., systems pathology. By incorporating high dimensional genome analysis and disease modeling efforts such as systems pathology, we illustrate how such advancements have helped bring systems biology to the clinic but have also served to make the medical decision and treatment algorithms a more patient-specific paradigm.

The objective of this study was to evaluate hospital directors' (study A) and community pharmacists' (study B) attitudes towards pharmacogenomics research and DNA banks in Japan. This is significant because pharmacotherapy is offered by both community pharmacies and hospitals in Japan. A total of 943 directors of all Japanese national, municipal and university hospitals were chosen for the study A. For the study B, 905 community pharmacists were randomly selected among pharmacies in all prefectures in Japan. The response rates were 45.0% (study A) and 37.5% (study B). The majority (> 75%) of both hospital directors and community pharmacists displayed a positive attitude towards pharmacogenomics research and DNA banks. By contrast, in terms of the attitudes for becoming involved in DNA sample collection, a marked asymmetry was observed: 61.3% of the directors showed a positive attitude while only 27.9% of the pharmacists had a positive attitude to be involved in DNA sample collection. Respondents collectively indicated three barriers to DNA sample collection: 1) necessity for clear definition of appropriate management of confidential information, 2) need for explanation of the aim of a DNA bank, and 3) understanding of how the research results will be utilized/published. Since asymmetries/discordance in perceptions of stakeholders can pose a formidable barrier in diffusion of innovations, prospective policies on pharmacogenomics and personalized medicine are needed to foster mutual understanding among hospital directors and community pharmacists in Japan. Additionally, these observations call for comparative social science data on pharmacogenomics and society from other global regions.

Antiplatelet therapy with aspirin and clopidogrel, aimed to inhibit platelet function and reactivity, is the recommended standard of care for reducing the occurrence of cardiovascular events in patients with acute coronary syndromes undergoing percutaneous coronary intervention with stent implantation. However, major adverse cardiovascular events including the severe complication of stent thrombosis occur in patients taking dual antiplatelet therapy. Clopidogrel requires intestinal absorption and hepatic conversion to active metabolite by several cytochrome P450 isoenzymes, among which the CYP2C19 plays a pivotal role; then, the active metabolite inhibits ADP-stimulated platelet activation by irreversibly binding to the P2Y12 receptor. Several factors interacting with each other are involved in determining the variability of individual response to clopidogrel. Nongenetic factors include chronic persistent factors (e.g., age, diabetes) and acute phase transient factors (e.g., inflammation). Among the numerous genetic variants investigated, recently, the loss-of-function CYP2C19*2 polymorphism has been associated with a decreased metabolization of clopidogrel, poor antiaggregant effect, and increased cardiovascular events. In high risk vascular patients, who experience percutaneous coronary intervention with stent implantation, the CYP2C19*2 polymorphism is a strong predictor of the adverse cardiovascular events and particularly stent thrombosis. Ongoing and future prospective studies evaluating if an antiplatelet treatment tailored on individual characteristics of patients — genetic variants, platelet phenotype, drug-drug interactions, as well as traditional and procedural risk factors - are now urgently awaited in order to define the optimal therapeutic strategies and management providing the best benefit for a given individual patient.

Pharmacogenomics, applied as an aspect of molecular autopsy, might become an integral part of forensic medicine in the near future. Pharmacogenomics is the study of the relationship between an individual's genetic/genomic information and the disposition/response to medications. As a result, pharmacogenomics may provide a deeper mechanistic insight necessary for forensic pathologists to fully understand/interpret postmortem toxicology results and correctly determine the cause and manner of death. In this paper, the use of pharmacogenomics as a molecular autopsy tool to raise the standards in forensic medicine is discussed, and illustrated with selected cases. In addition, the current limitations and hurdles for using pharmacogenomics in the postmortem forensic setting are also reviewed.

There have been many studies of phase-I drug metabolism (e.g., CYP450s) in personalized medicine research. By contrast, functional genetic variation in the phase-II detoxification pathways is relatively less appreciated. UDP-glucuronosyltransferases (UGTs) comprise a group of catabolic enzymes involved in the detoxification and excretion of drugs. This family glucuronidates many xenobiotic and endogenous substances in both intrahepatic and extrahepatic tissues. UGTs have two families, UGT1 and UGT2. UGT1 consists of 5 exons with a unique organization of the gene structure. There are thirteen exon 1s from UGT1A1 to UGT1A13P, whereas exon 2 to exon 5 are common to all expressed mRNAs. Each isoform of UGT1 results from differential splicing of the exon 1s to the common exon 2-5, and has a unique spectrum of substrate specificity. Nine UGT1s have been detected (UGT1A1, 1A3, 1A4, 1A5, 1A6, 1A7, 1A8, 1A9, 1A10), and are expressed in various tissues. Four exon 1s encode pseudogenes. In contrast, the gene structure of the UGT2 family consists of 6 exons, and all enzymes have an individual set of exon 1 to exon 6. There are seven UGT2B isoforms in the UGT2 family: UGT2B4, 2B7, 2B10, 2B11, 2B15, 2B17 and 2B28. UGT2A is a further subfamily of UGT2. Interestingly, UGT2A1 is expressed only in the olfactory epithelium and brain. This paper presents a critical review of the functional polymorphisms and mutations of UGTs and their impact on personalization of drug therapy. This inventory might usefully inform the next generation translational pharmacogenomics studies concerning Phase II drug metabolism.