Abstract: Estrogen hormones play critical roles in the regulation of many tissue functions. The effects of estrogens are primarily mediated by the estrogen receptors (ER) alpha and beta. ERs are ligand-activated transcription factors that regulate a complex array of genomic events that orchestrate cellular growth, differentiation and death. Although many factors contribute to their etiology, estrogens are thought to be the primary agents for the development and/or progression of target tissue malignancies. Many of the current modalities for the treatment of estrogen target tissue malignancies are based on agents with diverse pharmacology that alter or prevent ER functions by acting as estrogen competitors. Although these compounds have been successfully used in clinical settings, the efficacy of treatment shows variability. An increasing body of evidence implicates ERalpha polymorphisms as one of the contributory factors for differential responses to estrogen competitors. This review aims to highlight the recent findings on polymorphisms of the lately identified ERbeta in order to provide a functional perspective with potential pharmacogenomic implications.

Abstract: Genetic variation in drug targets (e.g. receptors) can have pronounced effects on clinical responses to endogenous and exogenous agonists. Polymorphisms in the gene encoding the β(2)-adrenergic receptor (β(2)-AR) have been associated with altered expression, down-regulation, and altered cell signaling in vitro. Because β(2)-ARs play a crucial role in the regulation of the cardiovascular system, the functional importance of genetic variation in the β(2)-AR on cardiovascular responses to physiological or pharmacological stimuli has gained widespread attention. The objective of this review is to characterize these intermediate cardiovascular phenotypes and their influence on cardiovascular disease and adrenergic drug responses.Two common single nucleotide polymorphisms, encoded at codon 46 (Gly(16)Arg) and 79 (Gln(27)Glu) of the β(2)-AR gene, have been studied intensively. They have been shown to be associated with altered vasodilator responses to regional and systemic administration of β(2)-agonists, altered cardiovascular responses to sympathoexcitatory maneuvers, and altered myocardial function. Importantly, these intermediate physiological patterns may influence the development of and the outcomes associated with hypertension and other cardiovascular diseases. As recently reported, β(2)-AR gene variation can risk-stratify patients receiving β-blocker therapy and may predict β-blocker efficacy in patients post acute coronary syndrome or in patients with heart failure.Further studies will advance our understanding of the link between β(2)-AR genotypes, intermediate cardiovascular phenotypes, and clinical phenotypes. In the long term, reassessment of the benefits of β-blocker-therapy within genotype groups should be carried out with the ultimate goal to design the optimal therapeutic regimen for the individual patient.

Abstract: Several lines of evidence indicate that apolipoprotein E (apoE) plays a central role in the brain's response to in- jury and neurodegeneration in the adult. The coordinated expression of apoE and several of its accessory proteins appears to regulate the transport and internalization of cholesterol and phospholipids during development and normal brain rein- nervation in the adult. The discovery, a few years ago, that a genetic variant in the apoE gene called apoE4 strongly links to both sporadic and familial late onset Alzheimer's disease (AD) has raised the possibility that a dysfunction of the lipid transport system in the brain could be central to AD pathophysiology. Pathophysiological evidence obtained in autopsy- confirmed sporadic AD cases clearly indicate that the presence of apoE4 allele in humans directly compromises choliner- gic function in the adult brain and indirectly modulate the efficacy of medications designed to enhance the cholinergic ac- tivity in diseased brain. The apoE4 allele was found to significantly increase the risk of progression to dementia for per- sons exhibiting amnestic mild cognitive impairment (aMCI), a transitional state between the cognitive changes associated with normal aging and early AD. Furthermore, two accessory enzymes involved in cholinergic neurotransmission called butyrylcholinesterase and paraoxonase-1 were shown i) to display polymorphic variants that increase the risk of develop- ing AD and ii) to modulate drug responsiveness in AD subjects exposed to cholinomimetic agents. This article reviews the most critical findings in this field and reassess the potent clinical value of pharmacogenomics of neurodegenerative dis- eases and dementia.

Abstract: Pharmacogenomics is an evolving research discipline in medicine. Within ophthalmology, the earliest candidate gene investigations have studied primary and secondary open-angle glaucoma (OAG), as well as normal tension glaucoma (NTG). At this time, pharmacogenomics data are not generally used to make clinical decisions. However, as we collect data from clinical trials, the role of pharmacogenomics in the care of patients with glaucoma and allied diseases will become clearer. There are at least two potential future roles for applying pharmacogenomics in the treatment of OAG and allied disorders. First, more targeted therapy may lead to better treatment outcomes, with less exposure to medications in patients unlikely to respond to them. Second, pharmacogenomic research may lead to the development of novel therapies for these diseases.

Abstract: Cutaneous malignant melanoma represents one of the most aggressive human cancers with high metastatic po- tential. Differences in the response and toxicity to current melanoma therapies among individuals are observed in nearly all-available treatment regimens. The first step toward personalized medicine is identifying a panel of biomarkers that al- low classification of melanoma patients for appropriate treatment and prediction of probable response to therapy. The tra- ditional approach to biomarker detection relied on studying a few candidate markers suspected of affecting clinical out- come. However, these studies have yielded contradictory results because of the small number of molecular determinants examined. This has been a major limitation of translational studies in malignant melanoma. Recent studies using high- throughput technologies, such as gene expression profiling and serum proteomic fingerprinting, have explored the utility of molecular markers to discriminate between clinical stages and predict disease progression in melanoma patients. This expert review highlights key approaches for the discovery and validation of biomarkers at the levels of DNA, RNA and protein. It also summarizes biomarker work performed by less invasive approaches, i.e., RT-PCR in detection of circulat- ing melanoma cells and serum markers that may be used to monitor early response to treatment and guide the therapeutic strategy. We anticipate that pharmacogenomics will play an integral role in disease assessment, patient selection and treatment response in melanoma clinical management with the ultimate goal of individualizing treatment and improving overall survival for patients.

Abstract: Inter-individual variations in response to pharmacotherapy such as adverse effects, treatment resistance and toxicities affect all patient populations. Multidrug resistance associated proteins (MRPs) work as efflux pumps for many xenobiotics and endogenous substances and hence, can affect the drug concentration at the target site which governs therapeutic response. Genetic polymorphisms of the MRPs can lead to an over- or under-expression of these transporter proteins. These polymorphisms can therefore play an integral role in drug disposition and therapeutic outcomes via pharmacokinetic and pharmacodynamic changes. These changes may cause drug-drug interactions, treatment resistance and/or toxicity. Overexpression of certain MRPs is thought to correlate with multidrug resistance in pharmacotherapy, especially with anticancer drugs. It is also evident that some genetic variants linked with MRP genes can lead to disease states such as pseudoxanthoma elasticum. With further research, more definitive functional characterization of MRPs and the understanding of this relationship with genetic polymorphisms can be achieved. This article highlights the genetic polymorphisms of MRPs and their clinical implications with an emphasis on MRP1-4. It also provides an insight into the role that these proteins can play in disease states and toxicities as well as the implications for future research and patient management.

Abstract: The main goal of pharmacogenomics is to study the effects of genetic variation on patient responses to therapies. Its applications range from the evaluation of safety and efficacy of treatment to the optimization of therapies and therapeutic regimens. Pharmacogenomics is becoming increasingly important in immunology, for the development of new generation vaccines, immunotherapies and transplantation. The human immune system is a complex and adaptive learning system which operates at multiple levels: molecules, cells, organs, organisms, and groups of organisms. Immunologic research, both basic and applied, needs to deal with this complexity. We increasingly use mathematical modeling and computational simulation in the study of the immune system and immune responses. Thus, quantitative models that appropriately capture the complexity in architecture and function of the immune system are an integral component of the personalized medicine efforts. In silico models of the immune system can provide answers to a variety of questions, including understanding the general behavior of the immune system, the course of disease, effects of treatment, analysis of cellular and molecular interactions, and simulation of laboratory experiments. We herein present the ImmunoGrid project that integrates molecular and system level models of the immune system and processes for in silico studies of the immune function. The ImmunoGrid simulator uses Grid technologies, enabling computational simulation of the immune system at the natural scale, perform a large number of simulated experiments, capture the diversity of the immune system between individuals, and provide a basis for therapeutic approaches tailored to the individual genetic make-up.

Abstract: US Senator Barack Obama recently proposed the Genomics and Personalized Medicine Act of 2006, which should it be enacted, would establish a Genomics and Personalized Medicine Interagency Working Group to coordinate personalized medicine efforts, fund genomics research to improve drug safety and establish a US Biobanking Research Initiative similar to efforts deployed in other countries. But what impact could personalized medicine have on the drug development process, the pharmaceutical industry and international health, including that in developing countries? Can personalized medicines support innovation, sustainability and growth in the pharmaceutical industry and also respond to changing world realities, emerging public demands for safer and more efficacious medicines and equitable access to pharmaceuticals? The present paper examines these socio-ethical and science policy questions by first elucidating their in- trinsic and often complex interactions with other economic and policy issues (and the often divergent interests of stakeholders). We then present some examples from other industries (e.g., the case of hybrid cars and attendant growth of consumer interest and confidence in high quality sustainable products), with a view to identifying the factors that might contribute to a successful integration of pharmacogenomics and related biomarker technologies in patient care, interna- tional health and public policy. In particular, we propose ways to integrate the concept of sustainability into corporate and investor models of pharmaceutical industry development. While the power of pharmacogenomics to serve as a driver for the pharmaceutical industry remains to be evaluated, we submit that biomedical innovation and economic prosperity can co-exist with ethical drug development and the sustainable commercialization of customized drug therapies.