Current Pharmacogenomics and Personalized Medicine (Formerly Current Pharmacogenomics) - Volume 7, Issue 2, 2009

The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) are activated by a variety of endogenous and exogenous ligands, such as steroid hormones, bile acids, pharmaceuticals, and environmental, dietary, and occupational chemicals. In turn, they induce phase I-III detoxification enzymes and transporters that help eliminate these chemicals. Because many of the chemicals that activate CAR and PXR are environmentally-relevant (dietary and anthropogenic), studies need to address whether these chemicals or mixtures of these chemicals may increase the susceptibility to adverse drug interactions. In addition, CAR and PXR are involved in hepatic proliferation, intermediary metabolism, and protection from cholestasis. Therefore, activation of CAR and PXR may have a wide variety of implications for personalized medicine through physiological effects on metabolism and cell proliferation; some beneficial and others adverse. Identifying the chemicals that activate these promiscuous nuclear receptors and understanding how these chemicals may act in concert will help us predict adverse drug reactions (ADRs), predict cholestasis and steatosis, and regulate intermediary metabolism. This review summarizes the available data on CAR and PXR, including the environmental chemicals that activate these receptors, the genes they control, and the physiological processes that are perturbed or depend on CAR and PXR action. This knowledge contributes to a foundation that will be necessary to discern interindividual differences in the downstream biological pathways regulated by these key nuclear receptors.

With parallel advances in genomics and in nutrition research, a new hybrid science has emerged at their intersection, often referred to as nutritional genomics which includes nutrigenomics and nutrigenetics. While the operational definitions will continue to evolve as nutritional genomics matures as a new field of inquiry, a central tenet will likely be on ways in which the human genome interacts with nutritional exposures. This emerging form of science has considerable implications for research in biomedicine and for public health. The progress in nutrigenomics research will likely increase our understanding of chronic disease etiology and the relationship between nutrients and common complex diseases. The potential for nutritional genomics in chronic disease prevention is also of great interest given that diet is a modifiable risk factor and because of the marked interindividual variability in response to the diet. The inclusion of genetic information as part of an overall strategy to improve the population health will be critical as more genomic data accumulate in nutrition science and used to develop recommendations for specific dietary requirements based on individual genetic make-up. In addition, use of genetic information from companies offering at-home direct-to-consumer nutrigenomics tests may have significant consequences for the population health and how we perceive and relate to food and other members of the society depending on human genetic variation. These implications of nutrigenomics and nutrigenetics such as the translation of research into public health practice will be discussed. Another dimension of interest is the need for well-trained health professionals. To this end, registered dietitians are essential to the efforts for incorporation of genomics into public health. Finally, future perspectives of nutrigenomics and nutrigenetics will be examined, with a view to how best to integrate the nascent field of nutrigenomics with established public health research and practices.

Variations in both the genome and epigenome can affect individual nutrient requirements. In order to optimise nutrient intake for good health, it becomes important to understand the way in which nutrients affect the expression of key genes. Epigenetic events imply a change of gene expression without a heritable change in DNA base pairs. These events may result from the action of transcription factors, the methylation of certain DNA bases, changes in chromatin structure through various histone modifications, or the action of non-coding RNAs. Each these classes of events is susceptible to both dietary and environmental influences. Transcription factors trigger gene expression in response to external signals, including certain dietary lipids. Changes in DNA methylation can occur directly, through an imbalance in the methyl donor pool. The key nutrient implicated here is folate, but vitamins B6 or B12, betaine, choline and selenium all play established roles. Dietary effects on DNA methylation may also occur indirectly, through inhibition of DNA methyltransferase enzymes. Inhibitors of such enzymes include various phytochemicals, including a range of polyphenols, such as epigallocatechin gallate, from green tea, or isothiocyanates, which are common in Brassicaceous vegetables. Post-translational modifications of histones play a key role, not only in regulating chromatin structure and gene expression, but also in genomic stability. A range of dietary compounds have been implicated as histone deacetylase inhibitors, including butyrate (produced through the digestion and fermentation of dietary fibres) and isothiocyanates. Single nucleotide polymorphisms in genes affecting methyl donor pools may impact individual susceptibility to epigenetic events, and these will be profoundly influenced by diet, not only pre-conception, but throughout the lifecycle. This paper addresses a hitherto neglected dimension in human nutrigenomics science literature - epigenetics and the importance of dietary effects on the epigenome - in the overarching context of tailoring diets to match people's genetic make-up.

Over the last decade there has been vast interest in and focus on the implementation of personalized genomic medicine. Although there is general agreement that personalized genomic medicine involves utilizing genome technology to assess individual risk and ensure the delivery of the “right treatment for the right patient at the right time,”different categories of stakeholders focus on different aspects of personalized genomic medicine and operationalize it in diverse ways. In order to move toward a clearer, more holistic understanding of the concept, this article begins by identifying and defining three major elements of personalized genomic medicine commonly discussed by stakeholders: molecular medicine, pharmacogenomics, and health information technology. The integration of these three elements has the potential to improve health and reduce health care costs, but it also raises many challenges. This article endeavors to address these challenges by identifying five strategic areas that will require significant investment for the successful integration of personalized genomics into clinical care: (1) health technology assessment; (2) health outcomes research; (3) education (of both health professionals and the public); (4) communication among stakeholders; and (5) the development of best practices and guidelines. While different countries and global regions display marked heterogeneity in funding of health care in the form of public, private, or blended payor systems, previous analyses of personalized genomic medicine and attendant technological innovations have been performed without due attention to this complexity. Hence, this article focuses on personalized genomic medicine in the United States as a model case study wherein a significant portion of health care payors represent private, nongovernment resources. Lessons learned from the present analysis of personalized genomic medicine could usefully inform health care systems in other global regions where payment for personalized genomic medicine will be enabled through private or hybrid public-private funding systems.

Lung cancer is the fourth most frequently diagnosed human malignancy and the most common cause of cancerrelated deaths in the western world. Consideration of human genetic variation in the post-genomics era increased the rate of discovery of novel therapeutic targets that could become the mainstay of personalized anti-cancer treatment. These targets include tumour suppressor genes such as tumour protein (TP)53, as well as oncogenes and cell cycle genes, such as epidermal growth factor receptor (EGFR), MYC, protein kinase and cyclin-dependent kinase inhibitor (CDKN2A) genes. Polymorphisms in the cytochrome P450, excision repair cross-complementing (ERCC) and nicotinic acetylcholine receptor (CHRNA) genes strongly influence the risk of developing lung cancer, and the risk attributable to these polymorphisms differs in non-smokers compared to smokers. Variants in the EGFR gene occur more frequently among women and non-smokers with lung adenocarcinoma, and are strongly associated with sensitivity to the EGFR tyrosine kinase inhibitors, gefitinib and erlotinib. Polymorphisms in the ERCC1, ATP-binding cassette, uridine diphosphate glucuronosyltransferase, cytidine deaminase and ribonucleotide reductase subunit M1 genes influence the metabolism, clinical efficacy and/or toxicity of other drugs used to treat lung cancer, including cisplatin, paclitaxel, irinotecan and gemcitabine. This review presents a critical synthesis of the major genetic changes associated with lung carcinogenesis, as well as the significance of pharmacogenetics approaches to forecast therapeutic response in lung cancer. We underscore that mechanism-based associations of human genetic variation with pharmacodynamics of current and emerging medicines will provide additional decision tools for anti-cancer pharmacotherapy to be personalized in clinical care of patients with lung cancer.